November 2021 Publications
| - McSweeney K, Boldison E. Lynch syndrome-hidden in plain sight. Histopathology. 2021;79(5):687-689. doi:10.1111/his.14444
This article is an impassioned editorial written by Katie McSweeney, who was diagnosed with Lynch syndrome in the UK after being diagnosed with colon cancer at age 29. She notes that while the NICE guidelines established in 2017 in the UK recommend evaluation of all colon cancer diagnoses for Lynch syndrome, adherence to these guidelines is not consistent. It is estimated that only 5% of individuals with Lynch syndrome in the UK are aware of their diagnosis. McSweeney notes many barriers to Lynch syndrome awareness and greater implementation of testing, including NHS funding shortages, genetic testing delays in the system, and less public awareness campaigns regarding hereditary colon cancer (when compared to breast cancer). On a global scale, McSweeney notes cites prior research showing inconsistent Lynch syndrome evaluation in a variety of countries (as well as variation within countries). Sadly, her sister was found to have colon cancer and passed away shortly after McSweeney’s own Lynch syndrome diagnosis. McSweeney makes a provocative plea for more uniform testing for Lynch syndrome in order to identify patients and allow them to undergo risk reducing screening procedures.
- Bancroft EK, Page EC, Brook MN, et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Lancet Oncol. 2021;22(11):1618-1631. doi:10.1016/S1470-2045(21)00522-2
There is mixed data on whether or not the risk for prostate cancer is increased for individuals with Lynch syndrome with some studies showing a 2-13x increased risk and others showing no increased risk. There is currently no consensus on screening for prostate cancer screening for individuals with Lynch syndrome. This study used the IMPACT cohort (828 carriers) to assess incidence, stage, and pathology of screen-detected prostate cancer compared with controls (134 non carriers). Overall, the incidence of prostate cancer was 4.3% in MSH2 carriers (3.6% for clinically significant cancers), 3.0% in MSH6 carriers (2.2% for clinically significant cancers), and no cancers were diagnosed in MLH1 carriers. These differences were significant between carriers and non carriers, with MSH2 and MSH6 carriers having a higher incidence of prostate cancer as compared to controls. The overall positive predictive value (PPV) of biopsy was 51.4% across Lynch syndrome carriers, and PPV value of biopsy after PSA was not significantly different between carrier status or gene. Age at diagnosis of prostate cancer was not significantly different between groups. Future screening rounds will determine the optimal frequency of PSA testing, the usefulness of PSA screening in MLH1 carriers, and provide further data on the value of annual screening in MSH2 and MSH6 carriers.
- Rodriguez M, Kang EY, Farrington K, et al. Accurate Distinction of Ovarian Clear Cell From Endometrioid Carcinoma Requires Integration of Phenotype, Immunohistochemical Predictions, and Genotype: Implications for Lynch Syndrome Screening. Am J Surg Pathol. 2021;45(11):1452-1463. doi:10.1097/PAS.0000000000001798
This study focuses on the differential diagnosis of ovarian clear cell carcinoma (OCCC) which infrequently is mismatch repair deficient (MMRd) and ovarian endometrioid carcinoma (OEC) which is more frequently MMRd. The study team integrated a panel-based ancillary immunohistochemistry (IHC) approach with novel markers in a step-wise approach and measured interobserver reproducibility for OCCC/OEC cases. A training set of 344 cases was used for the development of first-line and second-line panels while 844 cases were used to evaluate population-based frequency of histotypes. In the training set, the top three performing markers (HNF1B, PR and Napsin A) were used to create a first-line panel while a second-line panel utilizing three different markers (ELAPO1, CDX2, and AMACR) was created. This enabled accurate classification of 95.9% of test cases. Integration of combined IHC-derived first-line and second-line prediction results into histotype classification increased interobserver reproducibility among five observers from an average Cohen κ of 0.778 to 0.882, with average agreement being 94.1%. In the training set, 13.8% of OEC had MMRd while only 2.4% of OCCC exhibited MMRd. Among the population-based cases, overall 2.4% were MMRd, including 11.5% of OEC cases but only 1.7% of OCCC cases, 0.7% of high-grade serous carcinomas and 0% in mucinous and low-grade serous carcinomas. The majority of MMRd OEC cases were predicted to be Lynch syndrome cases; these cases were significantly younger and more commonly found to have synchronous endometrial and ovarian carcinomas. This study provides evidence in support of integrating first-line and second-line IHC panels into the diagnostic assessment for ovarian tumors as well as universal Lynch syndrome screening for MMRd for all patients with OEC.
- West NP, Gallop N, Kaye D, et al. Lynch syndrome screening in colorectal cancer: results of a prospective 2-year regional programme validating the NICE diagnostics guidance pathway throughout a 5.2-million population. Histopathology. 2021;79(5):690-699. doi:10.1111/his.14390
The National Institute of Health and Care Excellence (NICE) issued guidelines in 2017 which recommended Lynch syndrome (LS) screening for all newly diagnosed colorectal cancers (CRC). This pathway includes tumor testing for defective mismatch repair (dMMR) either through immunohistochemistry or microsatellite instability testing. This prospective study aimed to validate the efficacy of the NICE screening pathway for all diagnosed with CRC in the Yorkshire and Humber region of the United Kingdom during a two year span. Their findings were that dMMR was noted in 15% of cases. The majority of cases showing abnormal expression of MLH1 (76%) had a detectable BRAF mutation. The majority of those with MLH1 loss and no BRAF mutation, showed MHL1 promotor hypermethylation (77%). Germline testing was recommended at an overall rate of 2.9%.
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October 2021 Publications
| - den Elzen N, Joseland SL, Saya S, et al. "Left in limbo": Exploring how patients with colorectal cancer interpret and respond to a suspected Lynch syndrome diagnosis. Hered Cancer Clin Pract. 2021;19(1):43. Published 2021 Oct 16. doi:10.1186/s13053-021-00201-1
In this study from Australia, telephone interviews were conducted with 15 patients diagnosed with colorectal cancer whose immunohistochemistry test results were suggestive of Lynch syndrome, but no germline pathogenic variant was identified. The authors note that somatic testing can be used to identify sporadic causes of abnormal immunohistochemistry, but this testing has not had wide uptake in Australia. Participants were recruited from the larger ANGELS study cohort among 16 Australian genetics clinics. Overall participants reported being largely adherent to the cancer screening and risk reduction recommendations provided by the genetics clinics, but varied in recall, interpretation, and reaction to their genetic test results. Participants generally shared cancer screening information with their first degree relatives, but the recommendations were not always concordant with what had been recommended for their relatives by the genetics clinics.
- Crosbie EJ, Ryan NAJ, McVey RJ, et al. Assessment of mismatch repair deficiency in ovarian cancer. J Med Genet. 2021;58(10):687-691. doi:10.1136/jmedgenet-2020-107270
This study analyzed the efficacy of tumor testing in identifying Lynch syndrome (LS) in patients with ovarian cancer. The study utilized immunohistochemistry (IHC) for mismatch repair (MMR) deficiency and MLH1 promotor methylation testing when indicated for women considered to be high-risk for LS based on age, personal history or family history. This study was conducted at the Manchester Centre for Genomic Medicine; 261 ovarian cancers were tested with 27 showing MMR deficiency by IHC. Of these 27 individuals, 8 were found to have LS. Tumor MMR deficiency identified by IHC is a useful predictor of LS in high-risk women with ovarian cancer. This group will continue to perform IHC testing of all ovarian tumors suspicious for LS regardless of tumor histological subtype.
- Actkins KV, Srinivasan S, Spees LP, Turbitt E, Allen CG, Roberts MC. Uptake of Genetic Testing Among Patients with Cancer At Risk for Lynch Syndrome in the National Health Interview Survey. Cancer Prev Res (Phila). 2021;14(10):927-932. doi:10.1158/1940-6207.CAPR-21-0073
Uptake of genetic testing for Lynch syndrome did not increase between 2005 and 2015 despite universal screening guidelines being recommended in 2009. Data from the National Health Interview Survey (NHIS) were analyzed to discover that an upward trend of genetic testing uptake was seen in 2010 but not continued over time. This group urges genetic testing education at both the provider and patient level to improve testing uptake which would ideally lead to an increase in high-risk screening utilization.
- Hegazy S, Brand RE, Dudley B, et al. DNA mismatch repair-deficient non-neoplastic endometrial glands are common in Lynch syndrome patients and are present at a higher density than in the colon. Histopathology. 2021;79(4):573-583. doi:10.1111/his.14386
While immunohistochemistry has become standard to screen for colorectal and endometrial cancer patients for Lynch syndrome by evaluating mismatch repair (MMR) protein expression, this screening tool is not perfect. MMR deficient crypts in normal colonic tissue have previously been described as a promising indicator to also identify patients with Lynch syndrome. This study investigates the performance of this analysis for endometrial tissue. The study team compared four cohorts of female patients: Lynch syndrome patients with and without endometrial cancer as well as non-Lynch syndrome patients with either MLH1 promoter hypermethylation (sporadic MMR deficiency, dMMR) or MMR proficient endometrial cancer. Crypt analysis was performed on non-neoplastic tissue obtained from hysterectomy due to either the patient’s diagnosis or a risk-reducing surgery. The study team also assessed normal colonic mucosa in a separate group of patients with Lynch syndrome who had undergone colonic resected after being diagnosed with colon cancer. Though the number of cases in this study were small, the study team did find a significant difference between MMR expression within endometrial glands among those with Lynch syndrome with endometrial cancer (65% dMMR), those Lynch syndrome without endometrial cancer (29% dMMR) and those without Lynch syndrome (0% dMMR). Additionally, the observed dMMR glands were in large contiguous groups and in higher density in the endometrium compared to the colon crypts. While endometrial gland analysis does not appear to be as sensitive as MMR immunohistochemistry, it does appear to be more specific. This could be an important tool to help differentiate between sporadic dMMR and Lynch syndrome related dMMR tumors. Further study is needed to evaluate how well this analysis functions with endometrial biopsies rather than resected tissue.
- Sierra I, Pérez-Mayoral J, Rosado K, et al. Implementation of Universal Colorectal Cancer Screening for Lynch Syndrome in Hispanics Living in Puerto Rico. J Racial Ethn Health Disparities. 2021;8(5):1185-1191. doi:10.1007/s40615-020-00876-7
This study looks to determine the prevalence of Lynch syndrome microsatellite instability in colorectal tumors in Puerto Rico after 15 months of implementing universal tumor screening. 317 colorectal tumors were evaluated, mostly by immunohistochemistry testing (93%), and 11.8% of them had deficient mismatch repair protein expression. These tumors were more likely from females and more likely localized in the proximal colon compared to those with proficient MMR expression. Authors note that this rate is similar to other studies showing around 10% microsatellite instability in colorectal cancer.
- Galbraith LN, Preys CL, Rehm HL, et al. Primary care providers' responses to unsolicited Lynch syndrome secondary findings of varying clinical significance. Genet Med. 2021;23(10):1977-1983. doi:10.1038/s41436-021-01225-7
Prior studies of primary care physicians’ (PCPs) self-reported knowledge of genetics have shown large numbers of PCPs indicating their genetics knowledge is poor. This raises concerns about interpretation of patient genetic test results, particularly when they are released to patients as secondary findings from directed genetic tests or research. This study surveyed PCPs regarding their responses and recommendations when viewing secondary genetic test results showing either pathogenic variants, variants of uncertain significance, or benign variants in the genes associated with Lynch syndrome. Email invitations to take the survey were sent to 4,000 eligible members of AAFP (American Academy of Family Physicians). 142 respondents completed the survey. Each respondent viewed a similar scenario (30 year old female requesting assistance with interpretation of a secondary finding in a gene associated with Lynch syndrome in a genetic test report) with one of three test reports (pathogenic variant in MSH6, VUS in MLH1, or benign variant in MLH1). Equal proportions of respondents reviewed each result type. Providers answered questions regarding their perception of their genetics knowledge, their familiarity with Lynch syndrome, attitude toward the test report and its potential impact on patient care, laboratory responsibility, and provider interpretation of the report. 15 (10.6%) felt extremely/very familiar with Lynch syndrome; 29 (20.4%) reported having patients with Lynch syndrome. More providers indicated they would address further workup with the patient who received a pathogenic (43%%) or VUS report (43%) than the report showing the benign variant (4%). 96% of respondents who received a pathogenic report to review said the results would be important to the patient’s health and health care, compared with 83% who received a VUS result, and 49% who received a benign result. Overall, this study’s results shed further light on PCP interpretation of genetic test result types and identifies areas for further provider education about genetic test interpretation and Lynch syndrome management.
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September 2021 Publications
| - Kim SR, Tone A, Kim RH, et al. Maximizing cancer prevention through genetic navigation for Lynch syndrome detection in women with newly diagnosed endometrial and nonserous/nonmucinous epithelial ovarian cancer. Cancer. 2021;127(17):3082-3091. doi:10.1002/cncr.33625
This publication summarizes the gynecological Lynch syndrome screening efforts of three cancer centers in Ontario, Canada over a period of almost four years (Sept 2015 – June 2019), focusing on nonserous/nonmucinous ovarian (N=172) and endometrial (N=642) malignancies, including those with both malignancy types (N=27). This process included a genetic navigator to facilitate triage of MMR IHC and genetic counseling referrals for those with either a suspicious family history, dMMR or both. Among those flagged for genetics referrals, 91% completed a genetic assessment (N=164) and 67.7% of those that underwent assessment were offered genetic testing. The overall yield of this program in identifying women with Lynch syndrome was 4.0%, finding 34 women to have Lynch syndrome, with 17.7% of these being women with ovarian cancer and 14.6% being women with synchronous endometrial and ovarian malignancies. Among all participants with Lynch syndrome identified in this study, 97% had not had prior malignancies. This publication supports the utilization of universal screening for Lynch syndrome in women with endometrial and nonserous ovarian cancer and advocates for the inclusion of a genetics navigator to optimize the success of the program.
- Rasmussen M, Lim K, Rambech E, et al. Lynch syndrome-associated epithelial ovarian cancer and its immunological profile. Gynecol Oncol. 2021;162(3):686-693. doi:10.1016/j.ygyno.2021.07.001
Women with Lynch syndrome have a lifetime risk of ovarian cancer between 6 and 17%, compared to 1.4% in the general population. This study analyzed B2M and PD-L1 expression and correlated it to the host-induced immune response and MSI status in order to investigate benefit of immune checkpoint therapy in Lynch syndrome ovarian cancers. Tissue from 30 cases from 27 Lynch syndrome carriers was analyzed. Half of the ovarian tumors presented with high levels of tumor infiltrating lymphocytes. Loss of B2M expression was observed in 46.7% of the tumors, while expression of PD-L1 was seen in 28.0% of the cases. Of the 29 evaluable tumors, 27 were MMR-d (93.1%). Likewise of 26 evaluable tumors, 14 were MSI (53.8%). MMR-d/MMR-proficiency associated with MSI/MSS in 60.0%. There was no association between B2M/PD-L1 and MSI/TILs/survival. MMR-d, MSI, and TILs are also seen in Lynch syndrome-associated ovarian cancers making these potential candidates for checkpoint-based immunotherapy.
- Kalamo M, Mäenpää J, Seppälä T, Mecklin JP, Pylvänäinen K, Staff S. Descriptive study on subjective experience of genetic testing with respect to relationship, family planning and psychosocial wellbeing among women with lynch syndrome. Hered Cancer Clin Pract. 2021;19(1):38. Published 2021 Sep 14. doi:10.1186/s13053-021-00194-x
This study aims to determine some of the psychological impacts on women who have Lynch syndrome (LS). Women who underwent LS germline genetic testing in Finland were studied to better understand how a positive germline result impacts family planning and reproductive decision making. The study interviewed 35 women and found low impact on family planning, self image, and intimate relationships. Many women report that having compassionate healthcare professionals had a significant impact on this.
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August 2021 Publications
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- Kastrinos F, Ingram MA, Silver ER, et al. Gene-Specific Variation in Colorectal Cancer Surveillance Strategies for Lynch Syndrome. Gastroenterology. 2021;161(2):453-462.e15. doi:10.1053/j.gastro.2021.04.010
Due to the high variability in cancer risk across the mismatch repair genes, in recent years, national efforts have been underway to create gene-specific management recommendations for patients with Lynch syndrome rather than a single set of guidelines. The authors of this paper have assisted this effort by using published data in a colonoscopy surveillance simulation model to help determine optimal surveillance intervals and age of surveillance initiation for each of the mismatch repair genes measured by quality-adjusted life-years and incremental cost-effectiveness ratios. The study team found that optimal surveillance for patients with mutations in the mismatch repair genes with highest cancer risks (MLH1 and MSH2) includes colonoscopy every 1-2 years beginning at age 25. This is in line with current NCCN guidelines. However, the study team also found that optimal surveillance for patients with mutations in the less penetrant mismatch repair genes (MSH6 and PMS2) includes colonoscopy every 3 years beginning at ages 35 and 40, respectively. This actually differs from current NCCN guidelines and should be considered by the NCCN panel during the 2022 review of recommendations for patients with Lynch syndrome.
- Nakagawa M, Kobayashi E, Yamada M, et al. Myxofibrosarcoma harboring an MLH1 pathogenic germline variant associated with Muir-Torre syndrome: a case report. Hered Cancer Clin Pract. 2021;19(1):34. Published 2021 Aug 21. doi:10.1186/s13053-021-00192-z
Lynch syndrome patients have an increased risk to develop a broad spectrum of tumors, however sarcomas are not known to be among them. In this case report, the study team reports an unusual case where an individual with a specific type of sarcoma (a myxofibrosarcoma at the left abdominal wall) as well as a sebaceoma was found to have MLH1-associated Lynch syndrome after his myxofibrosarcoma was found to be MSI-H and exhibit loss of MLH1 and PMS2. The patient’s family history was Lynch-like, with one FDR having a history of EO CRC and EC as well as pancreatic cancer, another FDR having EO CRC and a SDR having CRC. Myxofibrosarcoma has been reported in very few individuals with Lynch syndrome, but immunohistochemistry of the mismatch repair genes should be performs on these tumors if an individual with Lynch syndrome develops one, as these sarcomas may be on the Lynch syndrome spectrum, and MSI status could help guide treatment decisions for these patients.
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July 2021
Publications
| - Biller LH, Horiguchi M, Uno H, Ukaegbu C, Syngal S, Yurgelun MB. Familial Burden and Other Clinical Factors Associated With Various Types of Cancer in Individuals With Lynch Syndrome. Gastroenterology. 2021;161(1):143-150.e4. doi:10.1053/j.gastro.2021.03.039
Clinical practice guidelines recommend that family history be used to aid in risk-stratifying Lynch syndrome carriers’ risks of specific cancers, although it remains unknown if family history is a significant risk factor, independent of age, sex, and gene. The authors found that familial burden (defined as the number of first- and second-degree relatives with a specific cancer type) of various Lynch syndrome– associated cancers was incrementally associated with Lynch syndrome carriers’ personal histories of endometrial, urinary tract, small bowel, gastric, and pancreaticobiliary cancers, as well as sebaceous neoplasms, independent of age, sex, and gene. However, optimal screening strategies for less common Lynch cancers, based on family history, are still unknown.
- Vyas M, Firat C, Hechtman JF, et al. Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies. Fam Cancer. 2021;20(3):201-213. doi:10.1007/s10689-020-00210-4
Some patients with synchronous/metachronous tumors in the gastrointestinal tract are found to have discordant mismatch repair protein expression between the tumors they develop. This research team at MSKCC aimed to find an explanation for this discordance. Over a five year period of time, 1.3% of their patients developed multiple colorectal cancers, and among these, approximately a quarter of the patients’ tumors had discordant MMR expression (N=7). The researchers analyzed these seven tumors as well as three additional discordant gastrointestinal tract tumors. Half of these ten individuals did not have hereditary cancer predispositions while the other half had Lynch syndrome, Familial Adenomatous Polyposis (FAP) or polymerase proofreading-associated polyposis (PPAP). The research team describes the molecular etiologies of the mismatch repair deficiencies foreach of these cases but did not find a single common etiology. Additional research would be helpful in this area.
- Sina M, Ghorbanoghli Z, Abedrabbo A, et al. Identification and management of Lynch syndrome in the Middle East and North African countries: outcome of a survey in 12 countries. Fam Cancer. 2021;20(3):215-221. doi:10.1007/s10689-020-00211-3
The aim of this study was to survey the state of Lynch Syndrome healthcare in Middle Eastern and North African countries. Nineteen professionals from twelve countries responded to a survey. Results revealed that guidelines for the diagnosis and management of Lynch syndrome were available in only three of the surveyed countries. In two countries, the respondents were unaware of clinical guidelines in their country. Genetic services were available in a research setting in one country, in only a few hospitals in six countries, in several hospitals in three countries and were absent in two countries. Explanations for the limited availability of these services included lack of funds, lack of interest or knowledge, and a lack of trained geneticists.
- Carwana H, Hoodfar E, Bergoffen J, Li D. Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated healthcare setting. Fam Cancer. 2021;20(3):223-230. doi:10.1007/s10689-020-00218-w
Paired germline and somatic mismatch repair analysis has been previously shown to explain the majority of unexplained mismatch repair deficiency (dMMR) colorectal and endometrial cases. As such, the study team at Kaiser Permanente retrospectively performed paired analysis of the mismatch repair genes for historically unexplained cases of colorectal tumors with dMMR (germline testing previously negative for pathogenic variants) from a 8.5 year time span. Among the cases of unexplained dMMR, 6% were actually found to have germline pathogenic variants causing Lynch syndrome which were previously not detected, 62% of cases were explained by somatic findings and 32% remained unresolved. This study adds to the evidence in support of paired germline and somatic genetic analysis for patients with dMMR colorectal tumors and against following patients with unexplained dMMR as Lynch-like in the absence of somatic analysis or other suspicious family history information. |
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June 2021
Publications
| - Liao CK, Lin YC, Hsu YJ, Chern YJ, You JF, Chiang JM. Deciding the operation type according to mismatch repair status among hereditary nonpolyposis colorectal cancer patients: should a tailored approach be applied, or does one size fit all?. Hered Cancer Clin Pract. 2021;19(1):29. Published 2021 Jun 29. doi:10.1186/s13053-021-00186-x
Determining the most appropriate surgical approach (extended versus subtotal colectomy) for patients with colorectal cancer in the setting of Lynch syndrome is challenging. This prospective longitudinal study in Taiwan looked at disease free survival and overall survival among Lynch syndrome patients with both dMMR and pMMR colorectal cancers. They found that Lynch syndrome ptaients with dMMR colorectal cancers had better overall survival rates as well as higher rates of metachronous cancers. They also reported that extended colectomy improved disease free survival in Lynch syndrome patients with dMMR colorectal cancer but not in the Lynch syndrome patients with pMMR colorectal cancer. This data may help guide surgical decision making.
- Raffone A, Catena U, Travaglino A, et al. Mismatch repair-deficiency specifically predicts recurrence of atypical endometrial hyperplasia and early endometrial carcinoma after conservative treatment: A multi-center study. Gynecol Oncol. 2021;161(3):795-801. doi:10.1016/j.ygyno.2021.03.029
Atypical endometrial hyperplasia (AEH) and early endometrial carcinoma (EEC) may be treated conservatively in patients desiring future pregnancy or who are at high risk for surgical complications. However, a number of patients experience poor outcomes including lack of regression of AEH/EEC or recurrence. This study seeks to determine the predictive role and accuracy of MMR-deficiency as a marker of AEH and EEC response to conservative treatment. In this retrospective study from Italy, conservative treatment consisted of progestin use plus hysteroscopic endometrial resection. The findings showed that MMR-deficiency was a highly accurate predictor of disease recurrence, but not a statistically significant predictor of disease resistance to conservative treatment.
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May 2021
Publications
| - Jung YJ, Kim HR, Kim MK, Lee EJ. A novel germline mutation in MLH1 in three Korean women with endometrial cancer in a family of Lynch syndrome: case report and literature review. Hered Cancer Clin Pract. 2021;19(1):28. Published 2021 Jun 3. doi:10.1186/s13053-021-00185-y
A novel MLH1 variant was identified in a Korean family who presented with endometrial adenocarcinoma. This family met Amsterdam II criteria for Lynch syndrome. Immunohistochemical analysis was performed when appropriate and showed loss of MLH1 and PMS2 expression. Genetic analysis identified a novel mutation specifically denoted as c.1367delC which meets the standards set forth by the American College of Medical Genetics and Genomics of a likely pathogenic classification. Additionally, a larger subset of Korean women were analyzed and the c.1757_1758insC variant in MLH1 was proposed as a possible Korean founder mutation.
- Chung J, Maruvka YE, Sudhaman S, Kelly J, Haradhvala NJ, Bianchi V, Edwards M, Forster VJ, Nunes NM, Galati MA, Komosa M, Deshmukh S, Cabric V, Davidson S, Zatzman M, Light N, Hayes R, Brunga L, Anderson ND, Ho B, Hodel KP, Siddaway R, Morrissy AS, Bowers DC, Larouche V, Bronsema A, Osborn M, Cole KA, Opocher E, Mason G, Thomas GA, George B, Ziegler DS, Lindhorst S, Vanan M, Yalon-Oren M, Reddy AT, Massimino M, Tomboc P, Van Damme A, Lossos A, Durno C, Aronson M, Morgenstern DA, Bouffet E, Huang A, Taylor MD, Villani A, Malkin D, Hawkins CE, Pursell ZF, Shlien A, Kunkel TA, Getz G, Tabori U. DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells. Cancer Discov. 2021 May;11(5):1176-1191. doi: 10.1158/2159-8290.CD-20-0790. Epub 2020 Dec 18. PMID: 33355208; PMCID: PMC8223607.
In this study, the research team examines microsatellite indel signatures in mismatch repair deficient tumors as well as the relationship between microsatellite instability and loss of polymerase proofreading function. The authors suggest how this information can be used for clinical management by anticipating tumor response to immunotherapy.
- McKenna DB, Dudzik CM, Kumar S, Mahmud N, Katona BW. COVID-19 Disruptions to Endoscopic Surveillance in Lynch Syndrome. Cancer Prev Res (Phila). 2021;14(5):521-526. doi:10.1158/1940-6207.CAPR-20-0565
This article examines endoscopic surveillance disruptions in individuals with Lynch syndrome caused by the COVID-19 pandemic between March 2020 and June 2020. Thirty-Four patients had a procedure scheduled during the study time frame and 27 of them had their procedures canceled due to the pandemic. Twenty-three of those that had canceled procedures were rescheduled and completed within 6 months with a median delay of 72 days. Three were outside of their 2 year recommended screening interval when rescheduled and 8 had clinical significant findings on endoscopy. Those who didn’t reschedule their procedure (4 patients) were younger than those that did reschedule.
- Thomsen W, Maese L, Vagher J, Moore K, Cheshier SH, Hofmann JW, Bruggers C. Early Presentation of Homozygous Mismatch Repair Deficient Glioblastoma in Teen With Lynch Syndrome: Implications for Treatment and Surveillance. JCO Precision Oncology no. 5 (2021) 670-675. DOI: 10.1200/PO.20.00323 EPub 2021 April 19.
This article is about a pediatric patient who presented with glioblastoma multiforme (GBM) and a family history of Lynch syndrome (MSH2 pathogenic variant). Upon further testing of the patient's GBM, he was found to have homozygous loss of MSH2 leading to the conclusion his tumor was driven by his germline MSH2 pathogenic variant and providing an opportunity for precision medicine for treatment of his GBM as well as testing of his family members.
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April 2021
Publications
| - Brouwer JGM, Snellen M, Bisseling TM, et al. Is a colorectal neoplasm diagnosis a trigger to change dietary and other lifestyle habits for persons with Lynch syndrome? A prospective cohort study. Fam Cancer. 2021;20(2):125-135. doi:10.1007/s10689-020-00201-5
This prospective longitudinal study reports on the likelihood of patients with Lynch syndrome to make lifestyle and dietary changes following a diagnosis of colorectal cancer compared to individuals with Lynch syndrome not diagnosed with colorectal cancer. Unlikely previous studies of individuals in the general population who are diagnosed with colorectal cancer and subsequently pursue healthier diets and decrease their BMI, no significant changes in dietary patterns, BMI, physical activity or NSAID use were reported though it was observed that those diagnosed with colorectal cancer were more likely to quit smoking. Additional research would be helpful to investigate motivational tools that would be more likely to affect these positive healthy lifetime habits among this patient population.
- Yamamoto G, Takenoya T, Takahashi A, et al. Quantitative evaluation of MSI testing using NGS detects the imperceptible microsatellite changed caused by MSH6 deficiency. Fam Cancer. 2021;20(2):137-143. doi:10.1007/s10689-020-00203-3
Microsatellite instability (MSI) is a widely used tool for identifying patients with Lynch syndrome. The standard for MSI testing has traditionally been through capillary electrophoresis. This group developed a novel way to evaluate MSI through next-generation sequencing (NGS). They found a 97% consistency rate of identification of MSI status by NGS and capillary electrophoresis. This new approach could be an exciting alternative to conventional MSI testing and could improve Lynch syndrome identification and care.
- Kunnackal John G, Das Villgran V, Caufield-Noll C, Giardiello F. Worldwide variation in lynch syndrome screening: case for universal screening in low colorectal cancer prevalence areas. Fam Cancer. 2021;20(2):145-156. doi:10.1007/s10689-020-00206-0
This study is a systematic review of published universal Lynch syndrome screening processes. A total of 89 studies were reviewed. Lynch syndrome positive screening rates varied with geography and colorectal cancer 5-year prevalence rates. 7.7% (113/1475) of patients included in Lynch syndrome screening studies that focused on patients at/under 50 were confirmed to have Lynch syndrome.
- Zhang M, Chen T. Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China [published correction appears in Hered Cancer Clin Pract. 2021 May 17;19(1):27]. Hered Cancer Clin Pract. 2021;19(1):26. Published 2021 May 1. doi:10.1186/s13053-021-00182-1
A number of ancestry specific Lynch syndrome mutations have been identified in different Asian countries, and one population study in China the carrier rate is 1.6%. Traditionally Lynch syndrome testing has been offered in China if patients meet Fudan criteria, which has slightly higher sensitivity than Amsterdam criteria; however, this paper explores differences in Lynch syndrome risks, screening, and outcomes and postulates that population screening should be investigated.
- Kim SR, Tone A, Kim RH, et al. Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study. Gynecol Oncol. 2021;161(1):221-227. doi:10.1016/j.ygyno.2021.01.002
A prospective study analyzing the effects of mismatch repair deficiency (MMRd) showed that individuals diagnosed with endometrial cancer who exhibited MLH1 methylation had more aggressive features when compared to MMRd or MMR-intact (MMRi) endometrial cancer. MMRd endometrial cancers tended to be of a higher grade with a larger propensity for lymph node involvement than MMRi tumors. However, within the subset of MMRd patients, MLH1 methylation exhibited worse prognostic features. This study highlights the possible need for further personalized management based on MLH1 methylation status.
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March 2021
Publications
| - Li, D., Udaltsova, N., Layefsky, E., Doan, C., & Corley, D. A. (2021). Natural Language Processing for the Accurate Identification of Colorectal Cancer Mismatch Repair Status in Lynch Syndrome Screening. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 19(3), 610–612.e1. https://doi.org/10.1016/j.cgh.2020.01.040
Immunohistochemistry (IHC) testing is often used to screen colon cancers for Lynch syndrome. However, IHC reports are typically text-based and embedded within larger pathology reports. Thus IHC results are not always queryable within an EMR. Researchers at Kaiser Permanente in Northern California developed an NLP (natural language processing) tool to help identify and track patients with abnormal IHC results. Data from patients diagnosed with colon cancer between 2008 – May 2017 within the Kaiser Permanente of Nothern California system was utilized in the development and validation of this tool. 5570 patients were identified who had IHC reports available. The NLP tool was created to identify pathology reports which included IHC results (by searching for the terms MLH1, MSH2, MSH6 and PMS) and categorize the results for each protein as positive, negative, or indeterminate. These results were then correlated with BRAF V600E and/or MLH1 methylation results (when applicable) to determine the case’s likelihood of having Lynch syndrome. Individual cases were then considered “Lynch Likely” if there was deficient mismatch-repair detected on IHC and were flagged as appropriate for germline genetic testing; however, cases with absent MLH1 staining but positive BRAF v600E or MLH1 methylation were considered “Lynch unlikely” and were not flagged for germline genetic testing. To develop the tool, 1,000 IHC reports were assessed by the NLP tool and compared to manual chart review. After making improvements based on the discrepancies noted, the NLP tool was re-run on the IHC reports against an independent manual chart review. Following this, the NLP tool was run on a second validation set of 300 IHC reports from MMR-deficient colon cancers. The NLP tool was highly accurate in identifying and correctly extracting IHC results from pathology reports. When comparing the NLP tool to manual chart review, the overall agreement (kappa) was 96%–100%. It was also extremely accurate (100%) in classifying cases as “Lynch likely” vs. “Lynch unlikely”. This tool could assist clinicians in identifying patients with MMR-deficient IHC results who are appropriate for germline testing, or whose chemotherapy regimen may need to be altered based on IHC results.
- Reyes-Uribe, L., Wu, W., Gelincik, O., Bommi, P. V., Francisco-Cruz, A., Solis, L. M., Lynch, P. M., Lim, R., Stoffel, E. M., Kanth, P., Samadder, N. J., Mork, M. E., Taggart, M. W., Milne, G. L., Marnett, L. J., Vornik, L., Liu, D. D., Revuelta, M., Chang, K., You, Y. N., … Vilar, E. (2021). Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Gut, 70(3), 555–566. https://doi.org/10.1136/gutjnl-2020-320946
In this double-blind, randomized, placebo-controlled, multicentric Phase 1 clinical trial, the authors tested the safety of naproxen for adults with Lynch syndrome (LS) and Lynch-like syndrome (LLS). The participants with LLS had a history of a dMMR tumor without a BRAF-V600E mutation nor MLH1 hypermethylation though the authors did not rule out these participants having double somatic mutations. Participants were required to have a portion of their distal colon or rectosigmoid colon intact as well as at least a 14 day history without aspirin, NSAID or COX inhibitor use. Participants (N=80) were stratified by LS vs LLS before equally randomization to the Placebo (N=28), Low-dose (220mg/day) Naproxen (N=27) or High-dose (440mg/day) Naproxen (N=25) arms. Participants in compliance for at least 90 days (taking at least 80% of intervention) including within the last seven days of the trial and with detectable levels of naproxen in their colonic mucosa and plasma were considered appropriate for evaluation. Ultimately, the study team was only able to evaluate 54 individuals across cohorts (23/27 in placebo group, 15/27 in low-dose group, 16/25 in high-dose group). The primary end points of the trial were to investigate Naproxen’s toxicity profile and tolerability for each dose level and to measure the effect of the drug doses on prostaglandin E2 (PGE2) concentration levels within normal colorectal mucosa. Adverse events were reported in 61 participants (185 SE total) though the not reported did not differ significantly across cohorts and non of which were severe. The most commonly reported AEs were GI and bleeding events. Seven AEs in the high-dose group and 38 in the low-dose group were reported as probably related to the study intervention. The level PGE2 were significantly decreased in the colorectal mucosa of the majority (>92%) participants in both treatment groups. Secondary outcomes were also reported. Additionally, the authors reported on a co-clinical trial assessing biomarkers and tumor development prevention in mice (N=83). Mice were randomized to receive Naproxen, Aspirin or placebo. Naproxen showed promising chemoprevention activity in the mouse model with mice in the Naproxen group lived significantly longer than the Aspirin or placebo groups which corresponded to lower intestinal tumor burden as well.
- Monahan, K. J., Lincoln, A., East, J. E., Benton, S., Burn, J., DeSouza, B., Hanson, H., Lalloo, F., McVeigh, T., Rutter, M. D., Snape, K., Thomas, H., & Sasieni, P. (2021). Management strategies for the colonoscopic surveillance of people with Lynch syndrome during the COVID-19 pandemic. Gut, 70(3), 624–626. https://doi.org/10.1136/gutjnl-2020-321993
The British Society of Gastroenterology (BSG) responded to the COVID-19 pandemic by issuing guidelines recommending the suspension of routine endoscopy and colonoscopy procedures. However, guidance for high-risk individuals such as those with Lynch syndrome was more limited. Lynch syndrome is thought to affect 1:125 individuals of the UK population. These individuals are recommended to have more frequent colonoscopies which may have been cancelled or postponed during the pandemic and may continue to be delayed given the backlog of colonoscopies many centers are now facing. This article proposes that faecal immunochemical test (FIT) which are effective at detecting cancers could be utilized in the interim. A clinical service pilot is beginning to rapidly evaluate FIT levels of individuals with Lynch syndrome. Those with high FIT levels will be prioritized for colonoscopy or endoscopy screenings. FIT will not be recommended to replace colonoscopy surveillance but could be effective as an emergency response.
- Xie, T., Feng, Q., Li, Z., Lu, M., Li, J., Lizaso, A., Xiang, J., Zhang, L., Shen, L., & Peng, Z. (2021). Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review. Hereditary cancer in clinical practice, 19(1), 7. https://doi.org/10.1186/s13053-021-00165-2
This study reports on a patient with CMMRD and metastatic colorectal cancer resulting from bi-allelic germline MSH6 mutation who had heterogeneous MMR-IHC with high tumor mutations burden (TMB-H) but microsatellite stable (MSS) status. Patient is a 32 year old male with early onset colon cancer (poor to moderately differentiated adenocarcinoma with mucinous features) and peritoneal metastasis (T4bN1M1). He received palliative first line FOLFOXIRI and a laparotomy and subtotal colectomy. A homozygous missense mutation in the exon 5 of MSH6 gene, c.3226C > T (p.R1076C), was consistently detected in both tissue samples and blood sample. He was born from fourth-degree consanguineous parents, has multiple café-au-lait macula and neurofibromas, and family member testing confirmed 1st degree relatives to be heterozygous carriers. This result confirm a diagnosis of CMMRD. He received multiple lines of chemotherapy and immunotherapy with no promising tumor response. Pembrolizumab plus regorafenib (D1: pembrolizumab 200 mg, D1-D21 regorafenib 80 mg q21d) was administered and surprisingly, his clinical symptoms of CRC including abdominal pain were markedly relieved, which led to a remarkable improvement in his ECOG PS from 3 to 0. Serum tumor marker CEA also decreased from 13.18 ng/ml to 4.04 ng/ml within 1 month of combination therapy. His disease remains stable for 6 months.
- Kumar, A., Paramasivam, N., Bandapalli, O. R., Schlesner, M., Chen, T., Sijmons, R., Dymerska, D., Golebiewska, K., Kuswik, M., Lubinski, J., Hemminki, K., & Försti, A. (2021). A rare large duplication of MLH1 identified in Lynch syndrome. Hereditary cancer in clinical practice, 19(1), 10. https://doi.org/10.1186/s13053-021-00167-0
This study reports a large duplication in the MLH1 gene identified through a whole-exome (WES)/whole-genome sequencing (WGS) project at the Hereditary Cancer Center, Szczecin in Poland. WES on CRC patients and healthy family members of 5 families and WGS on 14 families was performed. IHC and MSI analyses were performed in CRC samples from individuals with a MMR gene variant detected through WES or WGS. Pathogenic MMR variants were identified in three of the 19 families. Family one had a duplication of exons 4-13 that lead to a frameshift and premature stop codon at amino acid 539. Family two carried a one base pair deletion in MLH1 and family three a splice site variant in MSH2. Abnormal IHC MMR staining matched the tumor finding in all three families tested. None of the three variants identified are reported in InSiGHT and only one in ClinVar. Although all of these were unique, the duplication is of special interest as large duplications have rarely been reported for MMR genes.
- Bernstedt, S. W., Björk, J., Fritzell, K., Spigelman, A. D., Björck, E., & Backman, A. S. (2021). Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer. Hereditary cancer in clinical practice, 19(1), 18. https://doi.org/10.1186/s13053-021-00171-4
Among hereditary cancer syndromes, Lynch syndrome is relatively common (affecting an estimated 1/440 people in the U.S.). Diagnosing patients with Lynch syndrome before they develop cancer allow for opportunities for increased cancer surveillance and risk reduction. Researchers at the Karolinska University Hospital in Sweden conducted a study to interrogate the reasons for genetics referral among patients diagnosed with Lynch syndrome to see how many patients were being diagnosed prior to developing cancer vs. after. Patients with Lynch syndrome referred to the Hereditary GI division of Karolinska University Hospital for GI surveillance were included in this study (n= 305 eligible out of 336). Data from 1975 – 2018 was available from prospective patient intakes and retrospective chart reviews. Patients were considered as being diagnosed with Lynch syndrome at the time a pathogenic MMR gene mutation was identified (genetic testing data available between 1994-2018). Data regarding personal cancer diagnoses were collected and trends in genetic testing indications were compared by age at patient diagnosis, as well as over time. Among the 305 patients with Lynch syndrome, 190 (62%) had genetic testing due to a known familial mutation and 27 (9%) had a family history of cancer suggestive of Lynch syndrome. 43 (14%) patients had genetic testing due to a personal cancer diagnosis. 10 (3%) patients had both a personal cancer diagnosis and a known familial mutation as their indication for testing, while 35 (12%) patients had a personal history of cancer plus a family history of cancer consistent with Lynch syndrome given as their reasons for pursuing testing. Colon cancer was the most common cancer among the 88 individuals with a personal history of malignancy (67/88; 76%). In looking at age at time of Lynch syndrome diagnosis, 36 (12%) patients were diagnosed with Lynch syndrome at age 60 or over; over half of these patients (56%) tested positive for Lynch syndrome after a cancer diagnosis. These data illustrate that a substantial portion of patients are not referred for Lynch syndrome genetic testing until after they have personally experienced a cancer diagnosis. 45 (15%) of these patients with cancer could have been identified as having Lynch syndrome earlier due to their suggestive family history or the presence of a known Lynch syndrome mutation in their family. This study highlights the gaps that exist in the identification of Lynch syndrome in at-risk individuals prior to a cancer diagnosis.
- Tjalsma, A. S., Wagner, A., Dinjens, W., Ewing-Graham, P. C., Alcalá, L., de Groot, M., Hamoen, K. E., van Hof, A. C., Hofhuis, W., Hofman, L. N., Hoogduin, K. J., Kaijser, J., Makkus, A., Mol, S., Plaisier, G. M., Schelfhout, K., Smedts, H., Smit, R. A., Timmers, P. J., Vencken, P., … van Doorn, H. C. (2021). Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer. Gynecologic oncology, 160(3), 771–776. https://doi.org/10.1016/j.ygyno.2020.12.028
Routine Lynch syndrome screening for all endometrial cancer patients <70 years old was introduced in the Netherlands in 2016. This study reviewed data from 14 hospitals between July 2016 and July 2017. Lynch syndrome screening via IHC staining of MMR proteins, supplemented with MLH1 methylation analysis when indicated was performed in 183 of 204 tumors (90%). Abnormal MMR protein expression was identified in 41 cases (22%) with 25 of them being due to hypermethylation of the MLH1 promotor. One patient had a previously identified MLH1 pathogenic variant. Genetic counseling was discussed with 12 of the remaining 15 patients. Three declined testing, two had negative results, and seven were diagnosed with Lynch syndrome. This study showed a successful implementation of universal LS screening for endometrial cancer patients in the Netherlands with hopes to continue improving referrals to a clinical geneticist following abnormal results.
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February 2021
Publications
| - Lynch PM. The CAPP II trial of aspirin in Lynch syndrome/HNPCC: is it time for everyone to be treated?. Fam Cancer. 2021;20(1):9-11. doi:10.1007/s10689-020-00215-z
This editorial comment reviewed the CAPPII consortium's recently published outcomes following a group of patients who received aspirin or a placebo daily over 25 months. Their findings showed a significant reduction in Lynch syndrome related cancers in the aspirin arm. One key finding from the CAPII paper showed the HR was 0.56 for LS patients in the 600 mg/day aspirin arm with benefits beginning around 5 years after randomization. The author of this comment raised a number of questions from this study, including whether patients in either arm of the study decided to take aspirin after seeing the results of the published 2011 CAPPII report. This author also asks if there are other, safer NSAIDs that could show the same benefit. Additionally, would beginning a daily aspirin dose at younger ages have an even greater impact on cancer reduction? The author of this review also raises questions of behavioral considerations including whether individuals will view aspirin as an "easy fix" instead of choosing healthier eating and lifestyle habits. More research will need to be conducted to answer these questions.
- Seppälä TT, Dominguez-Valentin M, Sampson JR, Møller P. Prospective observational data informs understanding and future management of Lynch syndrome: insights from the Prospective Lynch Syndrome Database (PLSD). Fam Cancer. 2021;20(1):35-39. doi:10.1007/s10689-020-00193-2
This review looks at
the differences between the prospective observational studies such as those
developed by the Prospective Lynch Syndrome Database (PLSD) and current Lynch
syndrome management guidelines. The PLSD was established in 2012 through the
collaboration of a number of European centers. Their findings suggest the need
for gene and gender specific clinical guidelines. Research from PLSD suggest
that the impact of colonoscopy in preventing CRC may be less than previously
thought. Previous guidelines have changed to recommend shortening the interval
between colonoscopies but data from PLSD show that decreased intervals are not
associated with decreased incidence or earlier disease stage at diagnosis. This
review suggests the need for a review of the guidelines associated with other Lynch syndrome related cancers such as gynecologic cancers, urothelial, prostate, renal
cell, gastric, and pancreatic cancers. They report that no surveillance
strategies other than colon cancer screening have proven value and should be
analyzed in a multidisciplinary approach for a consensus on screening procedure
recommendations. Guidelines for Lynch syndrome should be revised to account for gene
specific and gender specific cancer risks.
- Suerink M, Wimmer K, Brugieres L, et al. Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019. Fam Cancer. 2021;20(1):67-73. doi:10.1007/s10689-020-00194-1
This publication summarizes the discussion held on 7/6/19 by the 'Care for CMMRD' (C4CMMRD) consortium. The C4CCMRD consortium was first established in 2013 and aimed to increase knowledge and awareness of constitutional mismatch repair deficiency (CMMRD), improve care for patients with CMMRD and their families, develop guidelines for diagnosis and care, establish a CMMRD database and promote collaborations for research. This report summarizes progress on all of these aims. The database is active and had enrolled 87 patients from 66 families at the time of the meeting, the majority of which were individuals with PMS2 and MSH6 pathogenic variants. Regarding diagnosis of CMMRD, the role of functional CMMRD assays were discussed due to the ambiguities of molecular testing results and variant classifications; at least one reliable MSI assay developed for CMMRD diagnosis was thought to be feasibly scalable for at-risk populations. The report includes discussion supporting molecular analysis of the POLE and POLD1 genes for patients with unexplained CMMRD-like phenotypes. Based on case reports, pediatric onset of systematic lupus erythematosus was suggested as a diagnostic criterion of CMMRD to aid early diagnosis. The importance of professional psychosocial support for patients with CMMRD and their families was discussed in comparison to the psychological needs of patients with Li-Fraumeni syndrome. Endoscopic evidence in support of colorectal risk and surveillance with CMMRD was outlined. Data on immunotherapy for affected patients with CMMRD was reviewed and continued research objectives in this area were outlined. Research questions regarding CMMRD and the role of vaccination in the prevention of cancer were also generated.
- Patel SG, Hampel H, Smith D, Gao D, Cockburn M, Kastrinos F. Advanced adenomas may be a red flag for hereditary cancer syndromes. Hered Cancer Clin Pract. 2021;19(1):8. Published 2021 Jan 12. doi:10.1186/s13053-020-00164-9
This
retrospective review was completed at a tertiary center and investigated the
prevalence of hereditary cancer predisposition syndromes among patients who had
underwent multigene panel testing for the indication of advance adenoma and who
had no personal history of colorectal or polyposis (>10 polyps). This was a
relatively small study (N=42). Polyp histology included tubular adenoma
(92.9%), tubulovillous adenoma (4.8%) and villous adenoma (2.4%). Most polyps
were large (>10 mm; 95.2%), with some larger than 30 mm (N=3). Two patients
(4.8%) were reported to have pathogenic variants (in MLH1 and CHEK2), and 38%
were reported to have variants of uncertain significance. The patient found to
have Lynch syndrome did meet NCCN testing criteria – as did 16.7% of the whole
cohort; however, their polyp was the indication for referral. The patients
studied were relatively young, ranging from 23-57 (mean 44.6) and most of them
(76.2%) had no first degree relatives affected with colorectal cancer. This
study suggests that patients with advanced adenomas may benefit from genetic
testing for hereditary cancer predisposition syndromes; however, more research
is needed in this area with larger cohorts.
- De Simone LM, Arjunan A, Vogel Postula KJ, Maga T, Bucheit LA. Genetic counselors' perspectives on population-based screening for BRCA-related hereditary breast and ovarian cancer and Lynch syndrome. J Genet Couns. 2021;30(1):158-169. doi:10.1002/jgc4.1305
This study from Northwestern University aims to gauge genetic counselors' opinions on population-based genetic testing for Hereditary Breast and Ovarian Cancer (HBOC), caused by mutations in BRCA1 and BRCA2, and Lynch syndrome. Both HBOC and Lynch syndrome are prevalent enough in the general population (1 in 300-500 people in the U.S.) to qualify as Tier 1 genetic screening conditions per the CDC. From a public health perspective, early diagnosis with a Tier 1 condition can allow for beneficial interventions (including increased cancer screenings and cancer risk reduction). Currently in the U.S., most genetic testing for HBOC and Lynch syndrome is conducted in people with a personal and/or family history of cancer suggestive of the disease. While there have been calls from some researchers for broader testing implementation, concerns have been raised at the patient and infrastructure level (i.e. not enough providers trained in interpreting genetic test results, lack of insurance coverage for population based testing, potential patient distress, etc.). The study team created a 72 question email survey using RedCap, which was sent to the membership of the National Society of Genetic Counselors (3,609 members) in 2017. The survey explored the following five areas: attitudes regarding population based screening (PBS) for HBOC and Lynch, preparedness to offer PBS (for respondents currently providing patient care), preferences on PBS delivery models, perceived benefits/risks of PBS, and logistical concerns about PBS. 367 respondents completed the survey and met eligibility criteria; partial survey responses were included in the analysis. 63.8% of respondents work specifically in cancer genetics. 286 respondents provide direct patient care (202 in cancer; 84 in non-cancer setting). 50% of respondents were against offering PBS for HBOC and Lynch at this time. Over 90% of respondents felt that the current healthcare system is unprepared to offer PBS for HBOC or Lynch. 60.4% (160/265) of those providing clinical care felt their current clinic would be unable to accommodate an increase in patient volume from PBS. Likewise, 77.7% (206/265) felt that the high-risk clinicians they refer patients to for management would be unable to currently accept an increase in patient volume from PBS. A majority of respondents who provide patient care (71.3%, 189/265) reported being comfortable with providing genetic counseling and cancer risk management recommendations to patients with a positive test result that is incongruent with their personal/family history of cancer. However, respondents also felt that implementation of PBS would identify more individuals with HBOC or Lynch and allow them to pursue cancer screening/risk reduction (95.4%, 292/306) and would benefit people who would be currently missed with current testing guidelines (96.1%, 294/306) and that this could lead to a reduction in mortality and morbidity. Concerns noted by respondents included potential over/under treatment based on misinterpretation of genetic test results, healthcare costs, and possible patient anxiety. This study indicates that many genetic counselors see potential benefits to PBS, but the current lack of preparedness of the healthcare system to implement PBS and concerns regarding ensuring appropriate patient management, costs, and patient anxiety currently lead to a lack of support for implementing PBS for HBOC and Lynch right now.
- Cohen R, Taieb J, Fiskum J, et al. Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials. J Clin Oncol. 2021;39(6):642-651. doi:10.1200/JCO.20.01600
This study seeks to explore whether microsatellite instability (MSI) status impacts disease free survival and overall survival in patients with stage III colon cancer receiving adjuvant fluoropyrimidine with or without oxaliplatin. Data was extracted from the ACCENT (Adjuvant Colon Cancer Endpoints) database on patients in randomized clinical trials who had received adjuvant fluoropyrimidine and had MSI data available. Out of 5,457 patients with known MSI status, 609 had microsatellite instability (MSI) (11.2%) and 4848 had microsatellite stability (MSS). 4250 patients received adjuvant fluoropyrimidine with oxaliplatin (461 had MSI, 3789 had MSS). For the patients receiving fluoropyrimidine with oxaliplatin, both overall survival and disease-free survival showed improvements in patients with MSI cancers compared to those with MSS cancers in the N1 group. However, survival outcomes were similar for patients with MSI or MSS cancers in the N2 group.
- Loughrey MB, McGrath J, Coleman HG, et al. Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series. Histopathology. 2021;78(3):401-413. doi:10.1111/his.14233
This study compared MSI PCR versus MMR IHC in a large, population based study using colon cancer tumors from the Northern Ireland Cancer Registry. MSI and IHC MMR testing was run for all cases. Of the analytical cohort of 593 cases, 135 (22.8%) had abnormal MMR IHC which most frequently showed loss of MLH1/PMS2 staining (17.9%). Of the 593 cases, 136 (22.9%) were MSI-H, and 10 (1.7%) were MSI-L. When MSI testing and MMR IHC were combined, 149 cases (135 with abnormal MMR IHC plus 14 with MSI-H/L status; 25.1%) showed some abnormality. Concordance between MSI-H cases and abnormal MMR IHC was high, with 97.1% of MSI-H cases showing abnormal MMR IHC, and 97.8% of cases with abnormal MMR IHC showing MSI-H status. The study notes near perfect correlation between assessment of MSI status and MMR IHC when the amount of tumor DNA was above the threshold for the sensitivity of the MSI test. This study suggests that either MSI testing or MMR IHC can be safely used for primary screening of colon cancer in order to determine dMMR/MSI-H status.
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