Risk For Lynch Syndrome Research Articles

Identification of Individuals at Risk for Lynch Syndrome Using Targeted Evaluations and Genetic Testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer Joint Practice Guideline

Identifying individuals who have Lynch syndrome (LS) involves a complex diagnostic work up that includes taking a detailed family history and a combination of various genetic and immunohistochemical tests. The National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC) have come together to publish this clinical practice testing guideline for the evaluation of LS. The purpose of this practice guideline is to provide guidance and a testing algorithm for LS as well as recommendations on when to offer testing. This guideline does not replace a consultation with a genetics professional. This guideline includes explanations in support of this and a summary of background data. While this guideline is not intended to serve as a review of LS, it includes a discussion of background information on LS, and cites a number of key publications which should be reviewed for a more in-depth understanding of LS. These guidelines are intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses and other healthcare providers who evaluate patients for LS.

Synchronous Breast Cancers With Different Morphologic and Molecular Phenotypes Occurring in Lynch Syndrome

The increasingly widespread use of immunohistochemistry in the detection of DNA mismatch repair proteins has led to the observation of various unusual tumor types that occur in Lynch syndrome and exhibit mismatch repair protein deficiency. Understanding the clinical significance of such unusual tumors has become increasingly desirable. Here, we report a case of 2 synchronous breast cancers occurring in a 74-year-old woman who carried a deleterious germline mutation in MSH2 and who survived an endometrial and a colonic carcinoma. Both breast cancers were of lobular type with similar expression patterns for estrogen receptor, progesterone receptor, and Her2/neu. However, the 2 cancers differed in other characteristics. One tumor showed a solid alveolar histologic pattern with prominent tumor-infiltrating lymphocytes and loss of MSH2 and MSH6 protein on immunohistochemical staining. In contrast, the other tumor was of classic type with no apparent lymphocytic infiltration and no loss of mismatch repair protein. Such a case carries practical implications as it suggests that certain breast cancers may serve as tissue samples for the detection of mismatch repair deficiency in families at high risk for Lynch syndrome, thus expanding the test sample repertoire for genetic workup in these families. Furthermore, the case exemplifies the complexity of tumorigenesis in Lynch syndrome patients. The observation that, of the 2 breast cancers, increased tumor-infiltrating lymphocytes were present only in the tumor that showed mismatch repair protein abnormality is in keeping with what has been observed in the colon and other sites. Such persistent genotype-phenotype correlation across different organs affords the promise that molecular classification may allow identification of biologically distinct tumor subsets beyond the confines of the tumor's primary anatomic location.

Detection of DNA mismatch repair proteins in fresh human blood lymphocytes - towards a novel method for hereditary non-polyposis colorectal cancer (Lynch syndrome) screening

BackgroundA broad population-based assay to detect individuals with Lynch Syndrome (LS) before they develop cancer would save lives and healthcare dollars via cancer prevention. LS is caused by a germline mutation in a DNA mismatch repair (MMR) gene, especially protein truncation-causing mutations involving MSH2 or MLH1. We showed that immortalized lymphocytes from LS patients have reduced levels of full-length MLH1 or MSH2 proteins. Thus, it may be feasible to identify LS patients in a broad population-based assay by detecting reduced levels of MMR proteins in lymphocytes.MethodsAccordingly, we determined whether MSH2 and MLH1 proteins can also be detected in fresh lymphocytes. A quantitative western blot assay was developed using two commercially available monoclonal antibodies that we showed are specific for detecting full-length MLH1 or MSH2. To directly determine the ratio of the levels of these MMR proteins, we used both antibodies in a multiplex-type western blot.ResultsMLH1 and MSH2 levels were often not detectable in fresh lymphocytes, but were readily detectable if fresh lymphocytes were first stimulated with PHA. In fresh lymphocytes from normal controls, the MMR ratio was ~1.0. In fresh lymphocytes from patients (N > 50) at elevated risk for LS, there was a bimodal distribution of MMR ratios (range: 0.3-1.0).ConclusionsFinding that MMR protein levels can be measured in fresh lymphocytes, and given that cells with heterozygote MMR mutations have reduced levels of full-length MMR proteins, suggests that our immunoassay could be advanced to a quantitative test for screening populations at high risk for LS.

Endometrial cancer patients and compliance with genetic counseling: Room for improvement

Introduction Immunohistochemistry (IHC) for the presence or absence of DNA mismatch repair (MMR) proteins in tumor samples is a quick and relatively inexpensive method to screen for Lynch syndrome (LS). At our institution we have found that > 20% of patients lack expression of MMR proteins and > 10% would be expected to benefit from genetic counseling (GC). However, compliance with referral to GC is poor. Therefore, we set out to analyze the reasons for noncompliance, hypothesizing that it could be due to a perception of a low risk for developing other cancers. Methods All patients with endometrial cancer between 2007 and 2009 were identified. Patients with absence of MMR protein expression who would be expected to benefit from GC were identified. These patients were sent a questionnaire assessing the utilization of GC services as well as their perception of LS and Lynch-associated cancers. Results Forty-seven patients out of 384 were identified who would have been expected to benefit from GC. Of the responders, 20 patients (77%) reported that they were referred by their physician for GC, of which 9 saw a genetic counselor, 8 had genetic testing, and 3 mutations were detected. The primary reason for not seeing a genetic counselor was no insurance coverage/cost of the visit followed by anxiety for the results. Nine patients stated that the patient/family did not want to know information regarding cancer risk. As compared to the general population 35% thought their risk of having LS was higher, 12% thought it was the same, 15% lower, and 38% was unsure. Forty-six percent of patients thought the risk of colon cancer was higher than background risk, and 26% thought it was the same. Conclusion Most patients underestimate their risk of LS associated heritable cancer. Physicians should pay more attention to family history and IHC in order to refer patients appropriately. In addition, more verbal and written information may enable patients to accurately assess their cancer risk. This could further improve compliance with genetic counseling and detection of Lynch syndrome.

Abstract B29: Screening and communication with physicians for women with Lynch syndrome: Findings from a qualitative study

Abstract Background: Lynch syndrome, which is also known as hereditary non-polyposis colon cancer (HNPCC), is an autosomal dominant hereditary cancer syndrome that confers women with a 40–60% lifetime risk of endometrial cancer (EC) and a 12% lifetime risk of ovarian cancer (OC). Consensus statements recommend annual EC and OC screening for women with Lynch syndrome, initiated at age 30–35 or 10 years younger than the earliest known case in the family. This study evaluated the prevalence of EC and OC screening behaviors among women at risk for Lynch syndrome, and communication with their physicians about EC and OC risk and screening needs. Methods: Women age > 25 years who were at risk for Lynch syndrome-related cancers, and who had not had both a hysterectomy and oophorectomy, completed a semi-structured interview either in person or over the phone. The domains covered included demographics and medical history, knowledge of screening recommendations, screening for Lynch-syndrome associated gynecological cancers, and physician-patient communication. SPSS and NVivo™ were used for data analysis. Results: Fifty-two women (mean=40.6 years old) participated. They were mostly white, married, well-educated, and had children. Approximately 70% were Lynch-syndrome mutation carriers while the remaining 30% met the Amsterdam II criteria. Approximately 70% reported a family history of EC or OC. All but five had received genetic counseling regarding their risk for Lynch syndrome. Half of the participants correctly answered questions about the appropriate age to begin screening, while approximately 75% correctly assessed the recommended screening frequency. Approximately half of the women reported never having had asymptomatic gynecological screening. Between 15 and 38% were currently adherent to screening recommendations because they received screening as part of a research study. Women who were seeing non-oncology gynecologists were not offered appropriate EC or OC screening, although they uniformly expressed a high level of trust and value in the care provided by these physicians and believed that their physicians were doing the best job possible to manage their health needs. Approximately 33% of the women report that cost and lack of insurance might prevent their screening adherence in the future. Conclusions: Lynch syndrome-affected families and their primary care physicians may lack accurate knowledge of EC and OC risks. Women who are at risk for Lynch syndrome may not receive appropriate EC or OC screening from their community physicians, and new prevention-communication strategies may be needed. Participation in research studies may improve adherence to screening for gynecologic cancers in Lynch syndrome. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B29.

Validation Microsatellite Path Score in a Population-Based Cohort of Patients With Colorectal Cancer

Bethesda guidelines are used to recognize patients at risk for Lynch syndrome. However, obtaining personal and familial tumor data can sometimes be difficult. The Microsatellite Path Score (MsPath), a pathological score, based on age, tumor location, and pathologic features, has been developed to effectively predict colorectal cancer with DNA mismatch repair (MMR) deficiencies. However, the MsPath model's performance in an unselected, population-based colorectal cancer (CRC) population is unknown. We analyzed all patients with CRC regardless of age, personal or family history, and tumor characteristics from the EPICOLON study, an independent, prospective, multicenter, population-based cohort (N = 1,222). All patients underwent tumor microsatellite instability (MSI) analysis and immunostaining for MLH1/MSH2, and those with MMR underwent tumor BRAF mutation analysis and MLH1/MSH2 germline testing. All the pathologic features were centralized and evaluated blinded to the MMR status. MsPath score for prediction of having MSI high, with the recommended MsPath cutoff score ≥1.0, had a sensitivity, specificity, and positive predictive value (PPV) of 92.8% (95% CI, 86.9 to 98.3), 64.1% (95% CI, 61.1 to 66.8), and 15.8% (95% CI, 12.2 to 18.6), respectively. MsPath score had a sensitivity, specificity, and PPV of 81.8% (95% CI, 59.0 to 99.8), 60.6% (95% CI, 57.8 to 63.4), and 1.9% (95% CI, 0.7 to 3.1), respectively, for the identification of MLH1/MSH2 gene carriers. Application of the MsPath score, resulted in two (18%) of 11 mutation carriers being missed, both pathogenic germline MSH2 mutations. In the general nonselected population, the MsPath score accurately predicted the probability of bearing a MSI high CRC, but it was insufficiently accurate to use for the selection of patients warranting MLH1/MSH2 mutation testing in the setting of Lynch syndrome.

A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas

Mismatch repair protein immunohistochemistry is a widely used method for detecting patients at risk for Lynch syndrome. Recent data suggest that a two-antibody panel approach using PMS2 and MSH6 is an effective screening protocol for colorectal carcinoma, but there are limited data concerning this approach for extraintestinal tumors. The purpose of this study was to review the utility of a two-antibody panel approach in colorectal carcinoma and extraintestinal tumors. We evaluated mismatch repair protein expression in two cohorts: (1) a retrospective analysis of intestinal and extraintestinal tumors (n=334) tested for mismatch repair protein immunohistochemistry and (2) a prospectively accrued series of intestinal, gynecologic tract, and skin sebaceous neoplasms (n=98). A total of 432 cases were analyzed, including 323 colorectal, 50 gynecologic tract, 49 skin sebaceous, and 10 other neoplasms. Overall, 102/432 tumors (24%) demonstrated loss of at least one mismatch repair protein. Concurrent loss of MLH1 and PMS2 was the most common pattern of abnormal expression (50/432, 12%) followed by concurrent loss of MSH2 and MSH6 (33/432, 8%). Of 55 cases with abnormal PMS2 expression, 5 (9%) demonstrated isolated loss of PMS2 expression. Of 47 cases with abnormal MSH6 expression, 14 (30%) demonstrated isolated loss of MSH6 expression. Isolated loss of MLH1 or MSH2 was not observed. Colorectal carcinomas more frequently demonstrated abnormal expression of PMS2 (39/59, 66%). Skin sebaceous neoplasms more frequently demonstrated abnormal expression of MSH6 (18/24, 75%, respectively). A total of 65 tumors with abnormal mismatch repair protein expression were tested for microsatellite instability (MSI): 47 (72%) MSI high, 9 (14%) MSI low, and 9 (14%) microsatellite stable (MSS). Abnormal MSH6 expression accounted for 14/18 (78%) cases that were MSS or MSI low. Our findings confirm the utility of a two-antibody approach using PMS2 and MSH6 in colorectal carcinoma and indicate that this approach is effective in extraintestinal neoplasms associated with Lynch syndrome.

Gynecologic cancer screening in women at high risk of Lynch syndrome.

1559 Background: Endometrial cancer is the most frequent extracolonic tumor in women with Lynch syndrome (LS). The aim of this study was to assess adherence to screening of gynecological tumors by women with LS and determine the impact of monitoring and prophylactic surgery in these women. Methods: Between 2005-2008, 91 women with LS were subjected to gynecological examination (GE), transvaginal ultrasound (TVS) and endometrial aspirate (EA). The implementation of screening, its results and prophylactic surgery information were evaluated annually and verified with documentation. We analyzed factors associated with adherence: socioeconomic, clinical, genetic and family history, and the results of screening. Results: Of the 91 women with gynecological follow-up, 78 (85.71%) were performed at least once (GE and ETV). EA was zero, except in 3 women (3.3%) with abnormal TVS. 48 underwent a gynecological screening only once. The average gynecological screening examinations (EG + ETV) performed was 1.4 ± 1.07 (range 0-4). Women at risk without cancer adhered better (58.3% vs 52.5% vs 30.8%, p = 0.028). In addition, there was greater compliance if ≥ 2 first degree relatives were affected with endometrial cancer (80% vs 56.3 and 35.4%, p = 0.009). Socioeconomic status, educational, employment and mutational status had no effect on compliance. 3 (3%) women were diagnosed with endometrial cancer. 2 patients suspected diagnosis of endometrial cancer with the first GE including ETV, and confirmed with EA. The third case was detected by a prophylactic hysterectomy in a woman newly diagnosed with two synchronous colon cancers by screening colonoscopy. This was in the one case who underwent prophylactic surgery, and her endometrial cancer was at an early stage (stage IA). Conclusions: Compliance with the recommendations of gynecological screening was 44%. EA is not performed for screening of endometrial cancer. The number of relatives with endometrial cancer increases the likelihood of adhering to gynecological screening. The identification of a mutation has no effect. The first gynecological screening examination detects a significant number of endometrial cancers; and, in addition, prophylactic hysterectomy detects early stage tumors in women with LS.

Attitudes toward childbearing and prenatal testing in individuals undergoing genetic testing for Lynch Syndrome

To examine attitudes toward childbearing and prenatal genetic testing among individuals at risk for Lynch syndrome (LS), the most common type of hereditary colorectal cancer. Individuals undergoing clinical genetic testing for mismatch repair (MMR) gene mutations completed written questionnaires before and after testing. 161 of 192 (84%) eligible individuals participated in the study. Mean age was 46 years (range 20-75), 71% were female, 53% had a personal diagnosis of cancer, and 68% had children. Eighty percent worried about their children's risk for developing cancer; however only 9% reported their decision to have children was affected by their family history of cancer. When asked whether providing prenatal testing to carriers of MMR gene mutations was ethical, 66% (86/130) of respondents agreed/strongly agreed, 25% (32) were neutral and 9% (12) disagreed/strongly disagreed. Of 48 individuals planning to have children in the future, 57% (27) intended to have children regardless of their genetic test result. If found to carry a MMR gene mutation that confirmed LS, 42% (20) would consider prenatal testing for a future pregnancy and 20% (7/35) of women would consider having children earlier in order to have prophylactic surgery to reduce their risk for gynecologic cancers. Individuals undergoing genetic testing for LS may utilize test results to make reproductive decisions. Clinicians should be prepared to discuss options of reproductive genetic technologies during counseling of LS patients of childbearing age.

Identifying Lynch syndrome in women with endometrial cancer

Objective: Approximately 2% of endometrial cancers are attributable to Lynch syndrome. Selecting a subgroup of patients with endometrial cancer at higher risk for Lynch syndrome may identify a cohort for genetic counseling and testing.

Immunohistochemical Staining for DNA Mismatch Repair Proteins in Intestinal Tract Carcinoma

In recent years, immunohistochemistry has emerged as an efficient tool in the detection of DNA mismatch repair protein abnormality in colorectal cancers. Currently, the immunohistochemical test is mainly applied to cancer resection specimens. Detection of mismatch repair abnormality in biopsies carries obvious clinical importance, as it would allow informed decision about the extent of surgery (segmental resection vs total colectomy, prophylactic hysterectomy or not). Moreover, in the case of treated rectal carcinoma with no residual tumor, it provides a means to evaluate the mismatch repair proteins. However, whether biopsy samples can be reliably used for mismatch repair protein detection remains to be determined. Paired biopsy and resection specimens of adenocarcinomas of the gastrointestinal tract, enriched for patients at increased risk for Lynch syndrome, were analyzed for immunohistochemical staining patterns for MLH1, MSH2, MSH6, and PMS2. Abnormal staining was defined as total loss of protein in the tumor with appropriate control. Cases with focal and weak staining, defined as staining of no more than moderate intensity present in <10% of the tumor cells, were recorded. Correlation analysis with germline mutation data was in a subset of cases. Among 70 gastrointestinal tract cancers (3 from the small bowel, 36 from the right colon, 15 from the left colon, and 16 from the anorectum), both the biopsy and resection specimens detected the same 29 cancers as having loss of staining for at least 1 protein, 14 affecting MLH1/PMS2 and 15 affecting MSH2/MSH6. Focal and weak staining was most commonly seen for MLH1 stain in biopsies (4 of 70, 6%), followed by MSH6 stain in biopsies (3 of 70, 4%). Concordant staining patterns between biopsies and resections were reached in all 70 cases for MSH2 and PMS2, whereas discordant patterns were identified in 3 cases (3 of 70, 4%) for MLH1 and in 2 cases (2 of 70, 3%) for MSH6. None of the discordant patterns affected the final interpretation of whether the immunohistochemistry test was normal or abnormal in either the biopsy or the resection. In 13 of the 13 cases that were known to have a pathogenic germline mutation (5 in MLH1 and 8 in MSH2), the stains were abnormal for the corresponding protein and/or its partner protein in both the biopsy and the resection specimens. This study provides data indicating that biopsy samples are as reliable as resections in the immunohistochemical detection of mismatch repair protein abnormality in intestinal cancers. Our study also shows that various staining variations can occur in both biopsies and resections. Awareness and further understanding of such variations will enhance the use of immunohistochemistry, a commonplace tool that is being increasingly used in the screening workup for Lynch syndrome.

Effects of a Decision Support Intervention on Decisional Conflict Associated with Microsatellite Instability Testing

Decision support to facilitate informed consent is increasingly important for complicated medical tests. Here, we test a theoretical model of factors influencing decisional conflict in a study examining the effects of a decision support aid that was designed to assist patients at high risk for hereditary nonpolyposis colorectal cancer (CRC) deciding whether to pursue the microsatellite instability (MSI) test. Participants were 239 CRC patients at high familial risk for a genetic mutation who completed surveys before and after exposure to the intervention. Half of the sample was assigned to the CD-ROM aid and half received a brief description of the test. Structural equation modeling was employed to examine associations among the intervention, knowledge, pros and cons to having MSI testing, self-efficacy, preparedness, and decisional conflict. The goodness of fit for the model was acceptable [FIML, full information maximum likelihood, χ(2) (df = 280) = 392.24; P = 0.00]. As expected, the paths to decisional conflict were significant for postintervention pros of MSI testing (t = -2.43; P < 0.05), cons of MSI testing (t = 2.78; P < 0.05), and preparedness (t = -7.27; P < 0.01). The intervention impacted decisional conflict by increasing knowledge about the MSI test and knowledge exerted its effects on decisional conflict by increasing preparedness to make a decision about the test and by increases in perceived benefits of having the test. Increasing knowledge, preparedness, and perceived benefits of undergoing the MSI test facilitate informed decision making for this test. Understanding mechanisms underlying health decisions is critical for improving decisional support. Individuals with Lynch syndrome have an elevated lifetime risk of CRC. Risk of Lynch syndrome may be assessed with a tumor-based screening test (MSI testing or immunohistochemical tissue staining).

Young age and a positive family history of colorectal cancer are complementary selection criteria for the identification of Lynch syndrome

Families at high risk for Lynch syndrome can effectively be recognised by microsatellite instability (MSI) testing. The aim of the present study is to compare the effectiveness of a MSI test for the identification of Lynch syndrome in patients selected by a pathologist mainly based on young age at diagnosis (MSI-testing-indicated-by-a-Pathologist; MIPA), with that of patients selected by a clinical geneticist mainly based on family history (MSI-testing-indicated-by-Family-History; MIFH).Patients with a Lynch syndrome associated tumour were selected using MIPA (n=362) or MIFH (n=887). Germline DNA mutation testing was performed in 171 out of 215 patients (80%) with a MSI positive tumour.MSI was tested positive in 20% of the MIPA-group group compared to 16% in the MIFH-group (P=0.291). In 91 of 171 patients with MSI positive tumours tested for germline mutations were identified as Lynch syndrome patients: 42% in the MIPA-group and 56% in the MIFH-group (P=0.066). Colorectal cancer (CRC) or endometrial cancer (EC) presenting at an age below 50years would have led to the diagnosis of Lynch syndrome in 89% of these families (CRC below 50years: 88% and EC below 50years: 12%). Families detected by MIPA were characterised more often by extracolonic Lynch syndrome associated malignancies, especially EC (P<0.001).Our results indicate that recognition of Lynch syndrome by CRC or EC below 50years is as effective as a positive family history. Families from patients selected by individual criteria more often harbour extracolonic Lynch syndrome associated malignancies.

Identification of patients at-risk for Lynch syndrome in a hospital-based colorectal surgery clinic

To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil. A consecutive sample of patients with CRC were interviewed regarding personal and family histories of cancer. Clinical data and pathology features of the tumor were obtained from chart review. Of the 212 CRC patients recruited, 61 (29%) reported a family history of CRC, 45 (21.2%) were diagnosed under age 50 years and 11 (5.2%) had more than one primary CRC. Family histories consistent with Amsterdam and revised Bethesda criteria for LS were identified in 22 (10.4%) and 100 (47.2%) patients, respectively. Twenty percent of the colorectal tumors had features of the high microsatellite instability phenotype, which was associated with younger age at CRC diagnosis and with Bethesda criteria (P < 0.001). Only 5.3% of the patients above age 50 years had been previously submitted for CRC screening and only 4% of patients with suspected LS were referred for genetic risk assessment. A significant proportion of patients with CRC were at high risk for LS. Education and training of health care professionals are essential to ensure proper management.

When brachytherapy met genetic oncology. Can radiation oncologists improve the detection of hereditary non-polyposis colorectal cancer?

Between January 1994 and December 2004, 696 patients with localized endometrial carcinoma have been treated at the Institute Jean-Godinot. Patients were selected on the following criteria: histologically proven adenocarcinoma of the endometrium; age at onset under 60 years; patient not deceased at the time of the study. One hundred twelve patients met these criteria and received a mailed specific questionnaire to establish their pedigree. Thirty-one patients (35.5%) were eventually found eligible for a genetic counselling but only 13 patients agreed to be informed later on. According to the obtained pedigrees and MSI test results, 7 genetic tests have been carried out and so far, 3 MMR mutations were detected. This study suggested the feasibility of a step by step screening of endometrial cancers to select patients at risk for Lynch syndrome and for whom a genetic test would be recommended. Authors suggest that either Amsterdam or Bethesda criteria should be systematically used prospectively in every newly diagnosed endometrial cancer and retrospectively using clinical databases available on endometrial cancers.

To Screen or Not To Screen for Lynch Syndrome

rosatellite instability (MSI) test. Patients with an abnormal screen can then have a diagnostic DNA test for mismatch repair mutations to confi rm or rule out Lynch syndrome. Family history is the basis for two different sets of criteria to determine which patients should be considered at risk for Lynch syndrome: the Amsterdam criteria and the Bethesda guidelines. But family history isn’t always available, and many patients are thus missed, along with the opportunity to identify their at-risk relatives. That’s why the federal Centers for Disease Control and Prevention (CDC) convened its independent panel — the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group — to consider a broader screening strategy. The working group released its fi ndings in January 2009. According to the CDC website, the group “found good scientifi c evidence to recommend that all individuals with a new diagnosis of colorectal cancer (regardless of age or family history) be offered genetic testing for Lynch syndrome, in order to help prevent cancer in their close relatives.” It did not fi nd enough evidence to recommend any specifi c preliminary screening strategy, e.g., MSI versus IHC.

Counterpoint: Implementing Population Genetic Screening for Lynch Syndrome Among Newly Diagnosed Colorectal Cancer Patients—Will the Ends Justify the Means?

Inherited mutations in 1 of 4 known mismatch repair genes (MLH1, MSH2, MSH6, PMS2) are associated with various cancer risks collectively referred to as Lynch syndrome. Roughly 3 of every 100 new colorectal cancers (CRCs) have an underlying Lynch mutation. Tumor-based screening for Lynch among all patients with newly diagnosed CRC could theoretically improve the ability to identify Lynch and prevent cancer among at-risk family members, but the patient-level and social implications of this approach must be carefully considered before adopting this strategy. Poorly addressed issues include the role/timing of informed consent for testing, access and cost barriers associated with genetic counseling and DNA testing, psychosocial burdens to the thousands of middle-aged and elderly patients with CRC coping with surgical and chemotherapy treatments and poor prognosis, the need for providers to warn third-party relatives of risk for Lynch syndrome, limited effectiveness of screening, and the cost burden to society when poor DNA testing uptake, test limitations, and modest screening compliance are considered. Diverse barriers to the success of a population-based Lynch screening program in the United States remain (e.g., clinical resource needs, financial limitations, clinical expertise gaps, educational deficits). Data supporting clinical efficacy (feasibility) and effectiveness (real-life performance) are critical before important policy changes are adopted, especially where issues of hereditary cancer risk and genetic privacy are involved.

T2015 Routine MSI-Analysis in Endometrial Cancer ≤ 70 Years Increases Identification of Patients at Risk for Lynch Syndrome

T2015 Routine MSI-Analysis in Endometrial Cancer ≤ 70 Years Increases Identification of Patients at Risk for Lynch Syndrome

S1981 Routine MSI-Analysis in Advanced Adenomas in Patients Younger Than 45 Years Leads to the Identification of More Patients at High Risk for Lynch Syndrome

S1981 Routine MSI-Analysis in Advanced Adenomas in Patients Younger Than 45 Years Leads to the Identification of More Patients at High Risk for Lynch Syndrome

Hereditary and Familial Colon Cancer

Between 2% to 5% of all colon cancers arise in the setting of well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines.