Lynch Syndrome Colorectal Cancer Research Articles

Abstract C06: Implementation of Universal Colorectal Cancer Screening for Lynch Syndrome: A Population-Based Study

Abstract Introduction: Colorectal cancer (CRC) is the leading cause of cancer death in Puerto Rico and the third one among US Hispanics. Up to 2-4% of colorectal cancer cases are caused by germline mutation in at least one of these four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. Mutations in these genes cause Lynch Syndrome (LS), the most common hereditary form of CRC. Immunohistochemistry (IHC) tests for the presence of MMR proteins and microsatellite instability (MSI) analysis is often performed on the tumor of CRC cases to screen for LS and as markers for prognosis. Universal screening of CRC for LS has been recommended by the National Comprehensive Cancer Network (NCCN) since 2014. Objective: The purpose of this study was to determine the prevalence of positive LS-screening test as determined by absence of MMR proteins in CRC since the implementation of universal tumor screening for LS in the largest private pathology laboratory in Puerto Rico. Methods: We collected the data from all CRC cases performed at Hato Rey Pathology Laboratories from September 2014 to December 2015. Pathologies performed where collected from 11 hospitals that cover the island of Puerto Rico. The data collected included results of IHC and MSI analysis as well as tumor location, gender, age, date reported and hospital. Results: A total of 317 CRC tumors were evaluated for LS-screening; with a mean age of 66 years, and 54.3% were males. IHC analysis was performed in 288 cases and of these, 11.1% demonstrated absence of one or more of the MMR proteins, compatible with a positive screening test for LS. There were 21 cases that had only MSI analysis performed and they were all reported as microsatellite stable. Conclusion: This is the first evaluation of a systematic program for Universal CRC screening for LS in Puerto Rico. Our data is consistent with results from other studies of US-Hispanics where approximately 10% of individuals of Hispanic origin with CRC have MSI. The observed prevalence of absence of MMR-proteins in our study supports universal screening of LS among Hispanics in accordance with NCCN guidelines. Citation Format: Isabel Sierra, Yaritza Diaz-Algorri, Valerie Maldonado, Kimberly Alicea, Kathia Rosado, Marcia Cruz-Correa. Implementation of Universal Colorectal Cancer Screening for Lynch Syndrome: A Population-Based Study. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C06.

Abstract IA11: Chemoprevention in hereditary GI cancer syndromes

Abstract IA11: Chemoprevention in hereditary GI cancer syndromes

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.

Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers.

Successful implementation of Lynch syndrome screening in a safety net institution

Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC), and national guidelines recommend screening patients with CRC for LS. However, there is a paucity of data related to Lynch syndrome in the underserved population, in which unique issues of access, cultural beliefs regarding cancer, language barriers, immigration status, and financial restraints exist. We performed a descriptive, retrospective review of a selective LS screening protocol at an urban safety net hospital between 2009 and 2014 with the aim of describing the detected prevalence of LS as well as reporting the high quality and suboptimal screening rates. A total of 154 cases of CRC were identified over the 5-year period, of which 57 met selective LS screening criteria. Eleven patients had a positive screen, and three patients were diagnosed with LS, leading to an overall detected LS prevalence of 1.9%. The rate of high quality screen was greater than 90%, consistent with prior studies. Thus, we show that screening for LS in a safety net hospital can be successful in achieving high quality screening and provide an example for other public hospitals considering implementation of hereditary cancer screening.

Microsatellite Instability in Colorectal Cancers by Race and Hispanic Ethnicity Group

Microsatellite instability (MSI) is found in nearly all Lynch syndrome colorectal cancers and in about half of serrated pathway cancers. Because serrated pathway cancer is more common, it produces about 80% of all microsatellite-unstable tumors. Current recommendations are to screen all colorectal cancers for MSI or failed expression of mismatch repair proteins. Positive tests for MSI or failure to express mismatch repair protein MLH1 should be followed by BRAF mutation tests or hypermethylation assays to …

Systematic immunohistochemical screening for Lynch syndrome in colorectal cancer: a single centre experience of 486 patients.

Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome. Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance. Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome. The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015. Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1, PMS2, MSH2 and MSH6, independent of clinical criteria. In the case of loss of MLH1, the somatic BRAF mutation V600E was assessed with molecular testing and/or immunohistochemistry. Clinical follow-up of potential Lynch syndrome carriers (patients with tumours showing loss of MLH1 expression with absence of BRAFV600E, loss of PMS2, MSH2 or MSH6) was evaluated. Of all patients (n = 486), loss of MMR protein expression was found in 73 (15.0%) tumours. Twenty-eight (6.0%) were classified as potential Lynch syndrome carriers. Of the genetically tested potential Lynch syndrome carriers (10 out of 28 patients), 40% were first diagnosed with Lynch syndrome. Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related. Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and, in MMR deficient cases, include clear recommendations for genetic counselling for all potential Lynch syndrome patients.

Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome.

People with a DNA mismatch repair (MMR) gene mutation have a substantially elevated risk of colorectal cancer (CRC) but the modifiers of this risk are not well established. We investigated the association between dietary supplement intake and CRC risk for carriers. This study included 1966 (56% female) carriers of an MMR gene mutation (719 MLH1, 931 MSH2, 211 MSH6 and 105 PMS2) who were recruited from the USA, Canada, Australia and New Zealand into the Colon Cancer Family Registry between 1997 and 2012. Information on lifestyle factors including supplement intake was collected at the time of recruitment. Using Cox proportional hazards regression weighted to correct for ascertainment bias, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between self-reported multivitamin, calcium and folic acid supplement intake and CRC risk. Of 744 carriers with CRC, 18%, 6% and 5% reported intake of multivitamin, calcium and folic acid supplements for at least 1 month, respectively, compared with 27%, 11% and 10% of 1222 carriers without CRC. After adjusting for identified confounding variables, a decreased CRC risk was associated with multivitam inintake for at least 3 years (HR 0.47, 95% CI 0.32-0.69) and calcium intake for at least 3 years(HR 0.42, 95% CI 0.23-0.74), compared with never users. There was no evidence of an association between folic acid supplement intake and CRC risk (P = 0.82). Intake of multivitamin and calcium supplements might be associated with a decreased risk of CRC for MMR gene mutation carriers.

CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome.

The implementation of regular colonoscopy programs has significantly decreased the mortality associated with colorectal cancer (CRC) in Lynch syndrome patients. However, interval CRCs in Lynch syndrome that remain undetected by colonoscopy still represent a substantial problem in the management of the syndrome. One possible reason of interval cancers could be a non-polypous pathway of cancer development. To examine the possibility of a non-polypous pathway of CRC development in Lynch syndrome, we analyzed the histological appearance of 46 Lynch syndrome-associated CRCs and compared them to 34 sporadic microsatellite unstable cancers. We observed that 25 (62.5%) out of 40 assessable Lynch syndrome-associated carcinomas lacked evidence of polypous growth, compared to 17 (50%) out of 34 sporadic MSI-H cancers. We detected CTNNB1 mutations in 8 (17.4%) out of 46 Lynch syndrome-associated cancers compared to 0 out of 34 sporadic MSI-H cancers (p=0.01). The majority of CTNNB1-mutant cancers presented with a histological appearance suggesting immediate invasive growth. Our results suggest that a distinct subgroup of CRCs in Lynch syndrome may in fact emerge from a non-polypous precursor, thus potentially explaining the phenomenon of interval cancers. Such a non-polypous precursor may be the recently described mismatch repair-deficient crypt focus, which remains invisible for the examiner during colonoscopy. This calls for considering the implementation of active, primary preventive measures in the management of Lynch syndrome. Future studies on pathogenic pathways and precursor lesions in Lynch syndrome are strongly encouraged, and the clinical efficacy of new prevention approaches should be evaluated in prospective clinical trials.

Rate of implementation of universal testing for Lynch Syndrome in a county hospital system.

533 Background: Lynch Syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal testing is recommended as a cost effective strategy for screening for LS in all patients with CRC diagnosed < 70 years of age. This has shown to be beneficial in clinical decision making and cancer surveillance of both the patient and at risk relatives. According to a study in 2012, 71% of NCI institutions were performing universal testing versus 15%-36% of programs in the community. The aim of our study was to determine the outcomes of Universal Testing for LS in CRC in a County Hospital System. Methods: IRB-approved retrospective chart review of all patients diagnosed with colorectal cancer from cancer registry at Harris County Hospital District from March 2010 to Dec 2013. Patients between 18-70 yr were included. We collected data on patient characteristics, universal testing [immunohistochemistry (IHC) at our institution], and LS diagnosis (confirmed with germline testing for mismatch repair gene) in our patient cohort diagnosed with CRC. Descriptive statistics were performed using t-test for continuous variables. Results: Overall, 430 patients had CRC diagnosis in our study period, and 54 years was median age of diagnosis. IHC was performed in 359/430 (83.4%) CRC cases. IHC was positive in overall 26/430 (6%) cases of CRC. LS was confirmed in 9/430 (2%) CRC cases. IHC was more often positive with CRC diagnosed in patients younger than 50 years than in patients 50 years or older (7.91% vs 3.09%; p = 0.04). Conclusions: Universal testing for screening of LS amongst patients with CRC can result in significant rates of detection. In this study we have shown that this is possible in a largely safety-net setting.

Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome

Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome

Genetic variants within the hTERT gene and the risk of colorectal cancer in Lynch syndrome.

Lynch syndrome is an inherited cancer-predisposing disorder caused by germline mutations in the DNA mismatch repair (MMR) genes but there is a high degree of variability in cancer risk observed among carriers, suggesting the existence of modifying factors. Our aim was to investigate variants within the hTERT gene as a potential colorectal cancer (CRC) risk modifier for MMR gene mutation carriers. We identified 1098 MMR gene mutation carriers (420 MLH1, 481 MSH2, 126 MSH6, 53 PMS2 and 18 EPCAM) from 330 families recruited from either family cancer clinics or population cancer registries of the Australasian Colorectal Cancer Family Registry between 1997 and 2012. Using weighted Cox regression after adjusting for ascertainment bias, we estimated associations between 23 SNPs within the hTERT gene and CRC risk. During 46,836 person-years observation, 392 (36%) carriers were diagnosed with CRC at a mean age of 42.2 (standard deviation 11.4) years. There was no evidence of association between any of the hTERT SNPs and CRC risk, overall and stratified by sex and MMR gene mutated, after adjustment for multiple testing. Our findings suggest no evidence for clinical utility of the SNPs within the hTERT gene in Lynch syndrome.

Gender-specific aspects of Lynch syndrome--an update

Approximately 3-5% of all colorectal cancers are based on a hereditary predisposition, of which Lynch syndrome is by far the most frequent hereditary cancer syndrome. Beside colorectal cancer Lynch-Syndrome is the most frequent predisposing hereditary cause of endometrial cancer and is also associated with gastric cancer, ovarian cancer, cancer of the urinary tract as well as several other cancers. Genetically Lynch syndrome is caused by a germline mutation in one of the so-called mismatch-repair-genes. Based on several epidemiological studies, increasingly differences in the penetrance of the different cancers occurring are associated with the affected gene and also gender of the patient have been reported. The lifetime risk of colorectal cancer for males with Lynch syndrome generally is significantly higher and the age of first manifestation significantly earlier compared to females. The difference is especially notable in men with a MSH6-mutation. Moreover, the lifetime risk for gastric, bladder, and urothelial cancer is much higher in males. Women with an MSH6 mutation have a much higher risk for endometrial (and ovarian) cancer than for colorectal cancer. In patients with Muir Torre syndrome again males are predominantly affected and almost all affected have a mutation in MSH2 rather than in any other MMR gene. This review is an update of the literature analyzing gen and gender specific aspects of Lynch syndrome. To date these associations are based on retrospective studies, that require confirmation in a prospective setting with large patient numbers in order to identify validated, individualized gene and gender screening recommendations in the future. Especially in a syndrome with multiple potential cancer targets, an intense yearly program comprising several invasive procedures has a negative effect on patient compliance.

Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome.

Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers. We included 1858 participants in the Colon Cancer Family Registry who had been found to have a pathogenic germline mutation in a MMR gene (carriers). We used weighted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. A total of 714 carriers (38%) were diagnosed with colorectal cancer at a mean age of 42.4 (standard deviation 10.6) years. A reduced risk of colorectal cancer was associated with aspirin use (for 1 month to 4.9 years: HR = 0.49, 95% CI = 0.27 to 0.90, P = .02; for ≥5 years: HR = 0.25, 95% CI = 0.10 to 0.62, P = .003) and ibuprofen use (for 1 month to 4.9 years: HR = 0.38, 95% CI = 0.18 to 0.79, P = .009; for ≥5 years: HR = 0.26, 95% CI = 0.10 to 0.69, P = .007), compared with less than one month of use. Our results provide additional evidence that, for MMR gene mutation carriers, use of aspirin and ibuprofen might be effective in reducing their high risk of colorectal cancer.

PWE-346 Lynch syndrome and application of the rcpath colorectal cancer dataset in the united kingdom

<h3>Introduction</h3> Lynch syndrome is estimated to cause over 1,000 cases of colorectal cancer in the UK every year. Individuals that have Lynch syndrome have a lifetime risk of developing colorectal cancer or other Lynch associated cancers of &gt;35%. Yet fewer than 5% of individuals with the condition have been diagnosed in the UK. The Royal College of Pathologists (RCPath) cancer dataset (July 2014) mandates the use of immunohistochemistry or other testing for molecular features of Lynch syndrome in colorectal cancer or Lynch associated cancer patients under the age of 50, at the time of diagnosis. Performing this type of screening test for Lynch syndrome identifies those at greater risk of recurrence as well as family members at extended risk through early cascade testing. <h3>Method</h3> The strategy was developed by Bowel Cancer UK with advice from the Medical Advisory Board of the charity. We identified all NHS hospital trusts in England, health boards in Scotland and Wales and health and social care trusts in Northern Ireland. A freedom of information (FOI) request was submitted to each of these bodies in which a number of questions were asked to establish whether they were implementing the RCPath core dataset requirement, with regard to mismatch repair (MMR) testing for Lynch syndrome. As this was an FOI request respondents were required to respond within 20 working days. <h3>Results</h3> In England, 78% of trusts responded, 100% responded in Scotland and Northern Ireland; one health board in Wales did not respond. In England and Scotland 50% of hospital trusts and health boards currently do not follow the RCPath cancer dataset. 4 health boards in Wales do not, and all health and social care trusts in Northern Ireland stated they perform MMR testing to identify suspected Lynch syndrome patients. In England only 28 of those that did not perform testing stated they were intending to implement the dataset and two in Wales. Scotland is in the process of developing a nationally agreed protocol for implementation of the dataset. We found that among trusts and health boards that do test for Lynch syndrome many do not yet have in place a systematic reflex service, as mandated by RCPath. <h3>Conclusion</h3> Our findings show that the RCPath dataset may have already had some impact on the application of MMR testing for Lynch syndrome in patients diagnosed under the age of 50. However there is considerable variation in approach. We recommend that: England and Wales carry out a nationwide initiative to look at ways of delivering a consistent approach to reflex testing for Lynch syndrome; that all CCGs commission to reflect the RCPath cancer dataset thus ensuring providers are compliant with the dataset. <h3>Disclosure of interest</h3> None Declared.

Morphological, molecular and genetic study of MMR-deficient colorectal cancer: Contribution of somatic tools in diagnosis of Lynch syndrome.

e14629 Background: Lynch syndrome (LS) is the most frequent inherited colorectal cancer (CRC) syndrome, due to germline mutations in one of the mismatch repair (MMR) genes. Out of the 15% of CRCs associated with deficient DNA mismatch repair system (dMMR) that are characterized by high levels of microsatellite instability (MSI-H), only 3% are attributable to Lynch syndrome. The other 12% are sporadic, with acquired dMMR phenotype caused in tumors by hypermethylation of the promoter of gene hMLH1, often associated with BRAF V600E mutation. A probably underestimated group does not respond to any of these definitions and is called Lynch-like syndrome (LLS). The aim of the study was to compare the pathological and clinical features of the LS, LLS, and sporadic CRCs and to evaluate the contribution of somatic tools to the screening of potential LS patients. Methods: Two hundred and twelve patients with a dMMR CRC were included. The clinical, surgical, pathological and genetic data were retrieved. A complete MM...

Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome

Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome

Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer.

Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch-like syndrome (LLS). v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1-deficient CRCs. In total, 165 CRCs were analyzed, including LS (n = 19), MSI BRAF-mutated CRC (n = 37), MSI BRAF wild-type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). MLH1 promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed. The average ± standard deviation methylation in LS (9% ± 7%) was significantly lower than that in MSI BRAF-mutated CRC (42% ± 17%; P < .001) and in MSI BRAF wild-type CRC (25% ± 19%; P = .002). Somatic MLH1 hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI BRAF-mutated CRC, and in 37 patients (61.7%) with MSI BRAF wild-type tumors. Patients with MSI BRAF wild-type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with MLH1 methylation (P < .05). The sensitivity for ruling out LS was 100% for BRAF analysis, 84.2% for MLH1 methylation analysis, and 84.2% for the combination of both analyses. Somatic MLH1 promoter methylation occurs in up to 15% of LS CRCs. Somatic BRAF analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS.

A Single Institution Experience in Compliance with Universal Screening for Lynch Syndrome in Colorectal Cancer

BackgroundDetection of Lynch syndrome has the potential to reduce morbidity and mortality among patients and their family members due to beneficial screening and treatment options. Several institutions have begun to adopt universal rather than risk-stratified screening protocols, but the lack of 100 % compliance rates requires identification of system-level interventions to improve screening practices. ObjectiveWe aimed to identify patient, tumor, and system factors associated with lack of screening and identify system-based interventions to improve Lynch syndrome screening. Design and SettingsThis study is a retrospective analysis of Lynch syndrome screening among colorectal cancer patients undergoing surgery in a single healthcare system. PatientsTwo hundred and sixty-two patients who underwent surgery for colorectal cancer were studied. Main Outcome MeasuresRate of Lynch syndrome screening. ResultsWe identified that 75 % of the total cohort was screened for Lynch syndrome. Of patients under the age of 50, 78 % percent were screened. Lower screening rates were found among patients with complete pathologic tumor response and lower pathologic stage of tumor. Higher screening rates were found at the academic hospital and with colorectal surgeons. In multivariable logistic regression analysis, lower screening rates were associated with community hospital location (OR, 0.22; 95 % CI, 0.08–0.56). LimitationsResults may not be generalizable to different hospital settings. ConclusionsSeveral potential system-level interventions were identified to improve screening rates including an emphasis on improved provider communication.

Is it all Lynch syndrome?: An assessment of family history in individuals with mismatch repair-deficient tumors.

Background & AimsMismatch repair deficient (MMRD) colorectal (CRC) and endometrial (EC) cancers may be suggestive of Lynch syndrome (LS). LS can only be confirmed by positive germline testing. It is unclear if individuals with MMRD tumors but no identifiable cause (MMRD+/germline−) have LS. As LS is hereditary, individuals with LS are expected to have family histories of LS-related tumors. Our study compared the family histories of MMRD+/germline− CRC and/or EC patients to LS CRC and/or EC patients.Methods253 individuals with an MMRD CRC or EC from one institution were included in analysis in 1 of 4 groups: LS, MMRD+/germline−, MMRD+/VUS, sporadic MSI-H (MMRD tumor with MLH1 promoter hypermethylation or BRAF mutation). Family histories were analyzed utilizing MMRpro and PREMM1,2,6. Kruskal-Wallis tests were used to compare family history scores.ResultsMMRD+/germline− individuals had significantly lower median family history scores (MMRpro=8.1, PREMM1,2,6=7.3) than LS individuals (MMRpro=89.8, PREMM1,2,6=26.1, p<0.0001).ConclusionMMRD+/germline− individuals have less suggestive family histories of LS than individuals with LS. These results imply that MMRD+/germline− individuals may not all have LS. This finding highlights the need to determine other causes of MMRD tumors so that these patients and their families can be accurately counseled regarding screening and management.