MSH2 Mutation Carriers Research Articles

Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesis

Lynch syndrome (LS) is one of the most common hereditary cancer syndromes worldwide. Dominantly inherited mutation in one of four DNA mismatch repair genes combined with somatic events leads to mismatch repair deficiency and microsatellite instability (MSI) in tumours. Due to a high lifetime risk of cancer, regular surveillance plays a key role in cancer prevention; yet the observation of frequent interval cancers points to insufficient cancer prevention by colonoscopy-based methods alone. This study aimed to identify precancerous functional changes in colonic mucosa that could facilitate the monitoring and prevention of cancer development in LS. The study material comprised colon biopsy specimens (n=71) collected during colonoscopy examinations from LS carriers (tumour-free, or diagnosed with adenoma, or diagnosed with carcinoma) and a control group, which included sporadic cases without LS or neoplasia. The majority (80%) of LS carriers had an inherited genetic MLH1 mutation. The remaining 20% included MSH2 mutation carriers (13%) and MSH6 mutation carriers (7%). The transcriptomes were first analysed with RNA-sequencing and followed up with Gorilla Ontology analysis and Reactome Knowledgebase and Ingenuity Pathway Analyses to detect functional changes that might be associated with the initiation of the neoplastic process in LS individuals. With pathway and gene ontology analyses combined with measurement of mitotic perimeters from colonic mucosa and tumours, we found an increased tendency to chromosomal instability (CIN), already present in macroscopically normal LS mucosa. Our results suggest that CIN is an earlier aberration than MSI and may be the initial cancer driving aberration, whereas MSI accelerates tumour formation. Furthermore, our results suggest that MLH1 deficiency plays a significant role in the development of CIN. The results validate our previous findings from mice and highlight early mitotic abnormalities as an important contributor and precancerous marker of colorectal tumourigenesis in LS. This work was supported by grants from the Jane and Aatos Erkko Foundation, the Academy of Finland (330606 and 331284), Cancer Foundation Finland sr, and the Sigrid Jusélius Foundation. Open access is funded by Helsinki University Library.

PD46-06 UROLOGICAL FOLLOW-UP AND MUTATIONAL PATTERNS IN LYNCH SYNDROME PATIENTS: A SINGLE CENTER EXPERIENCE

You have accessJournal of UrologyCME1 Apr 2023PD46-06 UROLOGICAL FOLLOW-UP AND MUTATIONAL PATTERNS IN LYNCH SYNDROME PATIENTS: A SINGLE CENTER EXPERIENCE Pietro Scilipoti, Mattia Longoni, Chiara Re, Giuseppe Rosiello, Alessandro Bertini, Mario de Angelis, Giorgio Gandaglia, Eugenio Ventimiglia, Umberto Capitanio, Andrea Salonia, Francesco Montorsi, Alberto Briganti, and Marco Moschini Pietro ScilipotiPietro Scilipoti More articles by this author , Mattia LongoniMattia Longoni More articles by this author , Chiara ReChiara Re More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alessandro BertiniAlessandro Bertini More articles by this author , Mario de AngelisMario de Angelis More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Eugenio VentimigliaEugenio Ventimiglia More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , and Marco MoschiniMarco Moschini More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003359.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lynch Syndrome (LS) is a genetic dominant autosomal disease that predisposes to a broad spectrum of tumors, among which Upper Tract Urothelial Carcinoma (UTUC) is the third most common manifestation. We present the first results of our LS dedicated outpatient clinic with the aim of evaluating the incidence of UTUC, patterns of mutation and individuate the optimal follow up schemes among patients affected by LS. METHODS: We observed 23 LS patients from December 2021 to October 2022 at a tertiary referral center. We collected prospectively data regarding LS mutations, medical and family history and simultaneously started a strict follow up strategy. Genetic diagnosis was obtained both by Immunohistochemistry (IHC) and by genetic test (DNA sequencing). For each patient we applied Bethesda, EAU guidelines, Amsterdam I and II criteria. Follow up strategy was based on Ultrasound (US), urinalysis and urinary citology every two years. In high-risk cases (age >50 years, MSH2 mutation carriers and family history of UTUC) CT-scans where alternated with US every year in addition to urinary citology. RESULTS: Among this court 52.2% of patients (n=12) had a LS diagnosis after cancer manifestation, meanwhile 47.8% (n=11) through genetic counseling due to investigation in first degree relatives. Among our patient population, 8 patients (34.8%) had a diagnosis of colorectal cancer, 4 (17.4%) UTUC, 1 (4.3%) endometrial, 1 (4.3%) gastric, 1 (4.34%) skin cancer and 2 rare LS related cancer (Renal Clear Cell Carcinoma and Lung Cancer). MSH2 mutation was detected in 39.1% of cases (n=9), while MLH1 was found in 34.8% of cases (n=8). In subgroup analysis colorectal cancer's most common mutation was MSH2 (50%) followed by MLH1 (25%) and MSH6 (25%), while among UTUC cases, MSH2 was the most common (75%) and MLH1 was reported in 25% of cases. Median age at UTUC diagnosis was 60, while median age at colorectal cancer diagnosis was 49 (p=0.007). Bethesda and EAU guidelines criteria were more accurate (91% vs 90%) compared to Amsterdam I and II criteria (74%). No tumor diagnosis was made during the observational time. CONCLUSIONS: The current study is a first attempt to establish a dedicated LS outpatient clinic. This will let us observe the most frequent mutations, thus potentially in the future allow us to diagnose UTUC earlier and provide a refined follow up to LS patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1172 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pietro Scilipoti More articles by this author Mattia Longoni More articles by this author Chiara Re More articles by this author Giuseppe Rosiello More articles by this author Alessandro Bertini More articles by this author Mario de Angelis More articles by this author Giorgio Gandaglia More articles by this author Eugenio Ventimiglia More articles by this author Umberto Capitanio More articles by this author Andrea Salonia More articles by this author Francesco Montorsi More articles by this author Alberto Briganti More articles by this author Marco Moschini More articles by this author Expand All Advertisement PDF downloadLoading ...

Risk of Gastric Cancer and Utility of Endoscopic Screening for Lynch Syndrome Patients

Background: Lynch syndrome (LS) is an autosomal dominant hereditary condition associated with a genetic predisposition to several cancers. Prior studies have shown an increased risk of gastric cancer (GC) in LS patients. The aim of this study was to synthesize the evidence for gastric cancer risk across Lynch syndrome-associated mutations and to assess the diagnostic utility of endoscopic screening for gastric cancer in these patients. Methods: A systematic literature review and meta-analysis of LS-associated gastric cancer risk and the diagnostic utility of endoscopic gastric cancer screening was conducted in accordance with PRISMA guidelines and GRADE methodology. Results: The results of this study found an elevated risk of GC in LS patients. Cumulative lifetime risk of GC in LS patients ranged from 2.6% to 38.7% when assessing across all LS mutations. Cumulative incidence ranged from 2.0% to 41.0%. When assessing cumulative incidence across specific LS mutations, MSH2 mutation carriers showed the highest cumulative incidence. RR across specific mutation carriers was generally highest in MSH2 carriers. A meta-analysis of 5 studies reporting diagnostic utility of endoscopic screening for gastric cancer in LS patients revealed a 2% incidence of GC (95% CI, 1.4%−2.9%). Conclusions: Gastric cancer risk in LS patients is greater than in the general population. Endoscopic screening yields low rates of GC in LS patients. Higher quality studies including RCTs are required to more accurately define GC risk and the yield of endoscopic surveillance in LS patients.

Extracolonic tumours in a pedigree with EPCAM-related Lynch Syndrome

Lynch Syndrome is characterized by phenotypic and genotypic heterogeneity. Despite scarce evidence, individuals with an EPCAM deletion appear to have a comparable risk of colorectal cancer (CRC) as MSH2 mutation carriers, but a lower risk of extracolonic cancer (such as endometrial cancer) unless the deletion extends close to the promoter of MSH2.A genotype-phenotype correlation is yet to be established for EPCAM alterations. In this report, we describe a family with EPCAM deletion characterized by a particularly aggressive phenotype and extracolonic cancer.We present a family with 5 members carrying an EPCAM deletion encompassing exons 8 and 9. Three female family members presented CRC at the ages of 32, 44 and 60 (mucinous moderately and well-differentiated adenocarcinoma); in two of them metachronous colon cancers and advanced adenomas were diagnosed in the intensive surveillance program.Two female patients (42 and 63 years-old) presented with gastric cancer (GC). Two patients presented with small bowel cancer at 51 and 60 years-old - the first one presented a metachronous jejunal cancer at 68 years. Only one family member was submitted to hemithyroidectomy due a right-lobe Hürthle cell carcinoma at 56 years-old.This report illustrates the existence of intrafamilial clinical heterogeneity among carriers of this EPCAM alteration, and hence the difficulty in predicting phenotype for EPCAM-associated Lynch syndrome.

Risk of first onset of colorectal cancer associated with alcohol consumption in Lynch syndrome: a multicenter cohort study.

Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site. Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC. Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer). Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.

Colorectal Cancer Risk in Lynch Syndrome: Of Genes and More

Colorectal Cancer Risk in Lynch Syndrome: Of Genes and More

Risk-Reducing Bilateral Salpingo-Oophorectomy for Ovarian Cancer: A Review and Clinical Guide for Hereditary Predisposition Genes.

Pathogenic germline variants underlie up to 20% of ovarian cancer (OC) and are associated with varying degrees of risk for OC. For mutations in high-penetrance genes such as BRCA1/2, the role of risk-reducing bilateral salpingo-oophorectomy (RRSO) in cancer prevention is well-established and improves mortality. However, in moderate-penetrance genes where the degree of risk for OC is less precisely defined, the role of RRSO is more controversial. Although national guidelines have evolved to incorporate gene-specific recommendations, studies demonstrate significant variations in practice. Given this, our multidisciplinary group has reviewed the available literature on risk estimates for genes associated with OC, incorporated levels of evidence, and set thresholds for consideration of RRSO. We found that the benefit of RRSO is well-established for pathogenic variants in BRCA1/2 as well as BRIP1 and RAD51C/D where the risk of OC is elevated beyond our threshold for RRSO. In PALB2, RRSO is particularly controversial as newer studies consistently demonstrate an increased risk of OC that is dependent on family history, making uniform recommendations challenging. Additionally, new guidelines for Lynch syndrome provide gene-specific risks, questioning the role of RRSO, and even hysterectomy, for MSH6 and PMS2 mutation carriers. Given these uncertainties, shared decision making should be used around RRSO with discussion of individual risk factors, family history, and adverse effects of surgery and premature menopause. Herein, we provide a clinical guide and counseling points.

PMS2 is the most frequently mutated Lynch syndrome (LS) gene in women with endometrial cancer (EC): what is the role that low penetrance LS genes play in EC?

Objectives: To determine the frequency and spectrum of LS pathogenic variants in EC patients using upfront germline testing for cancer susceptibility. Secondary objectives included determining the sensitivity and specificity of current LS screening. Methods: Women diagnosed with EC were prospectively enrolled at 9 institutions. Clinical germline testing (panel testing for common cancer susceptibility genes) was performed for 840 unselected EC patients between 10/1/2017 and 10/1/2020. Mismatch repair (MMR) IHC, MLH1 methylation status and relevant clinicopathologic data were abstracted from patients’ records. Detailed family history data were obtained for all subjects. Results: Germline testing revealed 26 of 840 EC patients (3.1%) had a pathogenic/likely pathogenic MMR gene mutation. Mutations in PMS2 were most frequent (10/26, 38%), followed by MSH6 (8/26, 31%), MSH2 (6/26, 23%), and MLH1 (2/26, 8%). Mean BMI for PMS2 carriers was greater than other mutation carriers (31.3 vs 27.8). Age at diagnosis was also higher for PMS2 carriers (59 vs 52). IHC combined with MLH1 methylation correctly predicted LS for all MLH1 and MSH2 mutation carriers. For MSH6 and PMS2, IHC and germline mutation status concordance was lower. Only 4/9 (44%) PMS2 carriers had isolated PMS2 loss. IHC was not completed for one PMS2 carrier (insufficient tumor). IHC correctly predicted MSH6 mutations in 7/8 (88%) carriers. Family history did not predict LS for PMS2 carriers: using PREMM5 (LS prediction model), all had low ( Conclusions: This is the largest cohort of prospectively enrolled EC patients to undergo germline genetic testing in an unselected manner, irrespective of patient age, family history or tumor results. It shows that a majority of LS mutations in EC are in the low-penetrance genes, MSH6 and PMS2. PMS2 mutations were the most common, 10/840 (1.2%). Universal screening with IHC would have missed three PMS2 carriers and one MSH6 carrier. Accurate identification of patients with MMR defects is critical not only for identification of LS, but potentially in consideration of treatment options. In the past, ascertainment of LS relied largely on a strong family cancer history, which is most often seen with MLH1 and MSH2 mutations. For all PMS2 carriers in our study, family history was not predictive of LS and the proband's EC diagnosis was the sentinel event leading to a LS diagnosis in the family. Our study may highlight an evolving LS phenotype in which gene/environment interactions are changing. The observation that EC patients with PMS2 mutations have higher BMIs leads us to hypothesize the existence of an obesity-mediated pathway important in PMS2-associated EC. It may be that in the general population, PMS2 mutation carriers face higher risks for EC than colon cancer.

Lynch Syndrome: Its Impact on Urothelial Carcinoma.

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.

Cancer-risk by family history and mismatch-repair mutation in Lynch syndrome

Introduction: Surveillance of Lynch syndrome (LS) is recommended to reduce cancer-risk. There is an increased awareness that cancer-risk may vary with mismatch-repair mutation and family history. However, gene-specific and family-specific surveillance are not recommended. Therefore, we aimed to estimate the cumulative incidence of lesions and to assess the cancer-risk by family history and mismatch-repair mutation (MMR).Methods: Single-centre retrospective cohort of all individuals (n = 241) in a specialized institution was conducted.Results: Forty-eight percent of individuals inherited MSH2 mutations, 32% MLH1, 15% MSH6 and 5% PMS2. The calculated cumulative incidence for any cancer increased with age. By age 70, the cumulative incidence for low-risk, high-risk adenomas and CRC was estimated at 66.6%, 57.7% and 25.7%, respectively. By age 70, the cumulative incidence of endometrial cancer (EC), gastric cancer and urinary tract cancer was estimated at 17.3%, 3.3% and 12.6%, respectively. MLH1 and MSH2 mutation carriers had lower mean age of CRC diagnosis than MSH6 and PMS2 [MLH1:44(CI95% 38–50); MSH2:43(CI95% 40–47); MSH6:52(CI95% 45–59); PMS2:46(CI95% 35–57)]. The risk of EC was higher when family history was present (RR = 2.39, CI95%[1.3;4.6]). MSH6 mutation carriers had higher risk of EC comparative to other MMR mutation carriers (RR = 1.9, p = .09). The risk of urinary tract cancer was higher with MSH2 (RR = 8.4, CI95%[2.7;25.9]) and positive family history (RR = 10.8, CI95%[1.4;82.8]).Conclusion: This cohort demonstrates the effectiveness of LS surveillance and suggests possible tailored surveillance strategies by gene mutation and family history.

Endoscopic management of Lynch syndrome and of familial risk of colorectal cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

ESGE recommends that individuals with Lynch syndrome should be followed in dedicated units that practice monitoring of compliance and endoscopic performance measures.Strong recommendation, low quality evidence, level of agreement 100 %.ESGE recommends starting colonoscopy surveillance at the age of 25 years for MLH1 and MSH2 mutation carriers and at the age of 35 years for MSH6 and PMS2 mutation carriers.Strong recommendation, moderate quality evidence, level of agreement 100 %. ESGE recommends the routine use of high-definition endoscopy systems in individuals with Lynch syndrome. Strong recommendation, high quality evidence, level of agreement 100 %. ESGE suggests the use of chromoendoscopy may be of benefit in individuals with Lynch syndrome undergoing colonoscopy; however routine use must be balanced against costs, training, and practical considerations.Weak recommendation, moderate quality evidence, level of agreement 89 %.ESGE recommends definition of familial risk of colorectal cancer as the presence of at least two first-degree relatives with colorectal cancer or at least one first-degree relative with colorectal cancer before the age of 50 years.Strong recommendation, moderate quality evidence, level of agreement 92 %.ESGE recommends colonoscopy surveillance in first-degree relatives of colorectal cancer patients in families that fulfill the definition of familial risk of colorectal cancer.Strong recommendation, moderate quality evidence, level of agreement 100 %.

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels.

Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized predefined panels according to clinical suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of opportunistic testing of BRCA1/2 and mismatch repair (MMR) genes in all patients. A total of 1,205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using panel testing. Overall, 1,048 females and 157 males were analyzed, mean age at cancer diagnosis was 48; 883 had hereditary breast/ovarian cancer-suspicion, 205 hereditary nonpolyposis colorectal cancer (HNPCC)-suspicion, 73 adenomatous-polyposis-suspicion and 44 with other/multiple clinical criteria. At least one PV was found in 150 probands (12%) analyzed by our customized phenotype-driven panel. Tumoral MMR deficiency predicted for the presence of germline MMR gene mutations in patients with HNPCC-suspicion (46/136 vs. 0/56 in patients with and without MMR deficiency, respectively). Opportunistic testing additionally identified five MSH6, one BRCA1 and one BRCA2 carriers (0.6%). The analysis of the extended 24-gene panel provided 25 additional PVs (2%), including in 4 out of 51 individuals harboring MMR-proficient colorectal tumors (2 CHEK2 and 2 ATM). Phenotype-based panels provide a notable rate of PVs with clinical actionability. Opportunistic testing of MMR and BRCA genes leads to a significant straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility within a standard genetic counseling framework.

Metachronous colorectal cancer risk in Lynch syndrome patients-should the endoscopic surveillance be more intensive?

Regular follow-up for patients with Lynch syndrome (LS) is vital due to the increased risk of colorectal (50-80%), endometrial (40-60%), and other cancers. However, there is an ongoing debate concerning the best interval between colonoscopies. Currently, no specific endoscopic follow-up has been decided for LS patients who already have an index colorectal cancer (CRC). The aim of this study was to evaluate the risk of metachronous cancers (MC) after primary CRC in a LS population and to determinate if endoscopic surveillance should be more intensive. A prospective cohort of patients with a confirmed diagnosis of hereditary CRC since 2009 was included. Patients with LS and a primary CRC were the cohort of choice. One hundred twenty-one patients were included with a median age of 44years(16-70). At least one MC occurred in 39 patients (32.2%), with a median interval of 67months (6-300) from index cancer. Fifteen (38.5%) developed two or more MCs during follow-up, with a median number of two (2-6) tumors occurring. Metachronous CRC were diagnosed after a median interval of 24 (6-57) months since last colonoscopy and were more commonly seen in MSH2 mutation carriers (58 vs. 35%, p = 0.001). After a median follow-up of 52.9 (3-72) months, no cancer-related deaths were recorded. Patients with LS have an increased risk of MC, especially CRCs. With a median time period of 24months between colonoscopy and metachronous CRC, the interval between surveillance colonoscopies following primary CRC should not exceed 18months, especially in patients with MSH2 mutation.

Risk of colorectal polyps and of malignancies in asymptomatic carriers of mutations in the main DNA mismatch repair genes

Objective: Mutation carriers (Mut+) in DNA mismatch repair genes are predisposed to cancer of various organs and to adenomatous polyps; however, they may remain asymptomatic and cancer or polyp-free for several years. We purposed to analyse the clinical follow-up of individuals carrying constitutional mutations in the MLH1, MSH2 or MSH6 genes who were unaffected by benign polyps or malignant tumours at diagnosis.Material and Methods: Mut + subjects (n.81) were members of Lynch syndromes in whom mutations were detected between 1993 and 2015; all were asymptomatic at diagnosis. They were informed of the cancer risk and surveillance was suggested. As controls, 113 nongene carriers (Mut−) in the same Lynch families were identified.Results: About one-fourth of the mutation carriers developed polyps, mostly adenomas; polyps were less (12%, p < .05) in Mut − subjects, and hyperplastic lesions were the prevalent histology. More polyps were detected in MLH1 vs. MSH2 mutation carriers. In Mut+, 21 malignant tumours developed in 14 carriers vs. 4 tumours in 3 patients among Mut− (p < .001). Tumours were mostly of the Lynch spectrum; however, three glioblastomas were developed, together with neoplasms of various organs (duodenum, thyroid, skin, lung and cervix). Mean age of tumour occurrence was 43.0 years in Mut + vs. 53.0 among Mut−.Conclusions: Cancer developed more often in Mut+, with no consistent difference between MLH1 and MSH2 carriers. More polyps (mostly adenomas) were detected in MLH1 carriers. The majority (13 of 21) of malignant tumours occurred in organs for which there is no recommended surveillance, and were lethal in three patients.

Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers

Until recently, no prediction models for Lynch syndrome (LS) had been validated for PMS2 mutation carriers. We aimed to evaluate MMRpredict and PREMM5 in a clinical cohort and for PMS2 mutation carriers specifically. In a retrospective, clinic-based cohort we calculated predictions for LS according to MMRpredict and PREMM5. The area under the operator receiving characteristic curve (AUC) was compared between MMRpredict and PREMM5 for LS patients in general and for different LS genes specifically. Of 734 index patients, 83 (11%) were diagnosed with LS; 23 MLH1, 17 MSH2, 31 MSH6 and 12 PMS2 mutation carriers. Both prediction models performed well for MLH1 and MSH2 (AUC 0.80 and 0.83 for PREMM5 and 0.79 for MMRpredict) and fair for MSH6 mutation carriers (0.69 for PREMM5 and 0.66 for MMRpredict). MMRpredict performed fair for PMS2 mutation carriers (AUC 0.72), while PREMM5 failed to discriminate PMS2 mutation carriers from non-mutation carriers (AUC 0.51). The only statistically significant difference between PMS2 mutation carriers and non-mutation carriers was proximal location of colorectal cancer (77 vs. 28%, p < 0.001). Adding location of colorectal cancer to PREMM5 considerably improved the models performance for PMS2 mutation carriers (AUC 0.77) and overall (AUC 0.81 vs. 0.72). We validated these results in an external cohort of 376 colorectal cancer patients, including 158 LS patients. MMRpredict and PREMM5 cannot adequately identify PMS2 mutation carriers. Adding location of colorectal cancer to PREMM5 may improve the performance of this model, which should be validated in larger cohorts.

Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry

BackgroundPrevious studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This...

MSH6 and PMS2 Mutation Carriers Ascertained Through Multi-gene Panel Testing May Present With a Hereditary Breast and Ovarian Cancer Phenotype

MSH6 and PMS2 Mutation Carriers Ascertained Through Multi-gene Panel Testing May Present With a Hereditary Breast and Ovarian Cancer Phenotype

MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome.

Heredity is a major risk factor for colorectal cancer (CRC). Identification of individuals and families at increased risk allows for targeted surveillance, which has been shown to reduce morbidity and mortality from CRC (1, 2). Lynch syndrome is a multi-tumor syndrome with particularly high risks for colorectal, endometrial, and ovarian cancer (3–6). The syndrome is caused by germline DNA-mismatch repair (MMR) gene mutations with major contributions from MLH1 (MIM#120436) (42%), MSH2 (MIM#609309) (33%), MSH6 (MIM#600678) (18%), and PMS2 (MIM#600259) (8%). Only about one-third of the Lynch syndrome families fulfill the Amsterdam criteria (AC) (7–9). The cumulative incidence of any cancer at 70 years of age is 72% for MLH1 and MSH2 mutation carriers but lower in MSH6 (52%) and PMS2 (18%) mutation carriers. MSH6 and PMS2 carriers developed no cancers before 40 years of age (10). Mutation screening in a relatively large proportion of South American families with suspected Lynch syndrome has recently identified 99 disease-predisposing mutations in MLH1 and MSH2, which mutation spectrum is predominated by MLH1 (60%) and MSH2 (40%). Among the reported mutations, genetic hot-spot regions, new and potential founder mutations have been described in the South American population (11, 12). Several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in at least 15 independent loci associated with CRC risk (odds ratio ranging from 1.10 to 1.26 per risk allele) (13–15). Although there is no evidence that these SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall and therefore any evidence of proven clinical utility in Lynch syndrome (16). The MLH1 Ile219Val (rs1799977) is a common germline alteration, located in exon 8 at the nucleotide 655. This polymorphism has been described in a high frequency of the South American Lynch syndrome population, but no modifier effect of CRC risk and MMR disease-predisposing mutation carriers was observed (17). However, it has been reported to confer a twofold-increased risk of CRC development in sporadic Mexican patients (18). Other conditions that have been associated with this polymorphism include childhood acute lymphoblastic leukemia, breast cancer, radiation-induced rectal or bladder toxicity, and ulcerative colitis (19–23). It is unknown whether the MLH1 Ile219Val polymorphism has an effect on cancer risk and in the MMR capacity in Argentinean families with suspected Lynch syndrome. Thus, we aim to determine its frequency, its correlation with disease-predisposing MMR gene mutations, and to delineate the clinical characteristics from these families.

Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database

ObjectiveEstimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates...

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