Gender-Specific Aspects of Lynch Syndrome and Familial Adenomatous Polyposis

Schneider, R.; Schneider, Claudia; Jakobeit, Christian; Fürst, Alois; Möslein, Gabriela

doi:10.1159/000360839

Cited by 10 publications

(10 citation statements)

References 40 publications

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“…Using the tumour-specific LR s to estimate variant TCLRs , the proportion of predicted VUS based on MVP+ TCLR pred model increased (online supplementary figure S5). Interestingly, we also observed higher MSI/IHC LRs in patients with younger diagnosis age (online supplementary table S8), which is consistent with previously reported higher cancer risks in patients with early-onset cancer,38 39 although the application of TCLR stratified by diagnosis age yielded a high AUC and predicted clinical significance for 62.7% of VUS, similar to results among all patients (online supplementary figure S5 and S6). Similarly, high AUCs and increased proportion of reclassified VUS based on MVP+ TCLR pred model were observed using gene-specific LRs (online supplementary figure S5 and S7).…”

Section: Discussionsupporting

confidence: 91%

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity

Qian

Thompson

et al. 2019

J Med Genet

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BackgroundPathogenic variants in mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes.MethodsAmong 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance of TCLR in combination with in silico predictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed.ResultsCompared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (p<0.0001). Among 150 classified missense variants, 73.3% were accurately predicted with TCLR alone. Models leveraging in silico scores as prior probabilities accurately classified >76.7% variants. Adding TCLR as quantitative evidence in an MVP model (MVP +TCLRPred) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP +TCLRPred resulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.ConclusionOur study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management.

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Section: Discussionsupporting

confidence: 91%

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity

Qian

Thompson

et al. 2019

J Med Genet

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“…Combined, these syndromes account for only 5% of all CRC cases. Lynch syndrome/hereditary non-polyposis colorectal cancer (HPNCC) and familial adenomatous polyposis (FAP), have been reported to present a significant gender gap in associated CRC risk ( 245 ). With Lynch syndrome/HPNCC females have a cumulative CRC lifetime risk of 30%, whereas men have a risk of 54%.…”

Section: Genetic Sexual Differentiation In Crcmentioning

confidence: 99%

“…As mentioned above, certain hereditary syndromes, such as Lynch syndrome and FAP, are associated with higher risk of developing CRC but that risk displays a significant gender gap. Lynch syndrome/HPNCC females have a cumulative CRC lifetime risk of 30%, whereas men have a risk of 54% ( 245 ). Based on this evidence, it is timely to suggest not only gene but sex-based adapted screening and surgical recommendations for both syndromes.…”

Section: Gender Gap In Crcmentioning

confidence: 99%

Sexual Dimorphism in Colon Cancer

et al. 2020

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A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18–44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.

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“…HNPCC mostly affects the proximal part of the colon in 70% of cases and in the remaining 30%, its localization is sporadic. According to our observation, HNPCC occurring in younger patients (age, <45 years) tends to involve the proximal areas and sporadic areas in older patients (age >65 years) ( 11 , 12 ). The average age of Lynch syndrome-associated CRC manifestation is 45 years, which is~20 years lower than in the sporadic counterpart ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 72%

“…According to our observation, HNPCC occurring in younger patients (age, <45 years) tends to involve the proximal areas and sporadic areas in older patients (age >65 years) ( 11 , 12 ). The average age of Lynch syndrome-associated CRC manifestation is 45 years, which is~20 years lower than in the sporadic counterpart ( 11 , 12 ). A study by Lindor et al ( 13 ) reported that >40% of HNPCCs were located on the proximal areas rather than having a sporadic location.…”

Section: Introductionmentioning

confidence: 72%

Efficacy, functional outcome and post‑operative complications of total abdominal colectomy with ileorectal anastomosis vs. segmental colectomy in hereditary non‑polyposis colorectal cancer

2018

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The primary objective of the present study was to compare the choice of colectomy, i.e. total vs. segmental colectomy, in cases of hereditary non-polyposis colorectal cancer (HNPCC/lynch syndrome), and to assess the efficacy, oncological safety, functional outcome and post-operative complications of total abdominal colectomy with ileorectal anastomosis vs. segmental colectomy in HNPCC. A total of 289 patients who fulfilled the Amsterdam I and II criteria for HNPCC were included in the present study. The criteria for confirmation of the diagnosis were five micro-satellite markers, namely BAT25, BAT26, D2s123, d5S346 and D17S250. Group 1 included those patients who received their diagnosis in the years 2011–2013 and those in group 2 had been diagnosed in the years 2014–2016. The cohort had been subjected to two different types of surgery: i) Standard and extended surgery including total colectomy with ileal pouch anal anastomosis and subtotal colectomy and ii) segmental resection of the colon. Analysis of patient data indicated that in group 1, the extended resection was performed more frequently than in group 2 (68 vs. 34% of cases) and accordingly, segmental resection was less frequent (32 vs. 66%; P<0.001). In conclusion, the extensive rather than the segmental resection has been commonly performed several years ago, but at present, the surgical method of choice in cases of lynch syndrome is segmental resection. Trial registry no. QU/MR2011/CRC5, dated 21 March 2011.

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Gender-Specific Aspects of Lynch Syndrome and Familial Adenomatous Polyposis

Cited by 10 publications

References 40 publications

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity

Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity

Sexual Dimorphism in Colon Cancer

Efficacy, functional outcome and post‑operative complications of total abdominal colectomy with ileorectal anastomosis vs. segmental colectomy in hereditary non‑polyposis colorectal cancer

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