Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome.
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ABSTRACT:
SUBMITTER: Brouwer JGM
PROVIDER: S-EPMC8210745 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations.MethodsWe obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period-specific standardized incidence ratios (SIRs) for each cancer, compared with the general population.ResultsFollowing endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14).ConclusionsWomen with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer.
| S-EPMC3576323 | biostudies-literature
Project description:BACKGROUND:Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population. METHODS:Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX. RESULTS:The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX. CONCLUSIONS:The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
| S-EPMC7245918 | biostudies-literature
Project description:BackgroundThe risk of cancers is well characterized in Lynch syndrome (LS) families but has been less studied in familial colorectal cancer type X (FCCTX) families.MethodsIn this article, we compare the risk estimates of first and second colorectal cancers (CRCs) in 168 FCTTX and 780 LS families recruited through the Colon Cancer Family Registry as well as the risk of cancer-related deaths and disease-free survival (DFS) after a first CRC. Our methodology is based on a survival analysis approach, developed specifically to model the occurrence of successive cancers (ie, first and second CRCs) in the presence of competing risk events (ie, death from any causes).ResultsWe found an excess risk of first and second CRC in individuals with LS compared to FCCTX family members. However, for an average age at first CRC of 60 years in FCCTX families and 50 years in LS families, the DFS rates were comparable in men but lower in women from FCCTX vs LS families, eg , 75.1% (95% confidence interval [CI] = 69.0% to 80.9%) vs 78.9% (95% CI = 76.3% to 81.3%) for the 10-year DFS. The 10-year risk of cancer-related death was higher in FCCTX families vs LS families, eg, 15.4% in men (95% CI = 10.9% to 19.8%) and 19.3% in women (95% CI = 13.6% to 24.7%) vs 8.9% (95% CI = 7.5% to 11.4%) and 8.7% (95% CI = 7.1% to 10.8%), respectively.ConclusionsIndividuals with CRCs arising in the context of FCCTX do not experience the same improved DFS and overall survival of those with LS, and that difference may be relevant in management decisions.
| S-EPMC7514801 | biostudies-literature
Project description:Patients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%-89.9%) and 76.7% (95% CI = 37.2%-99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%-57.7%) and 49.3% (95% CI = 21.9%-84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.
| S-EPMC8076276 | biostudies-literature
Project description:Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.
| S-EPMC6287783 | biostudies-literature
Project description:To establish whether colorectal cancer patients in two centres in the UK are screened appropriately for Lynch syndrome, in accordance with current international guidance.Patients newly diagnosed with colorectal cancer over an 18-month period were identified from the UK National Bowel Cancer Audit Programme. Their records and management were reviewed retrospectively.Two university teaching hospitals, Imperial College Healthcare and Oxford Radcliffe Hospitals NHS Trusts.Whether patients were screened for Lynch syndrome-and the outcome of that evaluation, if it took place-were assessed from patients' clinical records. The age, tumour location and family history of screened patients were compared to those of unscreened patients.Five hundred and fifty three patients with newly diagnosed colorectal cancer were identified. Of these, 97 (17.5%) satisfied the revised Bethesda criteria, and should have undergone further assessment. There was no evidence that those guidelines had been contemporaneously applied to any patient. In practice, only 22 of the 97 (22.7%) eligible patients underwent evaluation. The results for 14 of those 22 (63.6%) supported a diagnosis of Lynch syndrome, but only nine of the 14 (64.3%) were referred for formal mismatch repair gene testing. No factors reliably predicted whether or not a patient would undergo Lynch syndrome screening.Colorectal teams in the UK do not follow international guidance identifying the patients who should be screened for Lynch syndrome. Patients and their families are consequently excluded from programmes reducing colorectal cancer incidence and mortality. Multidisciplinary teams should work with their local genetics services to develop reliable algorithms for patient screening and referral.
| S-EPMC5369742 | biostudies-other
Project description:Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic inactivation. Determining the underlying cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely to reshape the current triaging schemes used to identify germline MMR gene mutations in cancer-affected individuals and their relatives.
| S-EPMC4199650 | biostudies-literature
Project description:Early-onset (<50 years-old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed "Lynch-like syndrome" (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003-2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.
| S-EPMC10423080 | biostudies-literature
Project description:ContextLynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.ObjectiveTo establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.Design, setting, and patientsPooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.Main outcomePerformance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).ResultsOf 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.ConclusionUniversal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.
| S-EPMC3873721 | biostudies-literature
Project description:BackgroundLynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions.MethodsWe obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion.Findings93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer.InterpretationEPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.
| S-EPMC3670774 | biostudies-literature