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[The Lynch syndrome].

Lynch syndrome is a peculiar disease, accounting for 5% of the total burden of colon cancer. Characteristics of this disease are autosomal dominant transmission, early onset, and frequent right colon localization. Diagnostic criteria, aimed to collaborative studies, are based on these features (so called Amsterdam criteria). Lynch syndrome has specific biomolecular features (microsatellite instability); mismatch repair genes have been identified as responsible of this syndrome. Lynch syndrome causes high risk for extracolonic malignancies, particularly for endometrial cancer, supposed to be related to mutation of hMSH2 gene. Another feature of Lynch syndrome tumours is better survival with respect to sporadic counterpart. Genetic test allows identifying the state of mutation carriers and selects the patients to submit to screening. Endoscopic screening has been demonstrated to reduce incidence of colorectal malignancies in this syndrome.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1988

Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome II).

Increasing recognition of the statistical burden posed by HNPCC (5 to 6 percent of all colorectal cancer) mandates that physicians have a better understanding of the genetics, natural history, and distinction between the hereditary site-specific variant (Lynch syndrome I) and the Cancer Family Syndrome (Lynch syndrome II). The authors report detailed cancer (all sites) family histories on two prototype families with Lynch syndrome I (Family R) and Lynch syndrome II (Family N), which have been under investigation for more than two decades. Emphasis is placed on shared clinicogenetic features; namely, early age of onset of colonic cancer (approximately age 44), multiple primary colonic cancer (24 percent of cases showed metachronous colonic cancer), predominance of proximal colonic cancer location (approximately 65 percent in the proximal colon), and vertical transmission consonant with an autosomal dominantly inherited factor. An increased predilection for extracolonic cancer, particularly endometrial carcinoma, occurs in Lynch syndrome II and is the primary basis for distinction from Lynch syndrome I. Surveillance and management programs must be wholly responsive to these natural history features.

Adult↗
PubMed2005

Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.

Codon, Nonsense↗
PubMed2005

The incidence of Lynch syndrome.

Lynch syndrome (LS) here is defined as carriership of a deleterious mismatch repair (MMR) gene mutation. By screening for MMR gene mutations in unselected colorectal or endometrial cancer patients, it was found that the prevalence of LS in colorectal and endometrial cancer patients is 1-3%. On extrapolation to the entire population, the incidence of LS is between 1:2000 and 1:660. As all screening methods are less than 100% sensitive, the above figures are underestimates.

Base Pair Mismatch↗
PubMed2001

[When and how to investigate a mutation predisposing to the Lynch syndrome].

Lynch Syndrom (or Hereditary Non-polyposic Colorectal Cancer (HNPCC)) can be described as the presence of an autosomic dominant mutation predisposing to early colorectal cancer. Suggestive familial history and young patient with colorectal cancer should undergo thorough investigation. In Switzerland, investigation will first attempt to show microsatellites instability in fumoral cells, then mutation in blood. If positive, direct progeny and family should be tested. Those who are mutation free may be followed as normal population. The others should have more frequent colorectal and gynecologic follow-up. Surgical treatment will attempt to prevent synchrone or metachrone colorectal cancer by total colectomy. Preventive colectomy is attractive but controversial.

Adult↗
PubMed1992

[Significance of the detection of the familial carcinoma syndrome (Lynch I and II) in the early diagnosis of colorectal carcinoma].

In 1982-1991 at the Fourth Medical Clinic 309 asymptomatic family members meeting the criteria of the hereditary form of colorectal carcinoma (Lynch syndrome--syndrome of familial cancer, also "non-polypous" hereditary colorectal carcinoma) which differs from familial polyposis (adenomatosis) of the colon. The syndrome is characterized by autosomal dominant heredity and by familial incidence of colorectal carcinoma (Lynch I) or colorectal carcinoma and carcinoma of other, in particular gynaecological areas (Lynch II) and a younger age of the affected subjects, a more frequent localization in the right colon, synchronous and metachronous neoplasia. In the authors group 34% were type I, the remainder type II. Initial total coloscopy revealed carcinoma in 51 subjects (78% in the right colon), adenomatous polyps in 99 (73% in the right colon). The mean age of the patients with carcinoma was 47.5 years, of those with adenoma 46.5 years. The majority of cases were recorded in subjects with three or more than three direct relatives with carcinoma (highest risk grade). During subsequent coloscopic check-up examinations at intervals depending on individual risk, colorectal carcinoma was detected in another six subjects. In 30 patients it was carcinoma Dukes A, in 12 B and in 3 Dukes C. These results indicate that identification of asymptomatic cases of Lynch syndromes via the family-history and coloscopic follow-up contributes to the early diagnosis of colorectal carcinoma.

Adenocarcinoma↗
PubMed1993

The Lynch syndromes.

The Lynch syndromes, also referred to as hereditary nonpolyposis colorectal cancer, are reviewed, with particular attention given to their natural history, diagnosis, surveillance, and management. Lynch syndrome I is characterized by an autosomal dominantly inherited predisposition to early onset colorectal cancer, with proximal predominance and an excess of synchronous and metachronous colorectal cancers. Lynch syndrome II manifests all of the features of Lynch syndrome I but, in addition, shows an integral association with extracolonic cancers, particularly carcinomas of the endometrium and the ovary. There are no premonitory physical signs or biomarkers of genotypic risk. Therefore, the natural history features of the Lynch syndromes are crucial to their surveillance and management.

Adenocarcinoma↗
PubMed1993

Cancer control problems in the Lynch syndromes.

The Lynch syndromes account for about 4 to 6 percent of the total colorectal cancer (CRC) burden. Despite more than two decades of documentation in the literature, many physicians fail to recognize the clinical features of these syndromes. The lack of premonitory physical stigmata, coupled with the absence of a biomarker of cancer susceptibility, mandates full reliance on a well-orchestrated family history for diagnosis. These deficiencies impede cancer control. Even if the diagnosis is made, proper surveillance and management measures that are responsive to the Lynch syndromes' natural history may fail to be implemented. We describe CRC occurrences in patients from four extended Lynch syndrome kindreds. Failures in cancer control were attributable to poor patient compliance and/or to limited physician knowledge about the natural history and surveillance recommendations for the Lynch syndromes. Physicians need to more effectively educate their high-risk patients about the significance of genetic risk, the natural history of CRC, and the appropriate surveillance strategies in the Lynch syndromes.

Adolescent↗
PubMed2005

Women with synchronous primary cancers of the endometrium and ovary: do they have Lynch syndrome?

PURPOSE: Lynch syndrome (hereditary nonpolyposis colorectal cancer; HNPCC) is an autosomal-dominant cancer predisposition syndrome that increases risk for multiple cancers, including colon, endometrial, and ovarian cancer. Revised Bethesda Criteria recommend that patients with two HNPCC-associated cancers undergo molecular evaluation to determine whether they have a mismatch repair (MMR) defect associated with HNPCC. The purpose of our study was to determine the likelihood of MMR defects (MSH2, MSH6, MLH1) in women with synchronous endometrial and ovarian cancer. PATIENTS AND METHODS: Between 1989 and 2004, 102 women with synchronous endometrial and ovarian cancers were identified; 59 patients had tumor blocks available for analysis. Patients were divided into risk groups based on family history: high (met Amsterdam criteria), medium (personal history or first-degree relative with an HNPCC-associated cancer), and low (all others). Protein expression for MSH2, MSH6, and MLH1 was evaluated by immunohistochemistry. Microsatellite instability and MLH1 promoter methylation analyses were performed on a subset of cases. RESULTS: Median age was 50 years. Two patients met Amsterdam criteria for HNPCC. Five additional patients, all medium-risk, had molecular findings consistent with a germline mutation of either MSH2 or MLH1. None of the low-risk patients had molecular results consistent with a germline mutation. CONCLUSION: Overall, 7% of women in our cohort met either clinical or molecular criteria for Lynch syndrome. All of these women had a prior history or a first-degree relative with an HNPCC-associated cancer. Limiting genetic evaluation to women with synchronous endometrial and ovarian cancer who have a family history suggestive of HNPCC may appropriately identify women with Lynch syndrome.

Adult↗
PubMed2006

What is the appropriate screening protocol in Lynch syndrome?

INTRODUCTION: Lynch syndrome families have a substantial risk of developing colorectal cancer (CRC). The recommended surveillance protocol includes colonoscopy every 2 years from age 20-25 years. It is yet unknown whether annual screening of patients aged 40-60 years is more effective than bi-annual screening, whether patients who had an adenoma removed should be re-examined after a year and whether surveillance of second-degree relatives is indicated. The aim of this study was to address these issues. METHODS: All carriers of a mismatch repair gene mutation who participated in the surveillance program were selected from the Dutch Lynch syndrome registry. The results of colonoscopy were prospectively collected. RESULTS: A total of 666 mutation carriers were identified in 110 families. Fourty-one CRCs were detected during endoscopic follow-up, of which 34 (83%) were diagnosed between age 40 and 60 years. In five of 34 patients, CRC was diagnosed within 1 year after colonoscopy, eight cancers were diagnosed between 1 and 2 years and the remaining tumors more than 2 years after colonoscopy. All eight CRCs detected between 1 and 2 years were at local stage. At least one adenoma was diagnosed at 141 examinations. The risk of developing CRC during follow-up in carriers with an adenoma was similar as in carriers without an adenoma at the previous colonoscopy. 280 parent-child couples with at least one Lynch syndrome-related carcinoma were identified in 110 families. In only 19 (6.8%) of these couples, CRC developed earlier in the child than an Lynch syndrome-associated cancer in the parent. CONCLUSION: The current surveillance protocol, i.e., bi-annual colonoscopy in first-degree relatives independent of age and endoscopic findings, appears to be appropriate.

Adenoma↗
PubMed2006

Prospective results of surveillance colonoscopy in dominant familial colorectal cancer with and without Lynch syndrome.

BACKGROUND & AIMS: Lynch syndrome is an autosomal dominant predisposition to colorectal cancer caused by mutations in DNA mismatch repair genes; colorectal cancer risk is high. Few studies have addressed colorectal cancer risk in individuals from dominant families without mismatch repair deficiency. We sought to establish whether these individuals are also at increased risk by examining the incidence of advanced neoplasia during surveillance. METHODS: In this prospective cohort study, BAT26 testing of tumors was carried out at 2 tertiary centers on 125 individuals from 97 families (with a dominant colorectal cancer history) to classify families as Lynch syndrome (microsatellite unstable) or non-Lynch syndrome (microsatellite stable). Colonoscopy results in 288 at-risk family members were compared. RESULTS: Twenty-nine families were classified as Lynch syndrome and 68 as non-Lynch syndrome. Seven hundred seventy-six colonoscopies were undertaken. High-risk adenomas occurred in 7 of 91 (7.7%) Lynch syndrome individuals and 15 of 197 (7.6%) non-Lynch syndrome individuals, adjusted relative risk 1.15 (95% CI: 0.6-2.3). Cancer was observed only in Lynch syndrome individuals (4/91; 4.4%), Fisher exact test, P = .010. Multiple adenomas were only seen in non-Lynch syndrome individuals (13/197; 6.6%), Fisher exact text, P = .06. CONCLUSIONS: Individuals with an autosomal dominant family history of colorectal cancer with and without evidence of Lynch syndrome are at equal risk of high-risk adenomas during surveillance, but colorectal cancer was only seen in Lynch syndrome. Therefore non-Lynch syndrome individuals do require colonoscopic surveillance, but the interval could be lengthened because risk of (interval) cancer is low. Lynch syndrome individuals require short surveillance intervals as is the recommended practice.

Age Distribution↗
PubMed2006

Prediction of MLH1 and MSH2 mutations in Lynch syndrome.

CONTEXT: Lynch syndrome is caused primarily by mutations in the mismatch repair genes MLH1 and MSH2. OBJECTIVES: To analyze MLH1/MSH2 mutation prevalence in a large cohort of patients undergoing genetic testing and to develop a clinical model to predict the likelihood of finding a mutation in at-risk patients. DESIGN, SETTING, AND PARTICIPANTS: Personal and family history were obtained for 1914 unrelated probands who submitted blood samples starting in the year 2000 for full gene sequencing of MLH1/MSH2. Genetic analysis was performed using a combination of sequence analysis and Southern blotting. A multivariable model was developed using logistic regression in an initial cohort of 898 individuals and subsequently prospectively validated in 1016 patients. The complex model that we have named PREMM(1,2) (Prediction of Mutations in MLH1 and MSH2) was developed into a Web-based tool that incorporates personal and family history of cancer and adenomas. MAIN OUTCOME MEASURE: Deleterious mutations in MLH1/MSH2 genes. RESULTS: Overall, 14.5% of the probands (130/898) carried a pathogenic mutation (MLH1, 6.5%; MSH2, 8.0%) in the development cohort and 15.3% (155/1016) in the validation cohort, with 42 (27%) of the latter being large rearrangements. Strong predictors of mutations included proband characteristics (presence of colorectal cancer, especially > or =2 separate diagnoses, or endometrial cancer) and family history (especially the number of first-degree relatives with colorectal or endometrial cancer). Age at diagnosis was particularly important for colorectal cancer. The multivariable model discriminated well at external validation, with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.76-0.84). CONCLUSIONS: Personal and family history characteristics can accurately predict the outcome of genetic testing in a large population at risk of Lynch syndrome. The PREMM(1,2) model provides clinicians with an objective, easy-to-use tool to estimate the likelihood of finding mutations in the MLH1/MSH2 genes and may guide the strategy for molecular evaluation.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Lynch Syndrome

CLINICAL CHARACTERISTICS: Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, prostate, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous epithelioma, sebaceous carcinomas, and keratoacanthomas), and pancreas. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome. DIAGNOSIS/TESTING: The diagnosis of Lynch syndrome is established in a proband with a germline heterozygous pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or a 3' EPCAM deletion identified by molecular genetic testing, or, rarely, constitutional inactivation of the MLH1 promotor due to methylation identified by DNA methylation analysis. MANAGEMENT: Treatment of manifestations: Polypectomy at the time of colonoscopy; referral to advanced endoscopist for lesions requiring advanced resection techniques; surgical resection of polyps when needed; individualized surgical management for colon cancer based on tumor location, stage, Lynch syndrome-associated gene, age, comorbidity, bowel function, anticipated quality of life, and risk of metachronous CRC; mismatch repair (MMR) testing, microsatellite instability (MSI) testing, and multidisciplinary evaluation for rectal cancer prior to treatment; consider immune checkpoint inhibitor therapy for metastatic or unresectable MMR-deficient or MSI-high tumors; other tumors are managed as in the general population. Prevention of primary manifestations: Risk-reducing hysterectomy with bilateral salpingo-oophorectomy can be considered after childbearing is completed. Prophylactic colectomy prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because screening colonoscopy with polypectomy is an effective preventive measure. Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome. Surveillance: Colonoscopy with removal of precancerous polyps with frequency and initial screening based on gene involved and family history; annual education for females regarding the symptoms of endometrial and ovarian cancers; consider transvaginal ultrasound examination and endometrial biopsy every one to two years beginning at age 30 to 35 years; consider upper endoscopy examination particularly for individuals with a family history of gastric cancer and those of Asian ancestry with frequency and initial screening based on gene involved and family history; biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed; consider capsule endoscopy and small bowel enterography for distal small bowel cancers in symptomatic persons; consider urinalysis with urine cytology annually beginning between ages 30 and 35 years; consider pancreatic cancer screening in individuals with a family history of pancreatic cancer; follow population screening guidelines and maintain awareness for signs and symptoms of other cancers. Agents/circumstances to avoid: Obesity, physical inactivity, cigarette smoking, alcohol consumption, and type 2 diabetes may increase CRC risk in individuals with Lynch syndrome. Evaluation of relatives at risk: Molecular genetic testing for the familial Lynch syndrome-related pathogenic variant is recommended for all first-degree relatives (parents, sibs, and offspring) of an affected individual in order to identify as early as possible those who would benefit from surveillance, risk-reducing interventions, and other preventive measures. Testing for constitutional MLH1 hypermethylation is recommended for all first-degree relatives of individuals with Lynch syndrome caused by constitutional MLH1 methylation. GENETIC COUNSELING: Lynch syndrome caused by a heterozygous germline Lynch syndrome-related pathogenic variant (i.e., a pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or a 3' EPCAM deletion) is inherited in an autosomal dominant manner. Individuals with Lynch syndrome caused by constitutional inactivation of MLH1 by methylation typically represent simplex cases, although affected individuals from a few families have been reported with inherited MLH1 promoter methylation. The majority of individuals with a heterozygous germline Lynch syndrome-related pathogenic variant inherited the pathogenic variant from a parent who may or may not have had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the Lynch syndrome-related pathogenic variant and the related cancer risks. If the reproductive partner of an individual with Lynch syndrome has a germline heterozygous pathogenic variant in the same Lynch syndrome-related gene, offspring are at risk of inheriting biallelic pathogenic variants and having constitutional mismatch repair deficiency. Once a germline Lynch syndrome-related pathogenic variant has been identified in an affected family member, predictive testing for at-risk asymptomatic family members and prenatal/preimplantation genetic testing are possible.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)↗
PubMed1993

[Early diagnosis of colorectal carcinoma in the familial carcinoma syndrome (Lynch I and II)].

The hereditary form of colorectal cancer (Lynch syndrome, cancer family syndrome "nonpolyposis hereditary colorectal cancer"), which is different from familial adenomatous polyposis, represents probably 5-8% of the development of this malignancy. The main characteristics of the syndrome include an autosomal dominant hereditary type, frequent familial occurrence of colorectal cancer (either solely at this site--Lynch variant I--or in combination with other, particularly gynecological sites of cancer-Lynch variant II), younger age at the time of diagnosis, more frequent localization in the right colon and more frequent occurrence of synchronic and metachronic cancer. During the years 1982-1992, we found 339 asymptomatic members of families meeting the criteria of the syndrome. After initial colonoscopy these individuals entered a long-term surveillance system with repeated colonoscopies; intervals between them where organized according to the individual degree of risk and to at the initial finding. Results of initial colonoscopy showed colorectal cancer in 16.2% and adenomas in 32.1% of the whole group. The right colon was affected in 74.5% of the cancers and in 64% of the adenomas; the mean age of the probands with these findings was 46.4% years. The Lynch variant I was found in 34%, the variant II in 66%. Cancer in relatives of the variant II was mostly in the colorectal, followed by the gynecological region. The highest number of cancers detected on initial colonoscopy was found in probands with the highest degree of genetic risk-with 3 or more than 3 direct relatives. On repeated colonoscopies a new cancer was found in 7 further probands. All the cancers were well resectable, mostly DUKES A and B.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2026

Exercise-associated epigenetic remodeling and TCR repertoire dynamics in Lynch syndrome carriers.

Lynch syndrome (LS) carriers are at elevated cancer risk. Emerging evidence suggests that exercise may serve as a non-pharmacologic preventive strategy, yet the epigenetic and immunological mechanisms underlying its protective effects in this population remain unclear. Here, we perform integrative multi-omics profiling of DNA methylation, gene expression, and the T cell receptor (TCR) repertoire in LS carriers undergoing a 52-week aerobic cycling intervention. We identify compartment-specific DNA methylation changes, including innate immune activation in cfDNA and oncogenic pathway repression in tissue. Integrative transcriptomic analysis highlights ISL1 as a key exercise-repressed, epigenetically regulated gene, and identifies FLCN as a colorectal cancer (CRC)-associated methylation target. TCR analysis reveals an exercise-associated increase in systemic repertoire diversity and tissue-specific clonal convergence, thus suggesting antigen-driven recruitment. Collectively, these findings uncover epigenetic and immune remodeling as potential mechanisms of exercise-mediated protection in LS.

Lynch syndrome↗
PubMed2005

What the physician needs to know about Lynch syndrome: an update.

The Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), is the most common form of hereditary colorectal cancer (CRC), accounting for 2% to 7% of all CRC cases. The next most common hereditary CRC syndrome is familial adenomatous polyposis (FAP), which accounts for less than 1% of all CRC. Lynch syndrome is of crucial clinical importance due to the fact that it predicts the lifetime risk for CRC and a litany of extra-CRC cancers (of the endometrium, ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelial tract, and brain) through assessment of a well-orchestrated family history. A Lynch syndrome diagnosis is almost certain when a mutation in a mismatch repair gene--most commonly MSH2, MLHI, or, to a lesser degree, MSH6--is identified. Once diagnosed, the potential for significant reduction in cancer-related morbidity and mortality through highly targeted surveillance may be profound. Particularly important is colonoscopy initiated at an early age (ie, 25 years) and repeated annually due to accelerated carcinogenesis. In women, endometrial aspiration biopsy and transvaginal ultrasound are important given the extraordinarily high risk for endometrial and ovarian carcinoma. These cancer control strategies have a major impact on at-risk family members once they have been counseled and educated thoroughly about Lynch syndrome's natural history and their own hereditary cancer risk.

Colectomy↗
PubMed1988

Tumor variation in three extended Lynch syndrome II kindreds.

Lynch syndrome II is characterized by an autosomal dominantly inherited susceptibility to early onset colon cancer with proximal predominance, an excess of synchronous and metachronous colonic cancer, carcinoma of the endometrium, ovary, and multiple primary cancer excess. Knowledge of the full tumor spectrum in this disorder(s) remains elusive. Cancers that are uncommon in this disease, but present in three extended Lynch syndrome II families, included brain tumors, carcinoma of the bile duct, duodenum, the urological system, and breasts. Long-term followup of these families (as long as two decades) provided the opportunity to trace in depth this tumor spectrum. Full scrutiny of cancer of all anatomic sites in the absence of biomarkers of high sensitivity and specificity to the cancer-prone genotype will be necessary to comprehend more clearly whether these (or other) cancer sites are integral to this disorder, whether common environmental exposures are involved and, finally, whether chance can explain these cancer associations.

Adolescent↗