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Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.

ABSTRACT: More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (approximately 30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC's proximal occurrence (70-80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40-60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10-25% of familial CRC.

SUBMITTER: Lynch HT

PROVIDER: S-EPMC2846640 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.

Lynch H T HT Lynch P M PM Lanspa S J SJ Snyder C L CL Lynch J F JF Boland C R CR

Clinical genetics 20090701 1

More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (approximately 30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC's proximal occurrence (70-80% proximal to the splenic ...[more]

PMID: 19659756

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Project description:ObjectivesLynch syndrome increases risks for colorectal and other cancers. Though published Lynch syndrome cancer risk-management guidelines are effective for risk-reduction, the condition remains under-recognized. The Cancer Genetics Program at an academic medical center implemented a population-based cancer family history screening program, Detecting Unaffected Individuals with Lynch syndrome, to aid in identification of individuals with Lynch syndrome.MethodsIn this retrospective cohort study, simple cancer family history screening questionnaires were used to identify those at risk for Lynch syndrome. Program navigators triaged and educated those who screened positive about hereditary cancer, and genetic counseling and testing services, offering genetic counseling if eligible. Genetic counseling was provided primarily via telephone. Genetic counselors performed hereditary cancer risk assessment and offered genetic testing via hereditary cancer panels to those eligible. Remote service delivery models via telephone genetic counseling and at-home saliva testing were used to increase access to medical genetics services.ResultsThis program screened 212,827 individuals, over half of whom were considered underserved, and identified 133 clinically actionable genetic variants associated with hereditary cancer. Of these, 47 (35%) were associated with Lynch syndrome while notably, 70 (53%) were not associated with hereditary colorectal cancer. Of 3,344 patients offered genetic counseling after initial triage, 2,441 (73%) elected to schedule the appointment and 1,775 individuals (73%) completed genetic counseling. Among underserved patients, telephone genetic counseling completion rates were significantly higher than in-person appointment completion rates (P < .05). While remote service delivery improved appointment completion rates, challenges with genetic test completion using at-home saliva sample collection kits were observed, with 242 of 1592 individuals (15%) not completing testing.ConclusionPopulation-based cancer family history screening and navigation can help identify individuals with hereditary cancer syndromes across diverse patient populations, but logistics of certain downstream service delivery models can impact outcomes.

Project description:BackgroundGuidelines recommend universal mismatch repair (MMR) tumour testing of colorectal adenocarcinomas (CRCs) to screen for Lynch syndrome (LS). However, its implementation remains disjointed and referral for genetic testing dismal, particularly among minorities. We aimed to increase referral, cancer genetic testing and eventually LS diagnosis by developing the CLEAR LS (Closed Loop Enhanced Assessment and Referral for Lynch Syndrome) intervention, a systems approach which in the second phase was automated.MethodsThis is a cohort study of all patients diagnosed with CRC at an academic centre between 1 January 2012, when implementation of universal CRC testing began, and 31 January 2021. The original cohort spanned through 31 May 2015. Tumour testing included MMR immunohistochemistry, followed by BRAF V600E/MLH1 promoter methylation testing when indicated. The intervention included a manual phase (1 June 2015 through 31 July 2018), which systematised pathology screening and cancer genetics (CG) referral mechanisms, and an automated phase (1 August 2018 through 31 January 2021) using computer programming.ResultsA total of 249/1541 CRC (17.38%) had MMR loss of expression and 129 (8.37%) qualified for CG evaluation. Referral was 27.58% in the original cohort and 92.1% in the intervention (p<0.001). Patients seen by CG among referred were 27.58% in the original cohort and 74.3% in the intervention (p two-sided<0.001). The distribution of race/ethnicity among patients qualifying and referred for CG evaluation was not significantly different across cohorts. LS diagnosis increased from 0.56% (original cohort) to 1.43% (intervention). Cost per new diagnosis of LS decreased from US$173 675 to $87 960 from original cohort to intervention.ConclusionImplementation of systematic case identification and referral support mechanisms significantly increased the proportion of patients undergoing genetic testing and doubled the percentage of patients diagnosed with LS with no referral differences across racial/ethnic groups.

Dataset Information

Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.

Publications

Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.

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