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Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges.

ABSTRACT: Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with germline mutations in DNA mismatch repair (MMR) genes. The carriers of pathogenic mutations in these genes have an increased risk of developing a colorectal cancer and/or LS-associated cancer. The LS-associated cancer types include carcinomas of the endometrium, small intestine, stomach, pancreas and biliary tract, ovary, brain, upper urinary tract and skin. The criteria for the clinical diagnosis of LS and the procedures of the genetic testing for identification of pathogenetic mutations carriers in MMR genes have long been known. A crucial point in the mutation detection analysis is the correct definition of the pathogenecity associated with MMR genetic variants, especially in order to include the mutation carriers in the endoscopy surveillance programs more suited to them. Therefore, this may help to improve the LS-associated cancer prevention programs. In the present review, we also report the recent discoveries in molecular genetics of LS, such as the new roles of MMR protein and immune response of MMR repair deficiency in colorectal cancer. Finally, we discuss the main therapeutic approaches, including immunotherapy, which represent a valid alternative to traditional therapeutic methods and extend the life expectancy of patients that have already developed LS-associated colorectal cancer.

SUBMITTER: Duraturo F

PROVIDER: S-EPMC6396136 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges.

Duraturo Francesca F Liccardo Raffaella R De Rosa Marina M Izzo Paola P

Oncology letters 20190118 3

Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with germline mutations in DNA mismatch repair (MMR) genes. The carriers of pathogenic mutations in these genes have an increased risk of developing a colorectal cancer and/or LS-associated cancer. The LS-associated cancer types include carcinomas of the endometrium, small intestine, stomach, pancreas and biliary tract, ovary, brain, upper urinary tract and skin. The criteria for the clinical diagnosis of LS and the procedu ...[more]

PMID: 30867733

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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

Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges.

Publications

Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges.

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