The contribution of Lynch syndrome to early onset malignancy in Ireland

Alice Talbot,Emily O’Donovan,Eileen Berkley,David Gallagher,Carmel Nolan,Roisin Clarke

doi:10.1186/s12885-021-08263-z

Abstract

BackgroundLynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2–4% of hereditary colorectal cancers (CRC). Mismatch repair protein deficiency (dMMR) is a characteristic feature of LS. It has been associated with a poor response to standard chemotherapy in metastatic colorectal cancer (mCRC). There is currently no LS database to monitor trends of disease in Ireland. We aim to centralise LS data in Ireland to assess the burden of LS in Ireland and guide improvements in prevention and treatment of LS-associated cancer.MethodsA retrospective review was carried out including all medical records for LS patients from two of the three cancer genetics clinics in Ireland between 2000 and 2018 was carried out. Clinicopathological data of probands (n = 57) and affected family members including demographics, mutation status, cancer diagnosis and outcome was recorded. Statistical analysis was carried out using SPSS software.ResultsFifty-seven families including three-hundred and forty-five individuals affected by cancer were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). One-hundred and thirty-eight confirmed carriers were identified: 65 path_MLH1 (47%), 43 path_MSH2 (31%), 11 path_MSH6 (8%), 17 path_PMS2 (12%) and two path_EPCAM (1%). Cancer type varied significantly by gene. Median age of first diagnosis was 44.5 years (range 23–81). Half of all deceased patients (n = 11) in this group died within 2.5 years of first diagnosis. These deaths were directly related to cancer in 59% of cases.ConclusionsUnder diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset dMMR cancer diagnoses with substantial societal impact. Implementation of ICBs into treatment policy for this small cohort of dMMR mCRC is an achievable therapeutic goal that may significantly improve survival. A prospective database for LS in Ireland is necessary to maximise prevention in this population.

Highlights

Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2–4% of hereditary colorectal cancers (CRC) [1, 2]
Nine family members of probands tested negative on predictive testing, all of whom were unaffected
We identified three families with the same path_MLH1 mutation

Summary

Introduction

Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2–4% of hereditary colorectal cancers (CRC) [1, 2]. In Ireland, patients with a new diagnosis of LS-associated cancer are assessed for LS risk using the revised Amsterdam and Bethesda criteria. Patients that meet these criteria have immunohistochemistry (IHC) testing or MSI testing [8]. Identification of MMR deficiency (dMMR) and MSI has additional preventative and therapeutic implications for affected individuals. The aim of this study was to construct and analyse a database of Irish MMR mutation carriers to assess the LS-associated cancer burden in Ireland and identify potential preventative and therapeutic opportunities. Mismatch repair protein deficiency (dMMR) is a characteristic feature of LS It has been associated with a poor response to standard chemotherapy in metastatic colorectal cancer (mCRC). We aim to centralise LS data in Ireland to assess the burden of LS in Ireland and guide improvements in prevention and treatment of LS-associated cancer

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