Abstract
586 Background: Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2 -6% of hereditary colorectal cancers. LS is caused by germ-line mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2 or EPCAM. This results in microsatellite instability, a phenotypic hallmark of LS-associated colorectal cancer. The aim of this study was to construct and analyse a database of Irish MMR mutation carriers. Methods: Records were from two of the three existing cancer genetics clinics in Ireland. Clinicopathological data of all probands (n=57) including names, dates of birth and death, carrier status and phenotype were recorded. Death certificates were used to confirm information regarding deceased mutation carriers. An ANOVA test was used to establish statistical significance of variations in age by gene. Length of survival based on stage was assessed using Kaplain Meier curves. Results: 345 affected individuals were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). 138 confirmed carriers were identified: 65 MLH1 (47%), 43 MSH2 (31%), 11 MSH6 (8%), 17 PMS2 (12%), and 2 EPCAM (1%). 22 patients have died since confirmation of Lynch Syndrome, 50% of whom died within 2.5 years of first diagnosis. All deceased carriers had at least one cancer diagnosis and 50% had developed multiple cancers. 59% of deaths were directly related to cancer. 7 of these patients had Stage 4 cancer at diagnosis. There was a significant difference in length of survival based on stage. (p=.048) Phenotype frequencies varied significantly by gene. (see table 1) Median age of first diagnosis of any cancer was 44.5 years (range 23-81). There was no difference in age at presentation by gene mutated. Conclusions: Under-diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset cancer diagnosis with substantial societal impact. A significant number of Lynch Syndrome cases have poor clinical outcomes. Genotype/Phenotype frequencies. [Table: see text]
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
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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