Abstract
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by heterozygous mutations in the mismatch repair (MMR) genes. Biallelic mutations in these genes lead however, to constitutive mismatch repair deficiency (CMMRD). In this study, we follow the diagnostic journey of a 12-year old patient with CRC, with a clinical phenotype overlapping CMMRD. We perform molecular and functional assays to discard a CMMRD diagnosis then identify by exome sequencing and validation in a cohort of 134 LS patients, a candidate variant in the MLH1 UTR region in homozygosis. We propose that this variant, together with other candidates, could be responsible for age-of-onset modulation. Our data support the idea that low-risk modifier alleles may influence early development of cancer in LS leading to a LS-to-CMMRD phenotypic continuum. Therefore, it is essential that larger efforts are directed to the identification and study of these genetic modifiers, in order to provide optimal cancer prevention strategies to these patients.
Highlights
Lynch syndrome (LS; OMIM 120435) is the most frequent hereditary colorectal cancer (CRC)syndrome that accounts for around 2.8% of cases
Considering the early presentation, we contemplated the idea that the patient suffered from constitutive mismatch repair deficiency syndrome (CMMRD)
In silico tools predicted a splicing effect, minigene experiments showed that this variants of unknown significance (VUS) generates only full-length transcripts (Figure S2), and it is very unlikely the second MSH2 hit
Summary
Lynch syndrome (LS; OMIM 120435) is the most frequent hereditary colorectal cancer (CRC). Syndrome that accounts for around 2.8% of cases It is caused by germline mutations in the mismatch repair (MMR) genes or 30 deletions in EPCAM. Biallelic MMR germline mutations lead to constitutive mismatch repair deficiency syndrome (CMMRD; OMIM 276300), characterized by haematologic, brain and colorectal tumours in Cancers 2019, 11, 1081; doi:10.3390/cancers11081081 www.mdpi.com/journal/cancers. We present a male patient from a LS family who developed CRC at 12 years of age. He carried a potentially spliceogenic MSH2 variant in addition to the familial mutation, functional analyses clearly reject
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