Lynch syndrome caused by a novel deletion of the promoter and exons 1-13 of MLH1 gene.

Lynch syndrome (LS) is the most common hereditary cancer syndrome involving multiple organ systems. The mutation patterns of the involved major DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, have not been fully elucidated. Herein, we report a case of LS caused by a novel large deletion in the promoter and exons 1-13 of MLH1 gene. A 30 year-old male was admitted for dull abdominal pain for 5 months with family history significant for dominant familial colon cancer. Abdominal computed tomography (CT) revealed masses in colon, lung and liver. His-plasma CA19-9 was 1250 units/ml and CEA 133 ng/ml. Targeted liver biopsy showed metastatic adenocarcinoma. Immunocytochemically, the tumor cells were positive for CK20 and CDX2, and displayed loss of MLH1 and PMS2 expression but with intact MSH2 and MSH6 proteins. Next-generation sequencing of the liver metastasis demonstrated copy loss of MLH1 gene spanning exons 1 to 13. Further SNP array detected copy neutral loss of heterozygosity (CN-LOH) expanding the short arm of chromosome 3p21.3 to 3pter regions and a 219 kb deletion involving the promoter and first 13 exons of MLH1 gene (arr[GRCh37] 3p22.2(36,856,328_37075457)x1). Germline sequencing using a blood sample confirmed the deletion of the MLH gene including the promoter and this first 13 exons (NG_007109.2(NM_000249.3:c.(?_-198)_(1558+1_1559-1)del). In summary, we identified a novel MLH1 mutation pattern of partial deletion and CN-LOH causing LS.