Bi-allelic MSH6 mutations in a case of early onset multiple primary tumors resembling Lynch and Turcot syndrome

Multiple primary tumors of the gastrointestinal tract, uterus, ovaries, cen¬tral nervous system and other organs are hallmarks of Lynch syndrome, caused by heterozygous germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Bi-allelic mutations of the same genes have been associated with a rare childhood cancer syndrome characterized by hematological malignancies, sarcomas, brain and gastrointestinal tumors together with cafè-au-lait spots resembling Neurofibromatosis 1. Here we report on a female patient who developed multiple primary tumors between 21 and 27 years of age including two metachronous colorectal cancers, a fillodes tumour of the breast, a glioblastoma and a clear cell carcinoma of the ovaries. Genetic testing identified two germline heterozygote MSH6 mutations: a frameshift mutation (c.1610_1613delAGTA) inherited from the father and a suspected deleterious missense mutation (p.Arg1076His) inherited from the mother. No TP53, MLH1 or MSH2 mutations were found. Microsatellite analysis revealed instability of BAT26 and BAT40 in both the colon and the ovarian carcinomas. The MLH1, MSH2 and PMS2 proteins sho¬wed nuclear staining in all specimens while MSH6 was completely absent in tumor and normal cells, including the fillodes tumor of the breast and the normal mucosa of the colon. Germline mutations in the MMR genes, either mono-allelic or bi-allelic, can therefore underlie a wide spectrum of cancer syndromes characterized by variable age at onset and severity of the cancer risk. Development of multiple primary tumors in young adults appears to be suggestive for the presence of bi-allelic mutations of the MMR genes.