Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor

• Published in: European journal of human genetics : EJHG Vol. 14; no. 5; pp. 561 - 566
• Main Authors: PLASCHKE, Jens, LINNEBACHER, Michael, KLOOR, Matthias, GEBERT, Johannes, CREMER, Friedrich W, TINSCHERT, Sigrid, AUST, Daniela E, VON KNEBEL DOEBERITZ, Magnus, SCHACKERT, Hans K
• Format: Journal Article
• Language: English
• Published: Avenel, NJ Nature Publishing 01.05.2006; Nature Publishing Group
• Subjects: Adult; Alleles; Base Pair Mismatch; Biological and medical sciences; Brain Neoplasms - complications; Colorectal Neoplasms - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Repair; DNA-Binding Proteins - genetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; General aspects. Genetic counseling; Hematologic Neoplasms - complications; Heterozygote; Humans; Medical genetics; Medical sciences; Microsatellite Repeats; Mutation; Neurology; Phenotype; Skin - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Tumors of the nervous system. Phacomatoses; Rectal disease; Carcinoma; biallelic mutations; Colorectal cancer; mismatch repair; Malignancy; Intestinal disease; Genetics; Repair; Human; Nervous system diseases; Corrective surgery; Patient; Malignant tumor; Intracranial tumor; Cerebral disorder; Heterozygosity; Colonic disease; MSH6; HNPCC; Treatment; Central nervous system disease; Digestive diseases; Early; Mutation
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/sj.ejhg.5201568

Heterozygous germline mutations in the human mismatch repair (MMR) genes MLH1, PMS2, MSH2 and MSH6 predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Biallelic mutations in these genes have been reported for a limited number of cases resulting in hematological malignancies, brain tumors and gastrointestinal tumors early in childhood. These tumor phenotypes are frequently associated with café-au-lait spots (CALS), one of the clinical hallmarks of neurofibromatosis type 1 (NF1). We report the first case of compound heterozygosity for two MSH6 mutations resulting in a nonconservative amino-acid change of a conserved residue and in a premature stop codon in a patient who developed rectal and endometrial cancer at ages 19 and 24 years, respectively, and presented few CALS in a single body segment. Immunohistochemistry and Western blotting revealed only residual expression of the MSH6 protein in the normal cells. The disease history resembles the HNPCC phenotype rather than a phenotype associated with biallelic MMR gene mutations. Therefore, we assume that one or both mutations abolish protein function only partially, further supported by the parents, which are both carriers of one of the mutations each, and not affected by the disease at ages 57 and 58 years. Our data suggest considering biallelic mutations in MMR genes for patients who develop HNPCC-associated tumors at an unusually young age of onset, even without hematological or brain malignancies.