Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue.

Germline mutations in mismatch repair (MMR) genes, predominantly in MLH1 and MSH2, are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), a cancer-susceptibility syndrome with high penetrance. In addition, MSH6 mutations have been reported to account for about 10% of all germline mismatch repair (MMR) gene mutations in HNPCC patients, and have been associated with a later age of onset of the disease compared to MLH1 and MSH2 mutations. Here, we report eight novel germline mutations in MSH6. The patients were selected by having developed tumors with loss of MSH6 protein expression. All tumors showed high-level microsatellite instability (MSI-H). Seven mutations resulted in premature stop codons, comprised of two nonsense mutations (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]). In addition, an amino acid substitution of an arginine residue (c.2314C>T [p.R772W]) conserved throughout a wide variety of mutS homologs has been found in a patient not fulfilling the Bethesda criteria for HNPCC. Our results emphasize the suitability of IHC as a pre-selection tool for MSH6 mutation analysis and the high frequency of germline mutation detection in patients with MSH6-deficient tumors. In addition, our findings point towards a broad variability regarding penetrance associated with MSH6 germline mutations.

Plaschke J ，Krüger S ，Dietmaier W ，Gebert J ，Sutter C ，Mangold E ，Pagenstecher C ，Holinski-Feder E ，Schulmann K ，Möslein G ，Rüschoff J ，Engel C ，Evans G ，Schackert HK ，German HNPCC Consortium ... -  《-》

Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic?

Kariola R ，Otway R ，Lönnqvist KE ，Raevaara TE ，Macrae F ，Vos YJ ，Kohonen-Corish M ，Hofstra RM ，Nyström-Lahti M ... -  《HUMAN GENETICS》

A novel missense germline mutation in exon 2 of the hMSH2 gene in a HNPCC family from Southern Italy.

Baudi F ，Fersini G ，Lavecchia A ，Terracciano R ，Leone F ，Quaresima B ，Faniello MC ，De Paola L ，Doldo P ，Cuda G ，Costanzo F ，Venuta S ... -  《CANCER LETTERS》

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

Plaschke J ，Linnebacher M ，Kloor M ，Gebert J ，Cremer FW ，Tinschert S ，Aust DE ，von Knebel Doeberitz M ，Schackert HK ... -  《EUROPEAN JOURNAL OF HUMAN GENETICS》

High frequency of microsatellite instability and loss of mismatch-repair protein expression in patients with double primary tumors of the endometrium and colorectum.

Planck M ，Rambech E ，Möslein G ，Müller W ，Olsson H ，Nilbert M ... -  《CANCER》