Pathogenicity of the Hereditary Colorectal Cancer Mutation hMLH1 del616 Linked to Shortage of the Functional Protein

TIINA E. RAEVAARA; CARLOS VACCARO; WAEL M. ABDEL-RAMANH; ESTEBAN MOCETTI; SHASHI BALA; KARIN E LÖNNQVIST; REETTA KARIOLA; HENRY T LYNCH; PÄIVI PELTOMÄKI; MINNA NYSTRÖM-LAHTI

GASTROENTEROLOGY

W B SAUNDERS CO-ELSEVIER INC

Lugar: Philadelphia; Año: 2003

0016-5085

Background & Aims: Hereditary nonpolyposis colorectal cancer is associated with mismatch repair deficiency. Most predisposing mutations prevent the production of functional mismatch repair protein. Thus, when the wild- type copy is also inactivated, the cell becomes mis- match repair deficient, and this leads to a high degree of microsatellite instability in tumors. However, tumors linked to nontruncating mutations may display positive or partly positive immunohistochemical staining of the mutated protein and low or atypical microsatellite insta- bility status, which suggests impaired functional activity but not a total lack of mismatch repair. We found hu- man mutL homology (hMLH) 1 del616, one of the most widespread recurring mutations in hereditary nonpol- yposis colorectal cancer, segregating in a large heredi- tary nonpolyposis colorectal cancer family. Because the predicted coding change is a deletion of only 1 amino acid, the pathogenicity of the mutation was evaluated. Methods: Many analyses were performed to assess the pathogenicity of hMLH1 del616 and to study the expres- sion and function of the mutated messenger RNA and protein. Results: Genetic and immunohistochemical ev- idence supported hMLH1-linked cancer predisposition in this family. Microsatellite instability varied from low to high, and the hMLH1 protein was lost in 2 tumors but was partly detectable in 1 tumor. Whereas similar opti- mal amounts of mutated hMLH1 del616 and wild-type hMLH1 proteins were equally functional in an in vitro mismatch repair assay, the amount of in vivo? ex- pressed hMLH1 del616 was much lower than the amount of wild-type protein; this suggests that the de- letion imparts instability to the mutant protein. Conclusions: Our results suggest that the pathogenicity of hMLH1 del616 is not linked to nonfunctionality, but to shortage of the functional protein.