Homozygous deletions inactivate DCC, but not MADH4/DPC4/SMAD4, in a subset of pancreatic and biliary cancers.

Loss of heterozygosity (LOH) of chromosome arm 18q is frequent in gastrointestinal cancers. Over 90% of pancreatic carcinomas have 18q LOH. Bi-allelic inactivation of the MADH4/DPC4/SMAD4 gene at 18q21.1 is seen in about half of pancreatic carcinomas with 18q LOH. In the remaining tumors with 18q LOH, MADH4 is not mutated and its expression is unaffected, and no alterations in MADH2/SMAD2, a MADH4-related gene at 18q12.3, have been found. A controversial candidate tumor-suppressor gene at 18q21.2 is DCC (deleted in colorectal carcinoma), which encodes a netrin-1 receptor component with functions in cell migration and apoptosis. Reduced or absent DCC expression has been observed in many cancers, but few somatic mutations that would clearly inactivate DCC function have been reported. We studied a panel of 115 pancreatic and 14 biliary cancers for homozygous deletions of DCC exons and flanking 18q regions. Seven homozygous deletions were seen in the region that includes the DCC gene. In two tumors, the deletions inactivate DCC but not MADH4. A physical and transcript map of the deleted regions was constructed, and DCC was the only known gene affected by all seven deletions. These data are the strongest mutational evidence presented yet in support of the hypothesis that DCC or another gene in the region distal to MADH4 is inactivated, playing a causal role in cancer development. Copyright 2000 Wiley-Liss, Inc.