2005 Articles

Two Somatic Biallelic Lesions Within and Near SMAD4 in a Human Breast Cancer Cell Line

Jakob, John; Nagase, Satoru; Gazdar, Adi; Chien, Minchen; Morozova, Irina; Russo, James J.; Nandula, Subhadra; Vundavalli, Murty V.; Li, Chi-Ming; Tycko, Benjamin; Parsons, Ramon E.

Loss of chromosome arm 18q is a common event in human pancreatic, colon, and breast cancers and is often interpreted as representing loss of one or more tumor-suppressor genes. In this article, we describe two novel biallelic deletions at chromo- some band 18q21.1 in a recently characterized human breast cancer cell line, HCC-1428. One lesion deletes a fragment of approximately 300 kb between SMAD4 and DCC that encodes no known genes. The second lesion is an in-frame SMAD4 dele- tion (amino acids 49–51) that affects the level of SMAD4 protein but not the SMAD4 message. This change accelerates 26S proteasome–mediated degradation of both endogenous and exogenous mutant SMAD4. Examination of normal DNA from the same patient demonstrated that both lesions are somatic and associated with loss of both normal alleles. These data sup- port the concept that two independent tumor-suppressor loci exist at chromosome segment 18q21.1, one at SMAD4 and the other potentially at an enhancer of DCC or an unrelated novel gene