Modeling non-random deletions in cancer.
Chromosome deletions do abound in cancer and are detected in certain regions in a non-random manner. Although their relevance remains elusive, it is a general agreement that segmental losses provide the cell with selective growth advantage. Consequently these may contain genes and/or regulatory sequences that control normal growth and inhibit malignancy. We have developed a monochromosomal hybrid based experimental model for the generation and functional analysis of deletions, that is called "elimination test" (Et). Focused on human chromosome 3 - that was known to carry multiple 3p deletions - the Et was expected to restrict a 3p tumor suppressor region to a sufficiently small segment that permits the selection of a critically important candidate gene. Surprisingly, we detected three regions that were lost in all or majority of tumors: CER1 (3p21.3, Mb: 43.32-45.74), CER2 (3p22, Mb: 37.83-39.06) and FER (3p14.3-p21.2, Mb: 50.12-58.03). In contrast a 3q26-qter region (CRR) was regularly retained. CER1 - our main focus - contains multiple genes that may inhibit tumor growth, but 3 genes, RIS1, LF (LTF) and LIMD1 have already the necessary experimental support to be considered bona fide tumor suppressors. Tumor suppressor region borders display instability features including: (1) they break in evolution and in tumors, (2) they evolve horizontally, and (3) they are enriched with pseudogene insertions. The most remarkable features at the breakpoint cluster regions were segmental duplications that drive horizontal evolution and contribute to cancer associated instability.
Kost-Alimova
Maria
M
Karolinska Institutet, Microbiology Tumor and Cell Biology Center (MTC), Box 280, 171 77 Stockholm, Sweden.
Imreh
Stefan
S
D000818:Animals; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D019143:Evolution, Molecular; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D011544:Pseudogenes