"Lineage Addiction" in Human Cancer: Lessons from Integrated Genomics

Abstract

Genome-era advances in the field of oncology endorse the notion that many tumors may prove vulnerable to targeted therapeuticavenues once their salient molecular alterations are elucidated. Accomplishing this requires both detailed genomiccharacterization and the ability to identify in situ the critical dependencies operant within individual tumors. To this end,DNA microarray platforms such as high-density single-nucleotide polymorphism (SNP) arrays enable large-scale cancergenome characterization, including copy number and loss-of-heterozygosity analyses at high resolution. Clustering analysesof SNP array data from a large collection of tumor samples and cell lines suggest that certain copy number alterations correlatestrongly with the tissue of origin. Such lineage-restricted alterations may harbor novel cancer genes directing genesis orprogression of tumors from distinct tissue types. We have explored this notion through combined analysis of genome-scaledata sets from the NCI60 cancer cell line collection. Here, several melanoma cell lines clustered on the basis of increaseddosage at a region of chromosome 3p containing the master melanocyte regulator MITF. Combined analysis of gene expressiondata and additional functional studies established MITF as an amplified oncogene in melanoma. MITF may thereforerepresent a nodal point within a critical lineage survival pathway operant in a subset of melanomas. These findings suggestthat, like oncogene addiction, "lineage addiction" may represent a fundamental tumor survival mechanism with importanttherapeutic implications.