Genome wide identification of recessive cancer genes by combinatorial mutation analysis

Abstract

We devised a novel procedure to identify human cancer genes acting in a recessive manner. Our strategy was to combine the contributions of the different types of genetic alterations to loss of function: amino-acid substitutions, frame-shifts, gene deletions. We studied over 20,000 genes in 3 Gigabases of coding sequences and 700 array comparative genomic hybridizations. Recessive genes were scored according to nucleotide mismatches under positive selective pressure, frameshifts and genomic deletions in cancer. Four different tests were combined together yielding a cancer recessive p-value for each studied gene. One hundred and fifty four candidate recessive cancer genes (p-value<1.56× 10-7, FDR = 0.39) were identified. Strikingly, the prototypical cancer recessive genes TP53, PTEN and CDKN2A all ranked in the top 0.5% genes. The functions significantly affected by cancer mutations are exactly overlapping those of known cancer genes, with the critical exception for the absence of tyrosine kinases, as expected for a recessive gene-set. © 2008 Volinia et al.