Genomic alterations in MPT patients with multiple primary tumors

Multiple primary tumors (MPT) usually develop in MPT patients with hereditary cancer syndromes. Nonetheless, the genetic etiology of a large proportion of MPT cases remains unclear. In this study, germline copy number variations (CNVs) and cnLOH (copy-neutral loss of heterozygosity) were investigated in 22 MPT MPT patients having no mutations in the main cancer predisposition genes. Our main goal was to uncover new genes potentially related to a high risk of developing MPT. Twenty MPT patients have family history of cancer and 12 met criteria for hereditary cancer syndromes. Seventeen rare germline CNVs covering 40 genes were identified in 11 MPT patients, including an EPCAM/MSH2 deletion in one Lynch Syndrome MPT patient. An enrichment analysis with the genes mapped in the rare CNVs revealed a significant number of genes associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. A network analysis emphasized the relevance of TP53 pathway in carcinogenesis. A high number of germline cnLOH was detected in nine MPT patients, especially in two cases. Eighteen genes were covered both by rare CNVs and cnLOH, seven of them (ABCC1, KDM4C, KIAA0430, MYH11, NDE1, PIWIL2 and ULK2) were directly related to cellular growth and proliferation. These genes may represent interesting candidates for further studies in MPT risk. Microarray experiments were conducted following the manufacturer's instructions (CytoScan HD, Affymetrix) on DNA extracted from peripheral blood of 22 MPT MPT patients.