Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development.

Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an EPCAM/MSH2 deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of TP53 pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (ABCC1, KDM4C, KIAA0430, MYH11, NDE1, PIWIL2, and ULK2) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development. KEY MESSAGE: CNVs may explain the risk of hereditary cancer syndromes in MPT patients. CNVs affecting genes related to cancer are candidates to be involved in MPT risk. EPCAM/MSH2 deletions should be investigated in patients suspected to have LS. Gene enrichment related to the TP53 network is associated with MPT development. cnLOH and CNVs contribute to the risk of MPT development.

Genomic profile of a Li-Fraumeni-like syndrome patient with a 45,X/46,XX karyotype, presenting neither mutations in TP53 nor clinical stigmata of Turner syndrome.

Li-Fraumeni syndrome (LFS) is a hereditary disorder that predisposes patients to several types of cancer and is associated with TP53 germline mutations. Turner syndrome (TS) is one of the most common aneuploidies in women. Patients with TS have a higher risk of developing cancer, although multiple malignant tumors are extremely rare. Herein, we describe a patient with a 45,X/46,XX karyotype with no classic phenotype of TS. She presented with a clinical diagnosis of Li-Fraumeni-like syndrome (LFL), showing papillary thyroid carcinoma and fibrosarcoma of the left flank, and had no TP53 germline mutations. Genome-wide analysis of copy number variations (CNVs) was assessed in DNA from peripheral blood cells and saliva. A total of 109 rare CNVs in the blood cells, including mosaic loss of the X chromosome (76% of cells), were identified. In saliva, three rare CNVs were detected, all of them were also detected in the blood cells: loss of 8q24.11 (EXT1), gain of 16q24.3 (PRDM7 and GAS8), and the mosaic loss of the X chromosome (50% of cells). Results of conventional G-banding confirmed the 45,X/46,XX karyotype. Surprisingly, the patient presented with an apparently normal phenotype. The PRDM and GAS8 genes are potential candidates to be associated with the risk of developing cancer in this LFL/TS patient.