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abstract
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.
Supplementary materials (eg. 1st-4th primary, variants)
Clinico-pathological information of the 22 patients enrolled in the study
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.
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