Germline large genomic alterations on 7q in patients with multiple primary cancers

R A R Villacis,M I Achatz,T R Basso,L M Canto,S R Rogatto,A F Nóbrega

doi:10.1038/srep41677

Abstract

Patients with multiple primary cancers (MPCs) are suspected to have a hereditary cancer syndrome. However, only a small proportion may be explained by mutations in high-penetrance genes. We investigate two unrelated MPC patients that met Hereditary Breast and Ovaria Cancer criteria, both presenting triple negative breast tumors and no mutations in BRCA1, BRCA2 and TP53 genes. Germline rearrangements on chromosome 7q, involving over 40 Mb of the same region, were found in both patients: one with mosaic loss (80% of cells) and the other with cnLOH (copy-neutral loss of heterozygosity) secondary to maternal allele duplication. Five children tested had no alterations on 7q. The patients shared 330 genes in common on 7q22.1-q34, including several tumor suppressor genes (TSGs) previously related to breast cancer risk and imprinted genes. The analysis of the triple negative BC from one patient revealed a mosaic gain of 7q translated for over-expressed cancer-related genes. The involvement of TSGs and imprinted genes, mapped on 7q, has the potential of being associated to MPC risk, as well as cancer progression. To our knowledge, this is the first description of patients with MPCs that harbor constitutive large alterations on 7q.

Highlights

Patients with multiple primary cancers (MPCs) are suspected to have a hereditary cancer syndrome
Part of the missing heritability in Breast cancer (BC) may be explained by copy number variations (CNVs), which are chromosomal regions altered by gains or losses, or by copy-neutral loss of heterozygosity, defined as homozygous regions appearing as a result of inheritance of a pair of alleles from a single parent[8,9]
The occurrence of MPCs in one individual may be due to environmental factors, aging, germline mutations or by chance[5,6]

Summary

Introduction

Patients with multiple primary cancers (MPCs) are suspected to have a hereditary cancer syndrome. We investigate two unrelated MPC patients that met Hereditary Breast and Ovaria Cancer criteria, both presenting triple negative breast tumors and no mutations in BRCA1, BRCA2 and TP53 genes. The involvement of TSGs and imprinted genes, mapped on 7q, has the potential of being associated to MPC risk, as well as cancer progression. To our knowledge, this is the first description of patients with MPCs that harbor constitutive large alterations on 7q. An increased frequency of cnLOH in cases where no mutations are present in the mismatch repair genes suggests the involvement of unknown germline alterations in familial colorectal cancer risk[13]. Genomic deletions on chromosome 7q have been associated with congenital defects, including developmental delay, learning difficulties, craniofacial dysmorphism and hypogenitalism[19,20,21,22]

Methods

Results

Conclusion