Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Abstract

Somatic mosaicism for DNA copy-number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array-based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC-CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

“…It is therefore likely that the disease process is frequently affecting considerable portions of cancer-affected breasts and that the above numbers are an underestimate. These results support the role of field cancerization in the development of SBC (Deng et al 1996;Forsti et al 2001;Heaphy et al 2009;Rennstam et al 2010;Bista et al 2012;Rivenbark and Coleman 2012;Foschini et al 2013;Ronowicz et al 2015) and are in agreement with the sick-lobe concept for the origin of SBC (Tot 2005(Tot , 2014. Our analysis represents a snapshot picture of a progressive process that is likely going on for many years, if not decades, eventually producing clinically and/or radiologically detectable PT(s).…”

Characterization of organoid cultured human breast cancer

“…This can only arise as a consequence of a selection of less aberrant cells during organoid cultures. That these nevertheless exhibit substantial genomic copy number alterations is not incompatible with a potential non-malignant or benign origin from uninvolved breast tissue of breast carcinomas [21]. Since most breast cancer predisposition loci are present already at the level of ductal carcinomas in situ (DCIS [22];), we also screened for breast cancer-associated single nucleotide variations.…”

“…Finally, it is important to appreciate the limitations of genomics in deciding between malignant and non-malignant since apparently uninvolved breast tissue from breast cancer patients shows many of the same aberrations as the cancer itself [21], and the majority of premalignant lesions resemble invasive cancer by the mutational profile [22].…”

Detection of gene mutations in gastric cancer tissues using a commercial sequencing panel

“…Three gene mutations in cancer tissues were found for two patients. Among these genes, TP53 acts as a tumor suppressor gene and plays the most important role in maintenance of genome integrity (19,20). The p53 protein also performs many complex functions within the cell (21–23).…”