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

Abstract

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1–14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

Coexisting genomic aberrations associated with lymph node metastasis in breast cancer

“…Interestingly, the duplicated haploid copy of chr1q in BN-T was not identical to that observed in the breast cancer samples ( Figure 3B). Although another study observed that oncogene amplification was a major factor in clonal expansion of premalignant cells (23) in the breast, this seems not to be the trigger event of premalignant cells in our study, but suggests that point mutations might be drivers of clonal expansion of premalignant cells.…”

Towards a personalized surgical margin for breast conserving surgery—Implications of field cancerization in local recurrence

“…Recently, Forsberg et al used whole genome analysis of breast cancer and adjacent histologically normal tissues (uninvolved margins at varying distances) to demonstrate that the most common genomic abnormality in adjacent normal tissue was a gain in gene copy number of ERBB2. Following ERBB2 genomic amplification, amplification of other growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) were the most frequent genetic aberrations [52]. The above studies provide compelling evidence that the presence of genomic instability and specific cancer-related chromosomal aberrations are often present in histologically normal tissue adjacent to breast tumors.…”

The ageing genome, clonal mosaicism and chronic disease

“…For example, sequencing data from a large-scale case-control study suggests mosaic protein truncating mutations in PPM1D may be a risk factor for breast and ovarian cancer[58], although further prospective studies are needed to verify this relationship. Additionally, a recent investigation of uninvolved margin tissue from breast cancer cases suggests mosaic copy number aberrations are present in over a third of cases and often include mosaic gains of ERBB2 and growth factor receptor genes[59]. Better understanding which events are important for future disease risk and the penetrance of such events will be important as the field moves forward in assessing clonal mosaicism as markers of risk for common diseases.…”