In the parous group, uniparous women were preferentially included in the study ( n uniparous = 15/17) and the average BMI of 29.3 was comparable with the US female population 20 (Fig. We analyzed a total of 29 frozen healthy breast tissues from donors with no previous use of hormonal contraception and without pathogenic mutations in BRCA1 or BRCA2.
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However, the samples are provided with a full record of parity and clinical history, including cancer history and BMI status, making them the preferred source of tissue for this study. These specimens are characterized by less material than a reduction mammoplasty, thus not allowing multi-sampling. Komen Tissue Bank at IU Simon Cancer Center, which provided us with single ~0.5 cm 2 biopsies collected by healthy donors. To avoid a bias for different BMIs in the sample cohort, we chose the open-access Susan G. The contribution of body-mass index (BMI) to the alteration of the genetic landscape of mammoplasty specimens is complex and not usually acknowledged and highlights the need for different sources of healthy breast tissue for research. While a higher BMI has been associated with a higher risk of developing BC in postmenopausal women 18, it confers a protection towards the malignancy in younger individuals 19. The most common source of research material for studies on the non-diseased breast is reduction mammoplasty, which is often characterized by a higher body mass index (BMI) of the donor. In this study, we sequence the whole genome of the healthy breast samples during reproductive years and determine how both age and pregnancy alter the genomic composition of the mammary gland, both in the epithelial and stromal compartments, and the implications on cancer development. However, pregnancy-specific mutational changes or clonal dynamics of the healthy breast, and in particular of cancer-associated genes are still unknown. Compartment-specific sequencing of healthy tissue is therefore crucial not only to understand the architecture of the normal breast but also to determine the probability of developing tissue-associated diseases, including BC. Several studies have recognized the complex contribution of parity and age to the healthy mammary genome, including to the risk of breast cancer (BC) development 15, 16, 17. Furthermore, after breast-feeding, a strong apoptotic drive, which determines the beginning of post-partum mammary involution 13, contributes to major tissue remodelling which can last up to 10 years after parturition 14. It has been estimated that the gain of 0.7 ± 0.1 new cells per day in pre-menopausal women 11, but the proliferation index can increase nearly 5 times during pregnancy 12. In all adult healthy tissues, somatic mutations increase through adult life 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, but the mutational landscape of the human breast has not been characterized thus far.Ĭompared to other solid tissues, the adult human breast is characterized by a generally slow proliferating epithelium, which undergoes significant changes during reproduction, and in particular during pregnancy. In conclusion, we describe the reference genome of the healthy female human breast during reproductive years and provide evidence of how parity affects the genomic landscape of the mammary gland. Parity is associated with an age-dependent increase in the clone size of mutated epithelial cells, suggesting that older first-time mothers have a higher probability of accumulating oncogenic events in the epithelium compared to younger mothers or nulliparous women. Parity- and age-associated differences are evident in the mammary epithelium, partly explaining the observed difference in breast cancer risk amongst women of different childbearing age.
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Both epithelial and stromal compartments contain mutations in breast-specific driver genes, indicative of subsequent positive selection. Our analysis of whole-genome sequencing shows that in line with other healthy organs, the healthy breast during the reproduction years accumulates mutations with age, with the rate of accumulation in the epithelium of 15.24 ± 5 mutations/year. The accumulation of somatic mutations in healthy human tissues has been extensively characterized, but the mutational landscape of the healthy breast is still poorly understood.
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