Concurrent DNA copy number alterations and mutations in genes related to maintenance of genome stability in uninvolved glandular tissue from breast cancer patients

Somatic mosaicism for DNA copy number alterations (SMC-CNA) is defined as gain or loss of chromosomal segments in mitotic cells within a single organism. As cells harboring SMC-CNA have the potential to undergo clonal expansion, SMC-CNA may be present in a substantial portion of cells in differentiated human tissues and may contribute to the predisposition of these cells to genetic disease including cancer. We characterized gross genomic alterations (>500 kbp) in uninvolved glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array based comparative genomic hybridization experiments showed 10% (6/59) of patients harbored 1 - 359 large SMC-CNA (mean: 1328 kbp; median: 961 kbp) in uninvolved glandular tissue. SMC-CNA were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-can, indicating genomic destabilization. Therefore, we hypothesized that the observed genomic destabilization is predetermined by mutations in genes related to maintenance of genomic integrity. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations in the following genes: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro) and TP53 (p.Arg306*). We demonstrated that gross SMC-CNA may be present in a substantial portion of glandular tissue cells, which are distant from that of the tumor cells, and may co-occur with point mutations in crucial cancer predisposing or somatic driver genes. Taken together, this highlights temporal and spatial neoplastic potential of uninvolved glandular tissue from breast cancer patients. Characterization of gross genomic alterations (>500 kbp) in uninvolved glandular tissue from 59 breast cancer patients and in the matched samples of primary tumors and lymph node metastases. Corresponding peripheral blood lekocyte DNA, a pool of female DNA (Promega), or uninvolved glandular tissue DNA was used as reference. No biological replicates are included.

DNA拷贝数变异的体细胞嵌合（Somatic mosaicism for DNA copy number alterations，SMC-CNA）被定义为单个有机体内有丝分裂细胞中染色体片段的获得或丢失。携带SMC-CNA的细胞具备克隆扩增潜力，因此SMC-CNA可在分化后的人体组织的大量细胞中存在，并会增加这些细胞罹患包括癌症在内的遗传疾病的易感性。本研究对59名乳腺癌患者的未受累腺体组织、匹配的原发性肿瘤样本及淋巴结转移灶中的大片段基因组变异（>500千碱基对）进行了特征分析。基于阵列的比较基因组杂交实验结果显示，59名患者中有10%（6/59）的未受累腺体组织中存在1至359个大片段SMC-CNA（平均长度1328千碱基对，中位长度961千碱基对）。尽管随机型SMC-CNA的贡献占比颇高，但SMC-CNA在肿瘤中呈现部分复发性特征，提示基因组存在不稳定现象。据此，我们提出假设：所观察到的基因组不稳定由与基因组完整性维持相关的基因突变预先决定。针对301个已知癌症易感位点与体细胞驱动位点的靶向重测序显示，下述基因存在突变：BRCA1（p.Gln1756Profs*74、p.Arg504Cys）、BRCA2（p.Asn3124Ile）、NCOR1（p.Pro1570Glnfs*45）、PALB2（p.Ser500Pro）及TP53（p.Arg306*）。本研究证实，大片段SMC-CNA可在远离肿瘤细胞的大量腺体组织细胞中存在，并可与关键癌症易感或体细胞驱动基因的点突变共同出现。综上，本研究结果凸显了乳腺癌患者未受累腺体组织的时空维度肿瘤转化潜能。本研究对59名乳腺癌患者的未受累腺体组织，以及匹配的原发性肿瘤与淋巴结转移灶样本中的大片段基因组变异（>500千碱基对）进行了特征分析。本研究采用的参照样本包括外周血白细胞DNA、普洛麦格（Promega）公司的女性DNA混合样本，或未受累腺体组织DNA。本研究未设置生物学重复样本。