Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Present Address: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, USA.
Breast Cancer Res. 2019 Feb 15;21(1):25. doi: 10.1186/s13058-019-1111-6.
Although parity and age at first pregnancy are among the most known extrinsic factors that modulate breast cancer risk, their impact on the biology of subsequent breast cancer has never been explored in depth. Recent data suggest that pregnancy-induced tumor protection is different according to breast cancer subtypes, with parity and young age at first pregnancy being associated with a marked reduction in the risk of developing luminal subtype but not triple negative breast cancer. In this study, we investigated the imprint of parity and age at first pregnancy on the pattern of somatic mutations, somatic copy number alterations, transcriptomic profiles, and tumor immune microenvironment by assessing tumor-infiltrating lymphocytes (TILs) levels of subsequent breast cancer.
A total of 313 patients with primary breast cancer with available whole genome, RNA sequencing, and TILs data were included in this study. We used a multivariate analysis adjusted for age at diagnosis, pathological stage, molecular subtypes, and histological subtypes. We compared nulliparous vs. parous, late parous vs. early parous, and nulliparous vs. pregnancy-associated breast cancer (PABC) patients. Late and early parous patients were grouped by using the median age at first pregnancy. PABC was defined as patients diagnosed up to 10 years postpartum.
Genomic alterations of breast cancer were associated with age at first pregnancy but not with parity status alone. Independently of clinicopathological features, early parous patients developed tumors characterized by a higher number of Indels (P = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7%; P = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%; P = 0.010), and MYC amplification (28% vs. 7%; P = 0.008). PABC were associated with increased TILs infiltration (P = 0.0495).
These findings highlight an unprecedented link between reproductive history and the genomic landscape of subsequent breast cancer. We further hypothesize that TP53-mutant premalignant lesions could be less susceptible to the protective effect of an early parity, which might explain the difference of parity-induced protection according to breast cancer subtypes. This work also advocates that reproductive history should be routinely collected in future large-scale genomic studies addressing the biology of female cancers.
尽管生育次数和首次妊娠年龄是调节乳腺癌风险的最已知的外在因素，但它们对随后发生的乳腺癌生物学的影响从未被深入探索。最近的数据表明，妊娠诱导的肿瘤保护作用因乳腺癌亚型而异，生育次数多和首次妊娠年龄小与 luminal 亚型乳腺癌风险显著降低有关，但与三阴性乳腺癌无关。在这项研究中，我们通过评估随后发生的乳腺癌肿瘤浸润淋巴细胞（TIL）水平，研究了生育次数和首次妊娠年龄对体细胞突变、体细胞拷贝数改变、转录组谱和肿瘤免疫微环境模式的影响。
共纳入 313 例具有全基因组、RNA 测序和 TILs 数据的原发性乳腺癌患者。我们使用了一种多变量分析方法，该方法调整了诊断时的年龄、病理分期、分子亚型和组织学亚型。我们比较了未育者与生育者、晚育者与早育者、未育者与妊娠相关乳腺癌（PABC）患者。晚育者和早育者通过首次妊娠的中位数年龄进行分组。PABC 定义为产后 10 年内诊断出的患者。
乳腺癌的基因组改变与首次妊娠年龄有关，但与生育次数无关。独立于临床病理特征，早育患者发生的肿瘤具有更高数量的插入缺失（Indels）（P=0.002）、更低频率的 CDH1 突变（1.2%比 12.7%；P=0.013）、更高频率的 TP53 突变（50%比 22.5%；P=0.010）和 MYC 扩增（28%比 7%；P=0.008）。PABC 与 TILs 浸润增加相关（P=0.0495）。
这些发现强调了生殖史与随后发生的乳腺癌基因组图谱之间前所未有的联系。我们进一步假设，TP53 突变的癌前病变可能对早期生育的保护作用不敏感，这可能解释了生育保护作用根据乳腺癌亚型的不同而不同。这项工作还主张，在未来的大规模基因组研究中，应常规收集生殖史，以解决女性癌症的生物学问题。
