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Abstract：
Early-onset breast cancer (EoBC), defined by a diagnosis <40 years of age, is associated with poor prognosis. This study investigated the mutational landscape of non-metastatic EoBC and the prognostic relevance of mutational signatures using 100 tumour samples from Alberta, Canada. The MutationalPatterns package in R/Bioconductor was used to extract de novo single-base substitution (SBS) and insertion-deletion (indel) mutational signatures and to fit COSMIC SBS and indel signatures. We assessed associations between these signatures and clinical characteristics of disease, in addition to recurrence-free (RFS) and overall survival (OS). Five SBS and two indel signatures were extracted. The SBS13-like signature had higher relative contributions in the HER2-enriched subtype. Patients with higher than median contribution tended to have better RFS after adjustment for other prognostic factors (HR = 0.29; 95% CI: 0.08-1.06). An unsupervised clustering algorithm based on absolute contribution revealed three clusters of fitted COSMIC SBS signatures, but cluster membership was not associated with clinical variables or survival outcomes. The results of this exploratory study reveal various SBS and indel signatures may be associated with clinical features of disease and prognosis. Future studies with larger samples are required to better understand the mechanistic underpinnings of disease progression and treatment response in EoBC.
摘要：
早发性乳腺癌（EoBC），由<40岁的诊断定义，与预后不良有关。这项研究使用来自艾伯塔省的100个肿瘤样本调查了非转移性EoBC的突变景观和突变特征的预后相关性。加拿大。R/Bioconductor中的MutationalPatterns软件包用于提取从头单碱基替换（SBS）和插入-缺失（indel）突变签名，并适合COSMICSBS和indel签名。我们评估了这些特征与疾病临床特征之间的关联，除了无复发（RFS）和总生存期（OS）。提取了五个SBS和两个indel签名。SBS13样特征在HER2富集亚型中具有较高的相对贡献。在调整其他预后因素后，贡献高于中位数的患者倾向于具有更好的RFS（HR=0.29；95％CI：0.08-1.06）。基于绝对贡献的无监督聚类算法揭示了三个拟合的COSMICSBS签名簇，但聚类成员与临床变量或生存结局无关.这项探索性研究的结果表明，各种SBS和indel特征可能与疾病的临床特征和预后有关。未来需要进行更大样本的研究，以更好地了解EoBC中疾病进展和治疗反应的机制基础。
