Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada.
BMC Cancer. 2020 Mar 12;20(1):212. doi: 10.1186/s12885-020-6684-z.
The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours.
In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages "deconstructSigs" and "SomaticSignatures" to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset.
Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young-onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young-onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. Signatures resembling COSMIC signatures 2 and 13 were observed among both age groups. We identified a class of tumours with a unique combination of signatures that may be associated with young age of onset.
The results of this exploratory study provide some evidence that the mutational landscape and mutational signatures among young-onset breast cancer are different from those of older-onset patients. The characterization of young-onset tumours could provide clues to their etiology which may inform future prevention. Further studies are required to confirm our findings.
在北美和欧洲，年轻女性（年龄≤40 岁）的乳腺癌发病率有所增加。年轻女性中不到 10%的病例归因于遗传性 BRCA1 或 BRCA2 突变，这表明体细胞突变起着重要作用。本研究调查了年轻和老年发病乳腺癌肿瘤之间的基因组差异。
在这项研究中，我们使用癌症基因组图谱的数据，对 89 例年轻发病乳腺癌（≤40 岁）的突变情况进行了特征描述，并检查了 949 例老年发病乳腺癌（>40 岁）的差异。我们检查了突变基因、突变负荷和突变类型。我们使用补充的 R 包“deconstructSigs”和“SomaticSignatures”来提取突变特征。递归分区混合模型用于确定突变特征的组合是否与发病年龄有关。
老年患者 PIK3CA、CDH1 和 MAP3K1 基因突变的比例较高，而年轻发病患者 GATA3 和 CTNNB1 基因突变的比例较高。年轻发病肿瘤的突变负荷较低，C>A 突变的比例较高，而 C>T 突变的比例较低，与老年发病肿瘤相比。在这两个年龄组中都发现了最常见的突变特征，即 COSMIC 数据库中的特征 1 和特征 3。在这两个年龄组中都观察到类似于 COSMIC 特征 2 和特征 13 的特征。我们确定了一类具有独特特征组合的肿瘤，这些特征可能与发病年龄较轻有关。
这项探索性研究的结果提供了一些证据，表明年轻发病乳腺癌的突变情况和突变特征与老年发病患者不同。年轻发病肿瘤的特征描述可能为其病因提供线索，从而为未来的预防提供信息。需要进一步的研究来证实我们的发现。
