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.

中文翻译：

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新发病例和较早发病的乳腺癌患者之间的变异景观差异

在北美和欧洲，年轻女性（≤40岁）的乳腺癌发病率有所增加。在年轻女性中，只有不到10％的病例归因于遗传的BRCA1或BRCA2突变，这表明了体细胞突变的重要作用。这项研究调查了年轻和较年长的乳腺肿瘤之间的基因组差异。在这项研究中，我们表征了89例年轻发病乳腺肿瘤（≤40岁）的突变情况，并使用The Cancer Genome Atlas的数​​据检查了949例较早发病乳腺肿瘤（> 40岁）的差异。我们检查了突变的基因，突变量和突变类型。我们使用互补的R包“ deconstructSigs”和“ SomaticSignatures”来提取突变签名。递归划分的混合模型用于确定突变特征的组合是否与发病年龄有关。老年患者在PIK3CA，CDH1和MAP3K1基因中发生突变的比例较高，而年轻发病患者在GATA3和CTNNB1中发生突变的比例较高。对于年轻发作的肿瘤，突变负荷较低，与老年发作的肿瘤相比，这些突变的比例较高的为C> A突变，但较低的比例为C> T突变。两个年龄组中最常见的突变特征是来自COSMIC数据库的特征1和3。在两个年龄组中均观察到类似于COSMIC签名2和13的签名。我们鉴定出一类具有独特特征组合的肿瘤，这些特征可能与年轻的发病年龄有关。这项探索性研究的结果提供了一些证据，表明年轻发作的乳腺癌中的突变情况和突变特征与老年发作的患者不同。新发肿瘤的特征可能为它们的病因提供线索，可能为将来的预防提供依据。需要进一步研究以确认我们的发现。