表型不同的炎性乳腺癌的全基因组测序揭示了与非炎性乳腺癌相似的基因组改变。

Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers.

机构信息

Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.

Yale Cancer Center, Breast Medical Oncology, Yale School of Medicine, 300 George Street, Suite 120, Rm133, New Haven, CT, 06511, USA.

出版信息

Genome Med. 2021 Apr 26;13(1):70. doi: 10.1186/s13073-021-00879-x.

DOI:10.1186/s13073-021-00879-x

PMID:33902690

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8077918/

Abstract

BACKGROUND

Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases.

METHODS

We performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin).

RESULTS

Overall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages.

CONCLUSIONS

Whole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets.

摘要

背景

炎性乳腺癌（IBC）具有高度侵袭性和转移性表型。然而，其遗传驱动因素知之甚少。为了解决这个问题，我们报告了最大的 IBC 全基因组测序（WGS）队列。

方法

我们对 20 例 IBC 样本和配对的正常血液 DNA 进行了 WGS，以鉴定基因组改变。为了比较，我们使用了来自癌症基因组图谱计划（TCGA）的 23 个匹配的非 IBC 样本。我们还使用国际癌症基因组联盟（ICGC）和全基因组泛癌分析（PCAWG）联盟的 WGS 数据验证了我们的发现。我们检查了广泛的基因组特征，以寻找 IBC 和常规乳腺癌之间的差异。这些特征包括（i）编码和非编码区域中的体细胞和种系单核苷酸变异（SNV）；（ii）源自这些 SNV 的突变特征和克隆结构；（iii）拷贝数和结构变异（CNV 和 SV）；（iv）肿瘤中的非人类序列（即细菌来源的外源性序列）。

结果

总体而言，IBC 具有与非 IBC 相似的基因组特征，包括特定的改变、整体突变负荷和特征以及肿瘤异质性。特别是，我们观察到 IBC 和非 IBC 之间每个基因和大多数癌症相关途径的突变频率相似。此外，我们没有发现特定于 IBC 样本的传染性病原体的外源性序列。尽管我们无法在两组之间找到任何具有统计学意义的强区分基因组特征，但我们确实在 IBC 中发现了一些提示性差异：（i）MAST2 基因更频繁发生突变（20% IBC 比 0%非 IBC）。（ii）TGFβ 途径更频繁地被种系 SNV 破坏（50%比 13%）。（iii）在包含癌症基因的几个基因组区域观察到不同的拷贝数谱。（iv）复杂的 SV 更常见。（v）克隆结构更简单，表明肿瘤进化谱系更同质。