Poudel Pawan, Nyamundanda Gift, Patil Yatish, Cheang Maggie Chon U, Sadanandam Anguraj
1Division of Molecular Pathology, Institute of Cancer Research, London, UK.
2Centre for Molecular Pathology, Royal Marsden Hospital, London, UK.
NPJ Breast Cancer. 2019 Aug 2;5:21. doi: 10.1038/s41523-019-0116-8. eCollection 2019.
Breast cancer is a highly heterogeneous disease. Although differences between intrinsic breast cancer subtypes have been well studied, heterogeneity within each subtype, especially luminal-A cancers, requires further interrogation to personalize disease management. Here, we applied well-characterized and cancer-associated heterocellular signatures representing stem, mesenchymal, stromal, immune, and epithelial cell types to breast cancer. This analysis stratified the luminal-A breast cancer samples into five subtypes with a majority of them enriched for a subtype (stem-like) that has increased stem and stromal cell gene signatures, representing potential luminal progenitor origin. The enrichment of immune checkpoint genes and other immune cell types in two (including stem-like) of the five heterocellular subtypes of luminal-A tumors suggest their potential response to immunotherapy. These immune-enriched subtypes of luminal-A tumors (containing only estrogen receptor positive samples) showed good or intermediate prognosis along with the two other differentiated subtypes as assessed using recurrence-free and distant metastasis-free patient survival outcomes. On the other hand, a partially differentiated subtype of luminal-A breast cancer with transit-amplifying colon-crypt characteristics showed poor prognosis. Furthermore, published luminal-A subtypes associated with specific somatic copy number alterations and mutations shared similar cellular and mutational characteristics to colorectal cancer subtypes where the heterocellular signatures were derived. These heterocellular subtypes reveal transcriptome and cell-type based heterogeneity of luminal-A and other breast cancer subtypes that may be useful for additional understanding of the cancer type and potential patient stratification and personalized medicine.
乳腺癌是一种高度异质性疾病。尽管对乳腺癌内在亚型之间的差异已有充分研究，但各亚型内部的异质性，尤其是管腔A型癌症，仍需进一步探究以实现疾病管理的个性化。在此，我们将代表干细胞、间充质细胞、基质细胞、免疫细胞和上皮细胞类型的特征明确且与癌症相关的异细胞特征应用于乳腺癌。该分析将管腔A型乳腺癌样本分为五个亚型，其中大多数样本富集于一种具有增加的干细胞和基质细胞基因特征的亚型（干细胞样），代表潜在的管腔祖细胞起源。管腔A型肿瘤的五个异细胞亚型中的两个（包括干细胞样）中免疫检查点基因和其他免疫细胞类型的富集表明它们对免疫治疗的潜在反应。这些免疫富集的管腔A型肿瘤亚型（仅包含雌激素受体阳性样本），与另外两个分化亚型一样，根据无复发生存率和无远处转移生存率评估显示出良好或中等的预后。另一方面，具有过渡扩增结肠隐窝特征的部分分化的管腔A型乳腺癌亚型预后较差。此外，已发表的与特定体细胞拷贝数改变和突变相关的管腔A型亚型与异细胞特征所源自的结直肠癌亚型具有相似的细胞和突变特征。这些异细胞亚型揭示了管腔A型和其他乳腺癌亚型基于转录组和细胞类型的异质性，这可能有助于进一步了解癌症类型以及潜在的患者分层和个性化医疗。
