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Breast Cancer Research and Treatment 肿瘤异质性包括肿瘤间异质性（不同患者同类肿瘤之间存在的差异性）和肿瘤内异质性（同一肿瘤内细胞之间存在的差异性）。肿瘤内异质性（ITH）对乳腺癌的进展和耐药起到关键作用。 2017年1月16日，美国《乳腺癌研究与治疗》在线发表复旦大学（附属肿瘤医院、上海医学院、生物医学研究院）马丁、江一舟、刘依熔、邵志敏等学者的研究报告，使用突变等位基因肿瘤异质性（MATH）算法衡量肿瘤内异质性，并探讨其与临床指标和多组学（包括基因组学、蛋白质组学、代谢物组学、转录组学、表观遗传组学、表型组学等）数据的相关性。 该研究根据美国国家卫生研究院（NIH）癌症基因组图谱（TCGA）分析了916例女性乳腺癌患者，计算了全外显子测序数据的MATH值，并分为低、中、高MATH组，进一步研究其与临床特征、体细胞突变、体细胞拷贝数改变、基因富集的相关性。 结果发现，高T分期、非洲裔美国人、三阴性或基底样亚型，与MATH水平较高有相关性（所有P＜0.001）。在激素受体阳性、人类表皮生长因子受体阴性患者中，高MATH组表现出总生存较差的趋势（P=0.052）；此外，TP53突变率随着MATH升高而增加（P＜0.001），而CDH1突变与MATH较低水平有相关性（P=0.002）。若干位点和染色体臂水平的体细胞拷贝数改变在高MATH组中较常见（P＜0.05），包括Chr8q24仅与MYC基因见于“峰”区。同样，高MATH与与MYC通路和增殖相关的基因集富集有相关性。 因此，该全面分析揭示了乳腺癌肿瘤内异质性的遗传和临床意义。这些结果还表明肿瘤内基因异质性和克隆进化的自然史和起源值得进一步研究。 Breast Cancer Res Treat. 2017 Jan 16. Clinical and molecular relevance of mutant-allele tumor heterogeneity in breast cancer. Ma D, Jiang YZ, Liu XY, Liu YR, Shao ZM. Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Shanghai Medical College, Fudan University, Shanghai, People's Republic of China; Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China. PURPOSE: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data. METHODS: We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment. RESULTS: The patients were divided into low, intermediate, and high MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P < 0.001). In hormone receptor-positive and human epidermal growth factor receptor-negative patients, the high MATH group showed a tendency toward a worse overall survival (P = 0.052); Furthermore, the TP53 mutation rate increased as MATH was elevated (P < 0.001), whereas CDH1 mutations were correlated with a lower level of MATH (P = 0.002). Several focal and arm-level SCNA events were more common in the high MATH group (P < 0.05), including Chr8q24 with only the MYC gene in the "peak" region. Similarly, high MATH was associated with gene set enrichment related to the MYC pathway and proliferation. CONCLUSION: Our integrative analysis reveals the clinical and genetic relevance of ITH in breast cancer. These results also suggest the origin and natural history of clonal evolution and intra-tumor genetic heterogeneity, which warrant further investigation. KEYWORDS: Breast cancer; Intra-tumor genetic heterogeneity; MYC; Mutant-allele tumor heterogeneity; The Cancer Genome Atlas PMID: 28093659 DOI: 10.1007/s10549-017-4113-z
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