PLoS Med：新型基因组学工具或可帮助预测癌症患者对疗法的耐受性

  近日，刊登在国际杂志PLoS Medicine上的一篇研究论文中，来自俄亥俄州大学癌症研究中的科学家通过研究开发了一种新方法，其可以测定肿瘤内部的遗传改变，这或许可以帮助医生们鉴别那些对疗法容易产生耐受性的恶性癌症患者。
  文章中，研究者利用他们开发的名为MATH（mutant-allele tumor heterogeneity，突变体等位基因肿瘤异质性）的新型评分方法测定了305名头颈癌患者机体肿瘤细胞的遗传改变；较高的MATH分数就表明在不同癌细胞中存在许多不同的基因突变。
  癌症往往表现出较高的遗传改变，名为肿瘤内部异质性，其和患者生存率下降相关，如果前瞻性研究证实了研究者的发现，那么MATH评分或可帮助患者选择最有效的疗法以及预测患者的预后情况。
  研究者Rocco说道，肿瘤内部的遗传改变促使患者对疗法产生耐受，而本文研究中我们证实了肿瘤内部的异质性和癌症患者的死亡率增加直接相关，MATH分数增加10%就代表着患者的死亡可能性会增加8.8%。
  研究者的回顾分析表明，相比低度异质性肿瘤患者而言，携带高度异质性肿瘤的患者死亡的可能性是前者的2倍多，而相关的研究获奖帮助研究者预测针对患者的疗法是否会成功以及开发出新型的靶向策略。研究人员认为这项研究首次结合并分析了成百上千名患者的数据来揭示肿瘤的异质性，这为预测患者对疗法的耐受性以及其总体生存率都提供了一定的帮助。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas
PLoS Med        DOI: 10.1371/journal.pmed.1001786
Edmund A. Mroz, Aaron M. Tward, Rebecca J. Hammon, Yin Ren, James W. Rocco 
Background

Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality.

Methods and Findings

Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed.

Conclusions

To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.