MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma.
MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma.
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DOI：
10.1016/j.oraloncology.2012.09.007
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发表时间：
2013-03
期刊：
影响因子：
4.8
通讯作者：
Rocco, James W.
中科院分区：
文献类型：
--
作者：
Mroz, Edmund A.;Rocco, James W.
关键词：
肿瘤内癌细胞之间的差异在肿瘤发生和治疗抗性中是重要的，但是没有肿瘤内异质性的测量适合于常规应用。我们开发了一种肿瘤内遗传异质性的定量测量方法，该方法基于肿瘤DNA的下一代测序（NGS）确定的突变基因座中的突变等位基因片段之间的差异。然后，我们评估了这项措施的应用，头颈部鳞状细胞癌（HNSCC）。我们分析了74例HNSCC的电子版NGS结果。对于每种肿瘤，我们计算了肿瘤特异性突变基因座中的多基因等位基因分数分布的宽度与中心的比值，即多基因等位基因肿瘤异质性（MATH）。通过MATH评估的肿瘤内异质性在3种预后不良的HNSCC类别中较高：TP53基因中具有破坏性突变的肿瘤（与野生型TP53或非破坏性突变相比），人乳头瘤病毒阴性与阳性的肿瘤（即使仅限于具有野生型TP53的肿瘤），以及来自吸烟者的HPV阴性肿瘤，其吸烟包年数更多（考虑TP53状态）。这种类型的肿瘤内异质性与HNSCC结果分类的关系支持其作为预后生物标志物的进一步评价。随着肿瘤DNA的NGS在临床研究和实践中的广泛应用，MATH应该提供一种简单，定量和临床实用的生物标志物，以帮助评估肿瘤内遗传异质性与任何类型癌症结局的关系。
Differences among cancer cells within a tumor are important in tumorigenesis and treatment resistance, yet no measure of intratumor heterogeneity is suitable for routine application. We developed a quantitative measure of intratumor genetic heterogeneity, based on differences among mutated loci in the mutant-allele fractions determined by next-generation sequencing (NGS) of tumor DNA. We then evaluated the application of this measure to head and neck squamous cell carcinoma (HNSCC). We analyzed published electronically available NGS results for 74 HNSCC. For each tumor we calculated mutant-allele tumor heterogeneity (MATH) as the ratio of the width to the center of its distribution of mutant-allele fractions among tumor-specific mutated loci. Intratumor heterogeneity assessed by MATH was higher in 3 poor-outcome classes of HNSCC: tumors with disruptive mutations in the TP53 gene (versus wild-type TP53 or non-disruptive mutations), tumors negative versus positive for human papillomavirus (even when restricted to tumors having wild-type TP53), and HPV-negative tumors from smokers with more pack-years of cigarette exposure (with TP53 status taken into account). The relation of this type of intratumor heterogeneity to HNSCC outcome classes supports its further evaluation as a prognostic biomarker. As NGS of tumor DNA becomes widespread in clinical research and practice, MATH should provide a simple, quantitative, and clinically practical biomarker to help evaluate relations of intratumor genetic heterogeneity to outcome in any type of cancer.
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影响因子：
64.8
作者：
Navin N;Kendall J;Troge J;Andrews P;Rodgers L;McIndoo J;Cook K;Stepansky A;Levy D;Esposito D;Muthuswamy L;Krasnitz A;McCombie WR;Hicks J;Wigler M
通讯作者：
Wigler M
影响因子：
158.5
作者：
Poeta, M. Luana;Manola, Judith;Koch, Wayne M.
通讯作者：
Koch, Wayne M.
DOI：
10.1158/1078-0432.ccr-11-2260
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Skinner HD;Sandulache VC;Ow TJ;Meyn RE;Yordy JS;Beadle BM;Fitzgerald AL;Giri U;Ang KK;Myers JN
通讯作者：
Myers JN
影响因子：
10.3
作者：
Fakhry, Carole;Westra, William H.;Gillison, Maura L.
通讯作者：
Gillison, Maura L.
影响因子：
8
作者：
Smeets, SJ;Braakhuis, BJM;Brakenhoff, RH
通讯作者：
Brakenhoff, RH