An analysis of genetic heterogeneity in untreated cancers

遗传异质性 肿瘤异质性 同种类的 生物 基因 遗传分析 癌症的体细胞进化 突变 遗传学 癌症研究 癌症 表型 物理 热力学
作者
Johannes G. Reiter,Marina Baretti,Jeffrey M. Gerold,Alvin Makohon‐Moore,Adil Daud,Christine A. Iacobuzio‐Donahue,Nilofer S. Azad,Kenneth W. Kinzler,Martin A. Nowak,Bert Vogelstein
出处
期刊:Nature Reviews Cancer [Nature Portfolio]
卷期号:19 (11): 639-650 被引量:159
标识
DOI:10.1038/s41568-019-0185-x
摘要

Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative. This Analysis article examines the extent of genetic heterogeneity within several types of untreated cancers, with particular regard to its clinical relevance, and finds that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception.
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