Intra-tumor Heterogeneity in Localized Lung Adenocarcinomas Delineated by Multi-region Sequencing
By Jianjun Zhang, J. Fujimoto, Jianhua Zhang, David C. Wedge, Xingzhi Song, Jiexin Zhang, S. Seth, C. Chow, Yu Cao, C. Gumbs and 17 more. Science, 2014
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Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas. Different mutations are present in different regions of any given lung cancer, and their pattern may predict patient relapse. [Also see Perspective by Govindan] Space, time, and the lung cancer genome Lung cancer poses a formidable challenge to clinical oncologists. It is often detected at a late stage, and most therapies work for only a short time before the tumors resume their relentless growth. Two independent analyses of the human lung cancer genome may help explain why this disease is so resilient (see the Perspective by Govindan). Rather than take a single “snapshot” of the cancer genome, de Bruin et al. and Zhang et al. identified genomic alterations in spatially distinct regions of single lung tumors and used this information to infer the tumor's evolutionary history. Each tumor showed tremendous spatial and temporal diversity in its mutational profiles. Thus, the efficacy of drugs may be short-lived because they destroy only a portion of the tumor. Science, this issue p. 251, p. 256; see also p. 169
Subfields: Cancer Research, Pathology and Forensic Medicine, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/7876067a76ab9eca6ecd4cd513ff51238c91bf81
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Citations in the corpus
- Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, neutral): “Similarly, recurrent and independent acquisition of copy number events such as deletions in PAX5, ETV6 and CDKN2A have been described in acute lymphoblastic leukemia (ALL) within distinct subclones (Anderson et al., 2011).”
- Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. (2015, background): “In 11 early-stage NSCLCs, primary tumors from three patients with relapsed disease had significantly larger subclonal fractions than tumors from patients with relapse free tumors (Zhang et al., 2014).”
- Current Challenges in Cancer Treatment. (2016, result): “Multiregion whole-exome sequencing in 11 localized adenocarcinomas did reveal high levels of intratumor heterogeneity but, importantly, the majority of mutations (76%) were present in all tumors regions, and most of the driver mutations tended to be truncal, occurring early in tumorigenesis.(52) Thi”
- Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “Multiregional sequencing of renal carcinoma, glioblastoma and lung cancer have all showed significant divergence between distinct areas of the same tumor (Gerlinger et al., 2012; Thrane et al., 2018; Yates et al., 2015; Zhang et al., 2014).”