title: Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer.
abstract: Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.
authors.affiliation: Department of Respiration, Center Lab in Research Center for Clinical Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Le-Le
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Department of Respiration, Center Lab in Research Center for Clinical Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Kan
authors.affiliation: Department of Respiration, Center Lab in Research Center for Clinical Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Man-Man
authors.initials: MM
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hai-Ning
authors.initials: HN
authors.lastname: Wang
authors.affiliation: Department of Respiration, Center Lab in Research Center for Clinical Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Shuang-Xia
authors.initials: SX
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Guang-Biao
authors.initials: GB
authors.lastname: Zhou
authors.affiliation: Department of Respiration, Center Lab in Research Center for Clinical Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
authors.affiliation: Department of Respiration, Center Lab in Research Center for Clinical Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Cui-Xia
authors.initials: CX
authors.lastname: Zheng
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018450:Disease Progression; D019143:Evolution, Molecular; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation; D010802:Phylogeny; D017422:Sequence Analysis, DNA / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: TP53 driver mutation; intratumor heterogeneity; multiregion sequencing; non-small cell lung cancer