Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing

Abstract

Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intra-tumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multi-region whole exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20/21 known cancer gene mutations were identified in all regions of individual tumors suggesting 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 post-surgery, 3 patients have relapsed and all 3 patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

“…The coexistence of subpopulations of tumor cells with distinct phenotypic and functional properties within the same tumor points to the existence of uncharted cellular interactions or pathways that contribute to tumor growth and dissemination. Studies in renal cell carcinoma (45) and lung adenocarcinoma (46) have revealed substantial intratumoral heterogeneity as a result of subclonal driver events. Additional studies establish that interactions between genetically distinct subclones of tumor cells are necessary for maintaining tumor heterogeneity (47) and that even minor subpopulations of tumor cells may promote bulk tumor growth via mechanisms of non-cell-autonomous stimulation (48).…”

Cancer evolution and heterogeneity

“…Somatic mutations are present in all cells and they are the consequence of multiple mutational processes, including the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, and enzymatic modification of DNA and, at present, they have been classified into 30 signatures 35, 36, 37, 38. The nucleotide substitutions in those tumors were characterized as C>T from ultraviolet light (signature 7)23 and C>A from smoking (signature 4) 19, 20. Both substitutions were observed as founder events.…”

“…In addition, low‐grade glioma showed an exacerbated diversity in ITH after treatment with the alkylating agent temozolomide 39. In non‐small‐cell lung cancers (NSCLC) and bladder cancer, the apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) family of proteins was associated with fostering many subclones (signature 2) 19, 20, 40…”

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”

Intratumoral heterogeneity of esophageal squamous cell carcinoma

“…In comparison to other solid malignancies, the amount of genetic ITH detected for ESCC can be regarded as modest: for example, the amount of ITH seems comparable to lung cancer, where 76% of common mutations were reported, but far lower than clear cell renal carcinoma, where 67% of non-synonymous somatic mutations were subclonal (3,9).…”