Intratumor heterogeneity (ITH) of lung adenocarcinomas defined by multiregion whole exome sequencing (WES).

Abstract

11032 Background: Individual cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed ITH. ITH may have profound impacts on biopsy strategy, characterization of actionable targets, treatment planning, and drug resistance. The extent and architecture of ITH of lung cancers are largely unknown. Methods: We performed multi-region WES of 48 samples from 11 surgically resected lung adenocarcinomas and their matched peripheral blood leukocytes to an average of 267-fold sequencing depth. All tumor samples were analyzed for point mutations, insertions/deletions, and copy number alterations. All somatic variations were validated with targeted capture ultra-deep sequencing to an average of 869-fold sequencing depth. Sub-clonal analysis based on a Bayesian statistics approach process was performed in each tumor sample. Phylogenetic trees of these 11 tumors were constructed after clonal ordering. Results: 17,572 somatic point mutations, insertions, and deletions were identified and validated. The numbers of somatic alterations varied significantly among different patients and among different samples within the same tumor suggesting significant inter- and intra-tumor heterogeneity. Sub-clonal analysis suggested presence of multiple related populations in each sample with the distribution allele frequencies varying substantially across regions of the same tumor. The majority of known driver mutations (e.g., EGFR, KRAS) were present in all regions of the sampled tumors. There was no correlation with extent/structure of ITH and age, gender, tumor size, lymph node status, or smoking status. With a median follow-up of 2.5 years, 2 patients recurred. Of potential interest, these 2 patients had the most complex ITH architectures in their primary tumors. Conclusions: Different lung adenocarcinomas may have distinct ITH architectures. Although the sample size is very small, the fact that both patients who relapsed had complex ITH architectures suggests that complex ITH architectures may lead to unfavorable clinical outcomes. Studies on larger cohorts are needed to elucidate the clinical impacts of ITH.