Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.
Zhang J., Fujimoto J., Zhang J., Wedge DC., Song X., Zhang J., Seth S., Chow CW., Cao Y., Gumbs C., Gold KA., Kalhor N., Little L., Mahadeshwar H., Moran C., Protopopov A., Sun H., Tang J., Wu X., Ye Y., William WN., Lee JJ., Heymach JV., Hong WK., Swisher S., Wistuba II., Futreal PA.
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.