Genetic and Epigenetic Intratumor Heterogeneity Impacts Prognosis of Lung Adenocarcinoma

Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). We investigated ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 LUAD patients. We found substantial SCNA and methylation ITH, and clonal architecture analyses showed congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Interestingly, methylation ITH mapping to gene promoter areas or tumor suppressor genes was low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes was found in several tumors. To quantify ITH for valid statistical association analyses we developed an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. APITH indexes for SCNAs and methylation aberrations were both significantly associated with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.