Molecular Pathology Abstracts, 6/17

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Intratumor heterogeneity and tumor evolution of non-small cell lung cancer

While several recent studies have characterized the molecular attributes of primary lung adenocarcinomas and squamous cell carcinomas, data on intratumor heterogeneity are limited. In an ongoing multi-center prospective cohort study in the United Kingdom, titled Tracking Non-Small Cell Lung Cancer Evolution through Therapy, or TRACERx, researchers will be following the lung tumors from 842 non-small cell lung cancer (NSCLC) patients to understand their evolution. Molecular and genetic techniques will be used to analyze the spatial and temporal heterogeneity of NSCLC. The authors reported on data from the first 100 patients recruited into the TRACERx study, focusing on spatial intratumor heterogeneity of NSCLC with respect to mutations and copy number alterations. They collected primary tumor samples from 100 patients, with disease stages ranging from IA through IIIA, all of whom had not received systemic therapy. The authors took samples from at least two tumor regions separated by 0.3 to 1.0 cm and performed whole exome sequencing on 327 tumor regions and 100 matched germline samples to a median depth of 426×. They observed extensive intratumor heterogeneity, with 30 percent of somatic mutations and 48 percent of copy number alterations classified as subclonal. The individual tumors, however, exhibited a wide variability in tumor heterogeneity, with the number of subclonal mutations ranging from two to 2,310. The authors observed a correlation between the proportion of subclonal copy number alterations and tumor stage. Additionally, the patients with higher proportions of subclonal copy number alterations had reduced relapse-free survival. This association remained significant in a multivariate analysis that accounted for age, smoking history, histology, adjuvant therapy, and tumor stage. Interestingly, a static measure of chromosome disruption did not correlate with survival, suggesting that the rate of ongoing dynamic chromosomal instability, rather than the state of the genome, is prognostic. For each individual tumor, the authors mapped the evolutionary history, identifying the individual subclones and creating a phylogenetic tree. Overall, they identified 525 mutation clusters, with a median of five per tumor. By analyzing the individual tumors, the authors were able to describe the evolutionary pressure acting on the lung tumors. For example, some targetable driver mutations, including those in EGFR, MET, and BRAF, were almost exclusively clonal and, therefore, deemed to be early events in tumorigenesis, while it was suggested that the subclonal driver mutations, including those in PIK3CA and NF1, were later events in tumor evolution. In some tumors, subclonal genes were seen only in a single region, highlighting concerns about limited tumor sampling. Therefore, classifying the driver mutations as clonal or subclonal has obvious implications for choosing effective targeted therapy. Overall, this study highlights the importance of understanding intratumor heterogeneity and demonstrates that chromosome instability, as measured by increased intratumor heterogeneity of copy number alterations, is a significant adverse prognostic factor.

Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017. doi:10.1056/NEJMoa1616288.

Correspondence: Dr. Charles Swanton at charles.swanton@crick.ac.ukn