Genomic Intratumor Heterogeneity and Evolution of NSCLC Tumors


Key Points

  • In 100 early-stage NSCLC tumors resected before systemic therapy, widespread intratumor heterogeneity was found for both somatic mutations and copy-number alterations.
  • Higher levels of subclonal copy-number alterations were associated with poorer disease-free survival.

In a study reported in The New England Journal of Medicine, Jamal-Hanjani et al found that early stage non–small cell lung cancer (NSCLC) tumors were characterized by widespread intratumor genomic heterogeneity and that increased subclonal copy-number alterations in this context were associated with poorer disease outcome.

Study Details

The study involved multiregion whole-exome sequencing of 100 early-stage NSCLC tumors resected before systemic therapy. Somatic mutations (defined as coding and noncoding single-nucleotide variants) and copy-number alterations (measured as the percentage of genome affected by such alterations) were classified as clonal (present in all cancer cells) or subclonal (present in a subset of cells).

Clonal and Subclonal Alterations

Widespread intratumor heterogeneity was found for both somatic mutations and copy-number alterations. A median of 30% (range = 0.5%–93%) of somatic mutations and a median of 48% (range = 0.3%–88%) of copy-number alterations were identified as subclonal, with this finding indicating ongoing genomic-instability processes at both mutational and chromosomal levels. Although driver mutations in EGFR, MET, BRAF, and TP53 were typically clonal, heterogeneous driver mutations occurring later in tumor evolution were identified in more than 75% of tumors, with such alterations being common in PIK3CA and NF1 and in genes affecting chromatin remodeling, histone methylation, and DNA damage response and repair.

A pattern of early clonal genome doubling and ongoing chromosomal instability was commonly observed, with these processes being associated with increased intratumor heterogeneity and evolution of driver somatic copy-number alterations that included amplifications in CDK4, FOXA1, and BCL11A.

A higher (above median) vs lower level of subclonal mutations was not significantly associated with poorer disease-free survival (hazard ratio [HR] = 0.86, P = .70), whereas a significant association was observed for higher vs lower level of subclonal copy-number alterations (HR = 4.9, P = 4.4 × 10−4).

The investigators concluded: “Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor.”

The study was funded by Cancer Research UK and others.

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