Multi-region exome sequencing reveals the intratumoral heterogeneity

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99).

Fig:  Mutational spectrum of SCLC: a Mutational landscape of SCLC (n = 40). Mutated gene frequency >15% involved in previously reported significant mutated genes in SCLC are shown for each region of the individual patient. Upper, TMB count; middle, heatmap for driver mutations; lower, mutational signatures. b Counts in clonal and subclonal mutations for each patient (n = 40). c Percentage of subclonal mutations for each patient (n = 40). SCLC small cell lung cancer, P-SCLC pure small cell lung cancer, C-SCLC combined small cell lung cancer, SNVs single-nucleotide variants, CDS coding sequence.

In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.

Zhou, H., Hu, Y., Luo, R. et al. Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer. Nat Commun 12, 5431 (2021).

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