Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

Abstract

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…Indeed, PIK3CA helical domain mutations are strongly correlated with A3 mutation enrichment across multiple tumor types, while an equally oncogenic and prevalent hotspot mutation (H1047R), which is not caused by an A3 signature mutation is largely confined to tumor types with reduced enrichment for this signature across the exome [43]. These observations, together with the finding that PIK3CA helical domain mutation coincides with appearance of the A3 signature in lung cancer subclones [75] strongly implicate A3 activity in generating these driver mutations.…”

“…The same study revealed evidence of distinct kataegis events occurring at separate points during the development of a given tumor. Similarly, in non-small cell lung adenocarcinomas a recent evolutionary analysis of dissected subclones showed the A3 signature is weaker early in the evolution of disease (when tobaccoassociated mutations predominate) but appears strongly in subclones [75]. This pattern was also apparent in lung adenocarcinomas but not in lung squamous carcinomas.…”

Cancer evolution and heterogeneity

“…Somatic mutations are present in all cells and they are the consequence of multiple mutational processes, including the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, and enzymatic modification of DNA and, at present, they have been classified into 30 signatures 35, 36, 37, 38. The nucleotide substitutions in those tumors were characterized as C>T from ultraviolet light (signature 7)23 and C>A from smoking (signature 4) 19, 20. Both substitutions were observed as founder events.…”

“…In addition, low‐grade glioma showed an exacerbated diversity in ITH after treatment with the alkylating agent temozolomide 39. In non‐small‐cell lung cancers (NSCLC) and bladder cancer, the apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) family of proteins was associated with fostering many subclones (signature 2) 19, 20, 40…”

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”