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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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Science. 2014 Oct 10;346(6206):251-6

 Año de publicación: 2014

Nº de páginas: 6

Tipo de publicación: Artículo de Revista

 DOI: 10.1126/science.1253462

ISSN: 0036-8075,1095-9203

Url de la publicación: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636050/pdf/emss-65871.pdf

Autores/as

BRUIN, ELZA C DE

MCGRANAHAN, NICHOLAS

MITTER, RICHARD

SALM, MAX

WEDGE, DAVID C

YATES, LUCY

JAMAL-HANJANI, MARIAM

HORSWELL, STUART

GERLINGER, MARCO

JONES, DAVID

MARSHALL, JOHN

VOET, THIERRY

LOO, PETER VAN

RASSL, DORIS M

RINTOUL, ROBERT C

JANES, SAM M

LEE, SIOW-MING

FOSTER, MARTIN

AHMAD, TANYA

LAWRENCE, DAVID

FALZON, MARY

CAPITANIO, ARRIGO

HARKINS, TIMOTHY T

LEE, CLARENCE C

TOM, WARREM

TEEFE, ENOK

CHEN, SHANN-CHING

BEGUM, SHARMIN

RABINOWITZ, ADAM

PHILLIMORE, BENJAMIN

DENE, BRADLEY SPENCER

STAMP, GORDON

SZALLASI, ZOLTAN

MATTHEWS, NIK

STEWART, AENGUS

CAMBELL, PETER

SVANTON, CHARLES