High-resolution genomic profiles of human lung cancer

doi:10.1073/pnas.0504126102

High-resolution genomic profiles of human lung cancer

^*Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; ^§Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; and Departments of ^¶Dermatology and ^∥Genetics and Medicine, Harvard Medical School, Boston, MA 02115

Communicated by Webster K. Cavenee, University of California at San Diego, La Jolla, CA, May 18, 2005 (received for review April 13, 2005)

Abstract

Lung cancer is the leading cause of cancer mortality worldwide, yet there exists a limited view of the genetic lesions driving this disease. In this study, an integrated high-resolution survey of regional amplifications and deletions, coupled with gene-expression profiling of non-small-cell lung cancer subtypes, adenocarcinoma and squamous-cell carcinoma (SCC), identified 93 focal copy-number alterations, of which 21 span <0.5 megabases and contain a median of five genes. Whereas all known lung cancer genes/loci are contained in the dataset, most of these recurrent copy-number alterations are previously uncharacterized and include high-amplitude amplifications and homozygous deletions. Notably, despite their distinct histopathological phenotypes, adenocarcinoma and SCC genomic profiles showed a nearly complete overlap, with only one clear SCC-specific amplicon. Among the few genes residing within this amplicon and showing consistent overexpression in SCC is p63, a known regulator of squamous-cell differentiation. Furthermore, intersection with the published pancreatic cancer comparative genomic hybridization dataset yielded, among others, two focal amplicons on 8p12 and 20q11 common to both cancer types. Integrated DNA–RNA analyses identified WHSC1L1 and TPX2 as two candidates likely targeted for amplification in both pancreatic ductal adenocarcinoma and non-small-cell lung cancer.

Footnotes

↵ ‡ To whom correspondence may be addressed at: Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail: kwong1{at}partners.org or ron_depinho{at}dfci.harvard.edu.
↵ † G.T., K.-K.W., and G.M. contributed equally to this work.
Author contributions: G.T., K.-K.W., C.B., Y.Z., D.B.K., L.C., and R.A.D. designed research; G.T., K.-K.W., G.M., C.B., B.F., D.B.K., Y.Z., A.P., M.J.Y., A.J.A., E.S.M., Z.Y., and H.J. performed research; C.B., B.F., Y.Z., and D.B.K. contributed new reagents/analytic tools; G.T., K.-K.W., C.B., Y.Z., and D.B.K. analyzed data; and G.T., K.-K.W., G.M., B.F., Y.Z., D.B.K., L.C., and R.A.D. wrote the paper.
Abbreviations: AC, adenocarcinoma; CGH, comparative genomic hybridization; aCGH, array-CGH; CNAs, copy-number alterations; Mb, megabase; MCR, minimal common region; NSCLC, non-small-cell lung cancer; PDAC, pancreatic ductal AC; QPCR, quantitative PCR; SCC, squamous-cell carcinoma.
Freely available online through the PNAS open access option.