Gene copy number aberrations are associated with survival in histologic subgroups of non-small cell lung cancer.
BACKGROUND
Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups.


METHODS
Short-term (<20 month; n = 53) and long-term survivors (>58 month; n = 47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh frozen tumor specimens. The samples were analyzed using high-resolution single-nucleotide polymorphism array technology to assess gene copy number variations and array-based gene expression profiling. The molecular data were combined with information on clinical parameters.


RESULTS
Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n = 50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term than in short-term survivors. In squamous cell carcinoma (n = 28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, messenger RNA expression levels of corresponding genes were increased or decreased, respectively.


CONCLUSIONS
Comprehensive tumor profiling permits the integration of genomic, histologic, and clinical data. We identified gene copy number gains and losses, with corresponding changes in messenger RNA levels that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung.
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. patrick.micke@igp.uu.se
Patrick
P
Micke
Karolina
K
Edlund
Lars
L
Holmberg
Hanna Göransson
HG
Kultima
Larry
L
Mansouri
Simon
S
Ekman
Michael
M
Bergqvist
Lena
L
Scheibenflug
Kristina
K
Lamberg
Gunnar
G
Myrdal
Anders
A
Berglund
Annsofie
A
Andersson
Mats
M
Lambe
Fredrik
F
Nyberg
Andrew
A
Thomas
Anders
A
Isaksson
Johan
J
Botling
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality* / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D017741:Survivors
D004273:DNA, Neoplasm