Genomic profiles of colorectal cancers differ based on patient smoking status.
Human sporadic colorectal cancer is the result of a lengthy somatic evolutionary process facilitated by various forms of genomic instability. Such instability arises endogenously from mutations in genes whose role is to preserve genomic integrity, and exogenously from environmental agents that generate genomic damage. We have found that cigarette smoking shifts the genomic profiles and genomic instability patterns of colorectal carcinomas. The genomic profiles of 57 consecutive cancers were examined; 31 cases were current or former smokers and 26 were nonsmokers. Genome-wide allelotypes of 348 markers were examined, along with comparative genomic hybridization (CGH) on ordered BAC microarrays, microsatellite instability, and inter-(simple sequence repeat) polymerase chain reaction instability. Tumors from nonsmokers exhibited losses of heterozygosity, particularly on chromosomes 14 and 18, whereas tumors from smokers exhibited a more diffuse pattern of allelic losses. Tumors from smokers exhibited higher overall rates of loss of heterozygosity, but showed lower rates of background microsatellite instability (MSI-L). On BAC array CGH, higher levels of generalized amplifications and deletions were observed in tumors from smokers, differentially affecting male smokers. In the transforming growth factor-beta signaling pathway, MADH4 mutations were more common in tumors from smokers, whereas transforming growth factor-beta RII mutations were more common among nonsmokers.
Swede
Helen
H
Connecticut Tumor Registry, 410 Capitol Avenue, Hartford, CT 06134, USA.
Bartos
Jeremy D
JD
Chen
Neng
N
Shaukat
Aasma
A
Dutt
Smitha S
SS
McQuaid
Devin A
DA
Natarajan
Nachimuthu
N
Rodriguez-Bigas
Miguel A
MA
Nowak
Norma J
NJ
Wiseman
Sam M
SM
Alrawi
Sadir
S
Brenner
Bruce M
BM
Petrelli
Nicholas J
NJ
Cummings
K Michael
KM
Stoler
Daniel L
DL
Anderson
Garth R
GR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D012727:Sex Characteristics; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000235:genetics
D004273:DNA, Neoplasm; D016212:Transforming Growth Factor beta