A population-based study of hedgehog pathway gene variants in relation to the dual risk of basal cell carcinoma plus another cancer.
BACKGROUND
A personal history of basal cell carcinoma (BCC) is associated with increased risk of other malignancies, but the reason is unknown. The hedgehog pathway is critical to the etiology of BCC, and is also believed to contribute to susceptibility to other cancers. This study tested the hypothesis that hedgehog pathway and pathway-related gene variants contribute to the increased risk of subsequent cancers among those with a history of BCC.


METHODS
The study was nested within the ongoing CLUE II cohort study, established in 1989 in Washington County, Maryland, USA. The study consisted of a cancer-free control group (n=2296) compared to three different groups of cancer cases ascertained through 2007, those diagnosed with: (1) Other (non-BCC) cancer only (n=2349); (2) BCC only (n=534); and (3) BCC plus other cancer (n=446). The frequencies of variant alleles were compared among these four groups for 20 single nucleotide polymorphisms (SNPs) in 6 hedgehog pathway genes (SHH, IHH, PTCH2, SMO, GLI1, SUFU), and also 22 SNPs in VDR and 8 SNPs in FAS, which have cross-talk with the hedgehog pathway.


RESULTS
Comparing those with both BCC and other cancer versus those with no cancer, no significant associations were observed for any of the hedgehog pathway SNPs, or for the FAS SNPs. One VDR SNP was nominally significantly associated with the BCC cancer-prone phenotype, rs11574085 [per minor allele odds ratio (OR) 1.38, 95% confidence interval (CI) 1.05-1.82; p-value=0.02].


CONCLUSIONS
The hedgehog pathway gene SNPs studied, along with the VDR and FAS SNPs studied, are not strongly associated with the BCC cancer-prone phenotype.
Department of Radiation Medicine, Georgetown University School of Medicine, Washington, DC, USA.
Timothy J
TJ
Jorgensen
Ingo
I
Ruczinski
Yin
Y
Yao Shugart
Lee
L
Wheless
Yvette
Y
Berthier Schaad
Bailey
B
Kessing
Judith
J
Hoffman-Bolton
Kathy J
KJ
Helzlsouer
W H Linda
WH
Kao
Lesley
L
Francis
Rhoda M
RM
Alani
Paul T
PT
Strickland
Michael W
MW
Smith
Anthony J
AJ
Alberg
D000328:Adult; D002280:Basal Cell Carcinoma / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D015897:Comorbidity; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008396:Maryland / Q000453:epidemiology; D008498:Medical Record Linkage; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*; D012907:Smoking / Q000453:epidemiology; D019014:fas Receptor / Q000235:genetics*
C491901:FAS protein, human; D053823:Hedgehog Proteins; D018167:Receptors, Calcitriol; C509239:SHH protein, human; D019014:fas Receptor