title: The HRAS1 minisatellite locus and risk of ovarian cancer.
abstract: Approximately 10% of ovarian cancers are due to mutations in highly penetrant inherited cancer susceptibility genes. The highly polymorphic HRAS1 minisatellite locus, located just downstream from the proto-oncogene H-ras-1 on chromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and bladder, and it was found that BRCAI mutation carriers with at least one rare HRAS1 allele have a greater risk of ovarian cancer than BRCA1 carriers with only common HRAS1 alleles. There are no conclusive studies of HRAS1 alleles in sporadic epithelial ovarian cancer. A case-control study of HRAS1 alleles was performed on DNA from 136 Caucasian patients with ovarian cancer and 108 cancer-free controls using conventional (Southern blot) and PCR-based methods to determine the frequency of rare HRAS1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression methods. A single degree of freedom test was used to assess the significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRAS1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated with a relative risk of 1.66 (95% CI, 0.91-3.01), whereas having two rare alleles increased the relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRAS1 allele types by the age of the case at diagnosis revealed that younger cases (<45 years) had a borderline statistically significant increased association with rare HRAS1 alleles compared to older cases (> or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRAS1 alleles contribute to ovarian cancer predisposition in the general population. Thus, the HRAS1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in both sporadic and hereditary ovarian cancer.
authors.affiliation: City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010-3000, USA. jweitzel@coh.org
authors.forename: J N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: S
authors.initials: S
authors.lastname: Ding
authors.forename: G P
authors.initials: GP
authors.lastname: Larson
authors.forename: R A
authors.initials: RA
authors.lastname: Nelson
authors.forename: A
authors.initials: A
authors.lastname: Goodman
authors.forename: E C
authors.initials: EC
authors.lastname: Grendys
authors.forename: H G
authors.initials: HG
authors.lastname: Ball
authors.forename: T G
authors.initials: TG
authors.lastname: Krontiris
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D005260:Female; D019398:Genes, BRCA1; D011905:Genes, ras; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D018598:Minisatellite Repeats; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D012016:Reference Values; D012307:Risk Factors; D014481:United States; D044465:White People / Q000235:genetics