title: Rare BRCA1 haplotypes including 3'UTR SNPs associated with breast cancer risk.
abstract: Genetic markers identifying women at an increased risk of developing breast cancer exist, yet the majority of inherited risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, BRCA1 mutations account for less then 5% of breast cancer risk. Since 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in the 3'UTR of BRCA1 and haplotypes containing these functional polymorphisms may be associated with breast cancer risk. We sequenced the BRCA1 3'UTR from breast cancer patients to identify miRNA disrupting polymorphisms. We further evaluated haplotypes of this region including the identified 3'UTR variants in a large population of controls and breast cancer patients (n = 221) with known breast cancer subtypes and ethnicities. We identified three 3'UTR variants in BRCA1 that are polymorphic in breast cancer populations, and haplotype analysis including these variants revealed that breast cancer patients harbor five rare haplotypes not generally found among controls (9.50% for breast cancer chromosomes, 0.11% for control chromosomes, p = 0.0001). Three of these rare haplotypes contain the rs8176318 BRCA1 3'UTR functional variant. These haplotypes are not biomarkers for BRCA1 coding mutations, as they are found rarely in BRCA1 mutant breast cancer patients (1/129 patients = 0.78%). These rare BRCA1 haplotypes and 3'UTR SNPs may represent new genetic markers of breast cancer risk.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Pelletier
authors.forename: William C
authors.initials: WC
authors.lastname: Speed
authors.forename: Trupti
authors.initials: T
authors.lastname: Paranjape
authors.forename: Katie
authors.initials: K
authors.lastname: Keane
authors.forename: Rachel
authors.initials: R
authors.lastname: Blitzblau
authors.forename: Antoinette
authors.initials: A
authors.lastname: Hollestelle
authors.forename: Kyan
authors.initials: K
authors.lastname: Safavi
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Daniel
authors.initials: D
authors.lastname: Zelterman
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Kidd
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Weidhaas
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D001741:Black or African American / Q000208:ethnology / Q000235:genetics; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1 / Q000502:physiology*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D005819:Genetic Markers