• The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

BRCA1 protein

BRCA2 protein

adult

aged

article

attributable risk

breast cancer

cancer risk

cancer susceptibility

clinical evaluation

controlled study

female

follow up

gene frequency

gene mutation

genotype

heterozygote

human

major clinical study

priority journal

probability

risk assessment

single nucleotide polymorphism

tumor suppressor gene

Aged

80 and over

Alleles

Breast Neoplasms

Genetic Predisposition to Disease

Humans

Middle Aged

Mutation

Polymorphism

Single Nucleotide

Receptors

Progesterone

Risk Factors

Sodium-Bicarbonate Symporters

Survival Analysis

Vesicular Transport Proteins

MEDICINE

Adult

Aged

Aged, 80 and over

Alleles

BRCA1 Protein

BRCA2 Protein

Breast Neoplasms

Female

Genetic Predisposition to Disease

Genotype

Heterozygote

Humans

Middle Aged

Mutation

Polymorphism, Single Nucleotide

Receptors, Progesterone

Risk Assessment

Risk Factors

Sodium-Bicarbonate Symporters

Survival Analysis

Vesicular Transport Proteins

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)