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A polymorphic variant in human MDM4 associates with accelerated age of onset of estrogen receptor negative breast cancer
- Publication Year :
- 2009
- Publisher :
- Oxford University Press, 2009.
-
Abstract
- Murine double minute 4 (MDM4) shares significant structural homology with murine double minute 2 (MDM2) and interacts and regulates transcriptional activity of the tumor suppressor p53. In tumors with wild-type p53, there is often overexpression of MDM2 or MDM4 leading to functional inactivation of p53. A single-nucleotide polymorphism (SNP) in the promoter of human MDM2 (SNP309) was shown to associate with increased MDM2 expression and increased risk of cancer. This study evaluated the association of a SNP in human MDM4 (C>T) with age of onset of breast cancer in two independent cohorts. In cohort 1 of 675 patients, the average age of diagnosis for women with estrogen receptor (ER)-positive and ER-negative breast cancers was 53.2 and 48 years, respectively. In this cohort, homozygous variant (TT) carriers developed ER-negative carcinomas at an earlier age than homozygous wild-type (CC) or heterozygous (TC) such that the age at diagnosis was accelerated by 5.0 years (P = 0.018). This association was validated in a second cohort of breast cancer patients (n = 148), where TT carriers with ER-negative cancer developed the disease 3.8 years earlier than CC carriers (P = 0.006). The effect was more pronounced in Caucasians with ER-negative ductal carcinomas with TT homozygotes developing disease 7.5 years (P = 0.031) and 6.2 years (P = 7 x 10(-5)) earlier than CC carriers in cohorts 1 and 2, respectively. No association was seen in ER-positive ductal cancers suggesting that the SNP in MDM4 only has a functional association in ER-negative breast cancer.
- Subjects :
- Oncology
Adult
Cancer Research
medicine.medical_specialty
Estrogen receptor
Single-nucleotide polymorphism
Breast Neoplasms
Cell Cycle Proteins
Biology
Polymorphism, Single Nucleotide
Cohort Studies
Breast cancer
Internal medicine
Proto-Oncogene Proteins
Genotype
medicine
SNP
Humans
Genetic Predisposition to Disease
Age of Onset
Molecular Epidemiology
Cancer
Nuclear Proteins
General Medicine
Middle Aged
medicine.disease
Carcinoma, Ductal
Endocrinology
Receptors, Estrogen
Female
Breast disease
Age of onset
Tumor Suppressor Protein p53
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....58523b46063f7af09f6a2f5e2455e05c