Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival

Mala Pande, Melissa L. Bondy, Kim Anh Do, Aysegul A. Sahin, Jun Ying, Gordon Mills, Patricia A. Thompson, Abenaa M. Brewster

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Obesity-related hormones and cytokines alter PI3 K-AKT-mTOR pathway activation in breast tumors contributing to poorer disease-free survival (DFS) and decreased responsiveness to tamoxifen and trastuzumab. We hypothesized that single nucleotide polymorphisms (SNPs) in candidate genes in the PI3 K-AKT-mTOR signaling pathway may act as genetic modifiers of breast cancer DFS. We analyzed the association of 106 tagging SNPs in 13 genes (ADIPOQ, IGF1, INS, IRS1, LEP, LEPR, LEPROT, PIK3CA, PIK3R5, PTEN, TSC1, TSC2, and AKT1) in the P13K-AKT-mTOR pathway with DFS in a sample of 1,019 women with stage I–II breast cancer. SNPs significantly associated with DFS in any genetic model (additive, dominant, or recessive) after correcting for false discovery rate (FDR = 0.10) were included in Cox proportional hazards multivariable analyses. After adjusting for race/ethnicity, age at diagnosis, tumor stage, and treatment, rs1063539 in ADIPOQ, rs11585329 in LEPR, and rs2519757 in TSC1 were associated with improved DFS, and rs1520220 in IGF1 and rs2677760 in PIK3CA were associated with worse DFS. The associations were not significantly modified by the type of systemic treatment received or body mass index. The SNPs were not associated with tumor characteristics such as tumor size, lymph node status, nuclear grade, or hormone receptor status. In this study, germline SNPs in the PI3 K-AKT-mTOR pathway were associated with breast cancer DFS and may be potential prognostic markers. Future studies are needed to replicate our results and to evaluate the relationship between these polymorphisms and activation of the PI3 K-AKT-mTOR pathway in breast tumors.

Original languageEnglish (US)
Pages (from-to)381-387
Number of pages7
JournalBreast Cancer Research and Treatment
Volume147
Issue number2
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

Fingerprint

Breast Diseases
Phosphatidylinositol 3-Kinases
Disease-Free Survival
Single Nucleotide Polymorphism
Obesity
Breast Neoplasms
Hormones
Neoplasms
Genetic Models
Tamoxifen
Genes
Body Mass Index
Lymph Nodes
Cytokines
Therapeutics

Keywords

  • Breast cancer
  • Disease-free survival
  • PI3 K-AKT-mTOR pathway
  • Prognosis
  • Single nucleotide polymorphisms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival. / Pande, Mala; Bondy, Melissa L.; Do, Kim Anh; Sahin, Aysegul A.; Ying, Jun; Mills, Gordon; Thompson, Patricia A.; Brewster, Abenaa M.

In: Breast Cancer Research and Treatment, Vol. 147, No. 2, 01.09.2014, p. 381-387.

Research output: Contribution to journalArticle

Pande, Mala ; Bondy, Melissa L. ; Do, Kim Anh ; Sahin, Aysegul A. ; Ying, Jun ; Mills, Gordon ; Thompson, Patricia A. ; Brewster, Abenaa M. / Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival. In: Breast Cancer Research and Treatment. 2014 ; Vol. 147, No. 2. pp. 381-387.
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