Genetic polymorphisms of diabetes‐related genes, their interaction with diabetes status, and breast cancer incidence and mortality: The Long Island Breast Cancer Study Project

Abstract

To examine 143 diabetes risk single nucleotide polymorphisms (SNPs), identified from genome-wide association studies, in association with breast cancer (BC) incidence and subsequent mortality. A population-based sample of Caucasian women with first primary invasive BC (n = 817) and controls (n = 1021) were interviewed to assess diabetes status. Using the National Death Index, women with BC were followed for >18 years during which 340 deaths occurred (139 BC deaths). Genotyping was done using DNA extracted from blood samples. We used unconditional logistic regression to estimate age-adjusted odds ratios and 95% confidence intervals (CIs) for BC incidence, and Cox regression to estimate age-adjusted hazard ratios and CIs for all-cause and BC-specific mortality. Twelve SNPs were associated with BC risk in additive genotype models, at α = 0.05. The top three significant SNPs included SLC30A8- rs4876369 (P = 0.0034), HHEX-rs11187146 (P = 0.0086), and CDKN2A/CDKN2B-rs1333049 (P = 0.0094). Diabetes status modified the associations between rs4876369 and rs2241745 and BC incidence, on the multiplicative interaction scale. Six SNPs were associated with all-cause (CDKAL1-rs981042, P = 0.0032; HHEX-rs1111875, P = 0.0361; and INSR-rs919275, P = 0.0488) or BC-specific (CDKN2A/CDKN2B-rs3218020, P = 0.0225; CDKAL1-rs981042, P = 0.0246; and TCF2/HNF1B-rs3094508, P = 0.0344) mortality in additive genotype models, at α = 0.05. Genetic polymorphisms that increase the risk of developing diabetes may also increase the risk of developing and dying from BC.

Using genetics to decipher the link between type 2 diabetes and cancer: shared aetiology or downstream consequence?

“…A recent analysis where this has been attempted used 143 type 2 diabetes predisposing variants and investigated their association with risk of mortality in~800 people. Twelve SNPs were associated with risk of breast cancer, three with all-cause mortality and three with breast cancer specific mortality, yet none of the associations were significant after multiple testing corrections [104]. Until data from larger cohorts are available, power is likely to be an issue in such studies.…”

Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality

“…The long island breast cancer study revealed that the genetic polymorphisms which account for an increased diabetes risk are involved in enhanced mortality and risk of developing breast cancer; for example, SLC30A8 (a zinc transporter insulin-related secretion gene), CDKN2A-CDKN2B (cell cycle related genes), IGFBP2 and IRS2 (Insulin pathway related genes). The single nucleotide polymorphisms (SNPs) listed indirectly suggest an association between genes involved in metabolic and molecular glucose signaling, the cell cycle, and risk/progression of cancer [38]. Type 2 diabetes (T2D) associated SNPs are also present in JAZF1 , which plays an important role in stromal cancer oncogenesis.…”

Aberrant DNA Methylation Predicts Melanoma-Specific Survival in Patients with Acral Melanoma

“…HHEX was found to play a role in the migration and invasion of breast and prostate epithelial cells through the direct transcriptional regulation of Endoglin. The association of HHEX with hematopoietic, colorectal, liver, breast, prostate, and thyroid cancers has been extensively reported [31][32][33][34][35][36][37][38].…”