The dyslipidemia-associated SNP on the APOA1/C3/A5 gene cluster predicts post-surgery poor outcome in Taiwanese breast cancer patients: a 10-year follow-up study

Abstract

BackgroundPost-surgery therapies are given to early-stage breast cancer patients due to the possibility of residual micrometastasis, and optimized by clincopathological parameters such as tumor stage, and hormone receptor/lymph node status. However, current efficacy of post-surgery therapies is unsatisfactory, and may be varied according to unidentified patient genetic factors. Increases of breast cancer occurrence and recurrence have been associated with dyslipidemia, which can attribute to other known risk factors of breast cancer including obesity, diabetes and metabolic syndrome. Thus we reasoned that dyslipidemia-associated nucleotide polymorphisms (SNPs) on the APOA1/C3/A5 gene cluster may predict breast cancer risk and tumor progression.MethodsWe analyzed the distribution of 5 selected APOA1/C3/A5 SNPs in recruited Taiwanese breast cancer patients (n=223) and healthy controls (n=162). The association of SNP (APOA1 rs670) showing correlation with breast cancer with baseline and follow-up parameters was further examined.ResultsAPOA1 rs670 A allele carriage was higher in breast cancer patients than controls (59.64% vs. 48.77%, p=0.038). The rs670 A allele carrying patients showed less favorable baseline phenotype with positive lymph nodes (G/A: OR=3.32, 95% CI=1.77-6.20, p<0.001; A/A: OR=2.58, 95% CI=1.05-6.32, p=0.039) and negative hormone receptor expression (A/A: OR=4.85, 95%CI=1.83-12.83, p=0.001) in comparison to G/G carriers. Moreover, rs670 A/A carrying patients had higher risks in both tumor recurrence (HR=3.12, 95% CI=1.29-7.56, p=0.012) and mortality (HR=4.36, 95% CI=1.52-12.47, p=0.006) than patients with no A alleles after adjustments for associated baseline parameters. Furthermore, the prognostic effect of rs670 A/A carriage was most evident in lymph node-negative patients, conferring to the highest risks of recurrence (HR=4.98, 95% CI=1.40-17.70, p=0.013) and mortality (HR=9.87, 95%CI=1.60-60.81, p=0.014) than patients with no A alleles.ConclusionsAPOA1 rs670 A/A carriage showed poor post-surgery prognosis in Taiwanese lymph node-negative breast cancer patients, whose prognosis were considered better and adjuvant treatment might be less stringent according to currently available assessment protocols. Our findings suggest that APOA1 rs670 indicate a post-surgery risk of breast cancer disease progression, and that carriers of this SNP may benefit from more advanced disease monitoring and therapy regimens than the current regular standards. Furthermore, control of lipid homeostasis might protect APOA1 rs670 minor allele carriers from breast cancer occurrence and progression.

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality

“…A meta-analysis of studies found that elevated total cholesterol (Ͼ6.5 mM) was associated with an 18% increased risk of cancer, elevated triglycerides (Ͼ1.71 mM) was associated with a 20% increased risk, and decreased HDL cholesterol (Ͻ1.03 mM) was associated with a 15% increased risk (133). Genetic population studies have reported that polymorphisms in genes (ApoA-I and ApoE) that are associated with hyperlipidemia (elevated VLDL and LDL, respectively) are also associated with increased breast cancer risk, greater risk of developing estrogen receptor negative breast cancer, and a greater risk of breast cancer recurrence and mortality (32,82,141). Recent studies have reported that cholesterol-lowering therapy, with 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase inhibitors, is associated with a lower risk of overall cancer mortality (145), with some studies reporting a lowering risk of developing specific cancers, including hepatocellular carcinoma (173), and others report decreased recurrence and mortality from prostate cancer and breast cancer (5,208).…”

Diagnostic and prognostic role of serum protein peak at 6449 m/z in gastric adenocarcinoma based on mass spectrometry

“…Apo-A1, a regulator of tumour growth and metastasis, has been shown to be involved in antiproliferative and proapoptotic activities via regulation of cancer cell differentiation ( Zamanian-Daryoush et al , 2013 ; Kim et al , 2014 ). Hsu et al (2013) recently demonstrated a correlation of dyslipidemia-associated apo-A1 minor allele with unfavourable baseline characteristics in Taiwanese breast cancer patients, and the 10-year follow-up revealed poorest survival in patients carrying both minor alleles in the lymph node-negative group. ApoC-I was identified as a potential serum biomarker for colorectal cancer, hormone-refractory prostate cancer and liver fibrosis ( Engwegen et al , 2006 ; Yamamoto-Ishikawa et al , 2009 ).…”

The AutGO Initiative: A Conceptual Framework for Developing Genetics‐Outcomes Research Hypotheses

“…The majority of the published data are related to cancers or cardiovascular diseases (e.g., using SNPs for predicting the prognosis [Choi et al, 2013, Jeon et al, 2013, Rinella et al, 2013, Qi et al, 2014], treatment outcomes [Keane et al, 2013; Offer et al, 2013; Scartozzi et al, 2013], and risk assessment [Pazik et al, 2013; Zheng et al, 2013; Romanos et al, 2014; Xie et al, 2014]). While the ultimate impact of some of these findings on health outcomes remains to be elucidated, identifying genetic risk factors may have the potential to improve subtyping, and help find high‐risk patient subgroups requiring a closer follow up [Hsu et al, 2013]. It would be intriguing to see how experiences gained from incorporating patient perspectives and genetic risk factors to direct decision making in clinical practice in other conditions (oncology and cardiology) could be applied to develop successful patient outcomes predictors for autism.…”