Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk

Yidong Bai,Bharat Thyagarajan,Jian-Min Yuan,Heather Nelson,Woon-Puay Koh,Renwei Wang,Helene Barcelo

doi:10.1371/journal.pone.0065968

Abstract

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (Ptrend = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2nd, 3rd, 4th, and 5th quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1st quintile (Ptrend = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (Ptrend = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk.

Highlights

Breast cancer is the most common cancer among women in the United States and accounts for 29% of all cancers in women with approximately 226,870 new cases expected to occur in 2012 [1]
Additional analyses evaluating the association between the relative mitochondrial DNA (mtDNA) copy number and risk of incident breast cancer stratified by time interval between blood sample collection and breast cancer diagnosis showed that relative mtDNA copy number was associated with breast cancer risk only among those women from whom a blood sample was collected within 3 years of breast cancer diagnosis
This is the first study to demonstrate a prospective association between increased relative mtDNA copy number and increased breast cancer risk

Summary

Introduction

Breast cancer is the most common cancer among women in the United States and accounts for 29% of all cancers in women with approximately 226,870 new cases expected to occur in 2012 [1]. As reviewed by Radppour et al, several studies have found somatic mitochondrial mutations and deletions in breast tumor tissue, suggesting that changes in mtDNA may play a significant role in breast carcinogenesis [8] This hypothesis has been supported by epidemiological studies that demonstrated a statistically significant association between increasing mtDNA copy number in peripheral blood and increased risk of breast cancer [9] as well as other malignancies including Non-Hodgkin lymphoma [10], lung cancer [11], pancreatic cancer [12], and colorectal cancer [13,14]. A retrospective case-control study showed decreased mtDNA copy number associated with increased breast cancer risk [15]. The present study allowed us to evaluate the association between mtDNA copy number and the risk of breast cancer in pre-diagnostic peripheral blood samples

Methods

Results

Conclusion