Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients

Abstract

SummarySomatic mutations and large-scale depletion in mitochondrial DNA (mtDNA) have been extensively detected in various human cancers. However, it still remains unclear whether the alterations in mtDNA content are related to the clinicopathological parameters and patient prognosis in breast cancer. In the present study, we analyzed the copy number of mtDNA in 59 cases of invasive breast tumors and paired nontumorous tissues using quantitative real-time PCR. Our data showed that the level of mtDNA was significantly decreased in tumor tissues as compared to the adjacent nontumorous counterparts (P ¼ 0.001). The reduced copy number in mtDNA was associated with an older onset age ( 50 years old, P ¼ 0.035) as well as a higher histological grade (P ¼ 0.012). Survival analysis measured by the Kaplan-Meier curves and the log-rank test indicated that patients with reduced mtDNA content had significantly poorer disease-free survival (DFS, P ¼ 0.0079) and overall survival (OS, P ¼ 0.011) rate. In addition, tumors harboring mutations in displacement (D)-loop region, particularly at the polycytidine stretch (T/N ratio ¼ 64.3 + 8.2%) or close to the replication origins of the heavy-strand (T/N ratio ¼ 68.7 + 5.5%), had a significantly lower copy number of mtDNA than the ones without D-loop alterations. Together, our results suggested that reduced copy number of mtDNA may be involved in breast neoplastic transformation or progression and mtDNA content might be potentially used as a tool to predict prognosis. Somatic mutation in the D-loop region probably is one of key contributing factors leading to decreased mtDNA level in breast tumors.

Correlation between increased copy number of mitochondrial DNA and clinicopathological stage in colorectal cancer

“…Numerous reports have indicated that the copy number of mtDNA changes in various types of cancer (6)(7)(8)(9)(10)(11)17). In 1989, Yamamoto et al first reported the increased mitochondrial genomic expression in pre-malignant lesions of the colon in patients with pre-cancerous familial polyposis coli (18).…”

“…Subsequently, alterations in mtDNA copy number have been observed in a variety of human cancers. The copy number is reduced in hepatocellular and renal cell carcinomas and breast cancer (6)(7)(8). However, it is increased in head and neck and ovarian cancers and esophageal squamous cell carcinomas (9)(10)(11).…”

Mitochondrial DNA content in paired normal and cancerous breast tissue samples from patients with breast cancer

“…Decreased mitochondrial DNA copy number is correlated with tumour progression and prognosis in Chinese breast cancer patients (Yu et al 2007). Increased mtDNA content in saliva is associated with head and neck cancer (Mizumachi et al 2008b).…”

Association between Mitochondrial D-loop Polymorphism and Copy Number

“…이 결과를 Bionics Inc. (Seoul, Korea)에 의 뢰하여 ABI 3730 DNA sequencer를 이용하여 직접 염기 서열분석을 시행하여 결과를 분석하여 D310과 D514의 다형성을 확인하였다. 미토콘드리아의 복제수는 real-time PCR의 방법으로 β-actin을 이용하여 input DNA의 양을 표준화하여 측정 하였다 [13,17]. 이가 종양에서 높게 나타나는 것을 보고하였다 [19].…”

“…다 [12,16,17]. 하지만 아직까지 미토콘드리아의 다형성 과 복제수의 관계는 암세포뿐 아니라 정상 세포에서도 연구가 되어 있지 않아서, 이들 관계의 질환에서의 의의 를 비교해볼 수 있는 대조군이 없는 현실이다.…”