Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer

Abstract

Somatic mutations in mitochondrial DNA (mtDNA) have been demonstrated in various tumors, including breast cancer. However, it still remains unclear whether the alterations in mtDNA are related to the clinicopathological features and/or the prognosis in the breast cancer. We analyzed somatic mutations in the D-loop region, the common 4,977-bp deletion, and the copy number of mtDNA in breast cancer and paired nontumorous breast tissues from 60 Taiwanese patients. We found that 18 of the 60 (30%) breast cancers displayed somatic mutations in mtDNA D-loop region. The incidence of the 4,977-bp deletion in nontumorous breast tissues (47%) was much higher than that in breast cancers (5%). The copy number of mtDNA was significantly decreased in 38 of the 60 (63%) breast cancers as compared to their corresponding nontumorous breast tissues (P ¼ 0.0008). The occurrence of D-loop mutations was associated with an older onset age (!50 years old, P ¼ 0.042), and tumors that lacked expressions of estrogen receptor and progesterone receptor (P ¼ 0.024). Patients with mtDNA D-loop mutation and breast cancer had significantly poorer disease-free survival than those without mutation, when assessed by Kaplan-Meier curves and logrank test (P ¼ 0.005). Multivariate Cox regression analysis indicated that a D-loop mutation is a significant marker that is independent of other clinical variables and that it can be used to assess the prognosis of patients. Our findings suggest that somatic mutations in mtDNA D-loop can be used as a new molecular prognostic indicator in breast cancer. V V C 2006 Wiley-Liss, Inc.

Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases

“…In a study conducted among 17 Brazilian women, lower levels of mtDNA 4977 mutation were observed in breast cancer tissue than in either the normal control tissue or adjacent normal tissue of breast cancer patients, suggesting that cancer cells are essentially free of this mutation (4). In the second study, a hospital-based study of 60 Taiwanese women with breast cancer, the mtDNA 4977 mutation was detected in 28 non-tumorous breast tissue samples (47%) and only three of the breast cancer samples (5%) (8). In our study, we found the mtDNA 4977 mutation to be ubiquitous in both tumor and non-tumor tissues.…”

“…Furthermore, these PCR methods use an endpoint determination that may not be truly quantitative because of plateau effects (21). There have been some reports demonstrating the advantages of using the real-time PCR method and its potential clinical value for the mtDNA 4977 mutation (8,(18)(19)(20)22). However, only two of these reports used the standard curve method, which is believed to be more reliable and sensitive (18,19).…”

“…Thus, the mutated mtDNA 4977 may represent a strong functional disadvantage, possibly thereby repressing the growth of cancer cells harboring deleted mtDNA. It was recently demonstrated in transmitochondrial cybrid cells that the common mtDNA deletion sensitized the cells to apoptosis at low heteroplasmy levels (8,24). A significant increased proportion of the mtDNA 4977 mutation has been reported in various type of cancer, including nasopharyngeal, esophageal cancer, stomach, thyroid, salivary glands, hepatocellular and oral cancers (5,18,(25)(26)(27)(28).…”

“…The mtDNA 4977 mutation may contribute to respiratory defects in many types of human malignancy such as colorectal, liver, lung, and prostate cancers, and may be associated with tumor progression. To date, only few studies have evaluated the association between the mtDNA 4977 mutation and breast cancer risk, and the findings from these studies have been inconsistent (4,(7)(8)(9). The inconsistency in previous studies may be due, in part, to the use of non-quantitative detection methods and/or failure in quantitative PCR strategies to identify, and disqualify from use, pairs of primers which will also efficiently co-amplify nuclear DNA.…”

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).…”