Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland

Abstract

Mitochondria are subcellular organelles that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). As suggested over 70 years ago by Otto Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and mitochondrial DNA (mtDNA) appear to be common features of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells, but very few reports document the prevalence of inherited mitochondrial DNA polymorphisms in cancer patients compared to healthy control populations. Here we report the abundance of the 10398G polymorphism in a Polish breast cancer population and its frequency in controls. Amongst individuals with breast cancer the G single nucleotide polymorphism (SNP) is present in 23% of affected females compared to 3% of controls. This difference is highly statistically significant (P = 0.0008). It is therefore possible that the 10398G SNP constitutes an inherited predisposition factor for the development of breast cancer.

Mitochondrial NADH-dehydrogenase polymorphisms as sporadic breast cancer risk factor

“…Breast nipple aspirate fluid with mtDNA mutations at positions 204, 207 and 16293 has been suggested as an indicative for breast cancer (6) and mtDNA D-loop mutations have been proposed as independent prognostic marker in breast cancer (7). We have shown that individuals who inherited the A10298G polymorphism are at higher risk for developing BC (8). As A10398G is located in the ND3 (NADHd-dehydrogenase subunit 3) we have been interested if any other polymorphisms are abundant in ND genes in the BC cohort.…”

“…In addition, the missense mutation G5460A affecting the ND2 was reported in pathologically proven Parkinson and Alzheimer's diseases (28). Therefore, it cannot be excluded that mtDNA polymorphisms may result in disturbed protein synthesis, synthesis rate or finally in changed protein structure and therefore influence mitochondrial and cell physiology with the consequence of cancer development susceptibility (3)(4)(5)8,29).…”

Mitochondrial genotype and breast cancer predisposition

“…Nevertheless, this haplogroup is characterized by many RFLP-markers and no single mtDNA position may serve as a cancer marker. Therefore, it is possible that the interactions of multiple mitochondrial DNA variant modify breast cancer risk in the case of haplogroup I (62), possibly with special role of A10398G polymorphism (35,37). Other haplogroups seem to be represented in the cancer population at a frequency similar to the general Polish population.…”

“…There is an association between somatic mtDNA mutations and cancer development, progression and metastasis (18,21,(30)(31)(32)(33)(34)(35)(36)(37). In addition, recent studies have shown that inherited polymorphisms or mutations of the mitochondrial genome may modulate the risk of developing cancer, including prostate, oral and colorectal cancers (18,(38)(39)(40)(41).…”

“…Somatic mtDNA mutations have been described in various types of human cancers including bladder, brain, breast, colon, head and neck, lung, ovaries, prostate, thyroid, and breast cancers (20,21,31,33). At the same time inherited polymorphisms have been identified as contributing factors in cancer development (35,39,40).…”