Identification of sequence polymorphism in the D-Loop region of mitochondrial DNA as a risk factor for hepatocellular carcinoma with distinct etiology

Abstract

BackgroundHepatocellular carcinoma (HCC) is frequently preceded by hepatitis virus infection or alcohol abuse. Genetic backgrounds may increase susceptibility to HCC from these exposures.MethodsMitochondrial DNA (mtDNA) of peripheral blood, tumor, and/or adjacent non-tumor tissue from 49 hepatitis B virus-related and 11 alcohol-related HCC patients, and from 38 controls without HCC were examined for single nucleotide polymorphisms (SNPs) and mutations in the D-Loop region.ResultsSingle nucleotide polymorphisms (SNPs) in the D-loop region of mt DNA were examined in HCC patients. Individual SNPs, namely the 16266C/T, 16293A/G, 16299A/G, 16303G/A, 242C/T, 368A/G, and 462C/T minor alleles, were associated with increased risk for alcohol- HCC, and the 523A/del was associated with increased risks of both HCC types. The mitochondrial haplotypes under the M haplogroup with a defining 489C polymorphism were detected in 27 (55.1%) of HBV-HCCand 8 (72.7%) of alcohol- HCC patients, and in 15 (39.5%) of controls. Frequencies of the 489T/152T, 489T/523A, and 489T/525C haplotypes were significantly reduced in HBV-HCC patients compared with controls. In contrast, the haplotypes of 489C with 152T, 249A, 309C, 523Del, or 525Del associated significantly with increase of alcohol-HCC risk. Mutations in the D-Loop region were detected in 5 adjacent non-tumor tissues and increased in cancer stage (21 of 49 HBV-HCC and 4 of 11 alcohol- HCC, p < 0.002).ConclusionsIn sum, mitochondrial haplotypes may differentially predispose patients to HBV-HCC and alcohol-HCC. Mutations of the mitochondrial D-Loop sequence may relate to HCC development.

Mitochondrial DNA haplogroup M is associated with late onset of hepatocellular carcinoma

“…We have previously performed a number of studies on D-loop SNPs as predictive factors for digestive tract cancers (24,25,29). In the present study, for the first time, we suggest that, other than as predictors for cancer risk and outcome, SNPs in the D-loop are also predictors for age-at-onset in HCC patients.…”

“…org) in the blood from HCC patients and identified 92 single nucleotide polymorphims (SNPs) in the D-loop. We also identified cancer risk and outcome associated SNPs (24,25). In the present study, we assess the correlation between germline SNPs of the D-loop and age-at-onset in HCC patients.…”

Identification of sequence polymorphisms in the displacement loop region of mitochondrial DNA as a risk factor for renal cell carcinoma

“…It has been reported that the 16293 site is associated with the risk of developing hepatocellular carcinoma (18) and the 16298 site is associated with resistance to small-cell lung carcinogenesis (20). The D-loop is the most variable region in mtDNA.…”

Sequence polymorphisms of the mitochondrial displacement loop and outcome of non-small cell lung cancer

“…We previously identified cancer risk and outcome-associated SNPs of the D-loop in several types of cancer (25,26,30). In this study, selected SNPs in the mtDNA D-loop were examined for their ability to predict cancer outcome in NSCLC patients.…”

“…Sequence changes have been examined extensively in the D-loop in cancers, but few single-nucleotide polymorphisms (SNPs) have been selected for predicting cancer risk and outcome; their predictive values are still unclear (25)(26)(27)(28)(29). In this study, we assessed the prediction power of these SNPs on the outcome of NSCLC patients.…”