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

Abstract

Background: Hepatocellular carcinoma (HCC) is frequently preceded by hepatitis virus infection or alcohol abuse. Genetic backgrounds may increase susceptibility to HCC from these exposures.

Methods: Mitochondrial 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.

Results: Single 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-HCC and 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).

Conclusions: In 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.

Figure 1

Distribution (spectrum) of D-Loop SNPs at 92 sites (x-axis) and their relative frequencies in percentage within each group (y-axis). Paired T-test: p = 0.0001 (HBV-HCC vs. control); p = 0.3416 (Alcohol-HCC vs. control); p = 0.2817 (HBV-HCC vs. Alcohol-HCC).