Abstract
Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3rd among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G→T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection.
Highlights
Liver cancer accounts for approximately 6% of all new cancer cases diagnosed worldwide; it is the fifth most common cancer in men and the eighth most common in females worldwide [1,2]
We have used a highly sensitive and quantitative mass spectrometric method, Short Oligonucleotide Mass Analysis (SOMA), to investigate the relationships between liver cancer and aflatoxin-related plasma TP53 R249S-mutated DNA concentrations in free circulating DNA using blood specimens collected in a hospital case: control design
We show that plasma R249S-mutated DNA was detected at .67 copies/mL in over 53% of patients with liver cancer or chronic liver disease, and only in 19% of control subjects
Summary
Liver cancer accounts for approximately 6% of all new cancer cases diagnosed worldwide; it is the fifth most common cancer in men and the eighth most common in females worldwide [1,2]. In a recent study on a small group of surgically resected HCC patients at the National Cancer Institute, Bangkok, we reported R249S mutation in 7/26 (27%) cases, suggesting that the contribution of AFB1 to the burden of HCC in Thailand is far from negligible [15]. In the Gambia and in the Qidong area of People’s Republic of China, two regions of high HBV prevalence and widespread AFB1 exposure, high plasma concentrations of R249S-mutated DNA were found to be strongly associated with HCC [18,19]. We have used plasma collected in a case-referent design at National Cancer Institute, Bangkok, to evaluate the association of R249S-mutated DNA plasma concentrations with the occurrence of HCC, CC or chronic liver disease. Our results suggest a preferential association between R249S and HCC developing in the absence of documented previous history of liver cirrhosis
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