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Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis.

Villar S, Ortiz-Cuaran S, Abedi-Ardekani B, Gouas D, Nogueira da Costa A, Plymoth A, Khuhaprema T, Kalalak A, Sangrajrang S, Friesen MD, Groopman JD, Hainaut P - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: International Agency for Research on Cancer, Lyon, France.

ABSTRACT
Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3(rd) 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.

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Distribution of the liver disease and reference groups at different cutoffs of positivity of TP53 R249S mutation.At 150 copies/mL there is a clear distinction among the three liver cancer groups the chronic liver disease subjects and the reference group. The proportion of patients at this cut-off is higher in HCC/no cirrhosis (44%) than in all other groups (HCC/cirrhosis (21%), CC (22%), CLD (12%) and R (3)).
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pone-0037707-g002: Distribution of the liver disease and reference groups at different cutoffs of positivity of TP53 R249S mutation.At 150 copies/mL there is a clear distinction among the three liver cancer groups the chronic liver disease subjects and the reference group. The proportion of patients at this cut-off is higher in HCC/no cirrhosis (44%) than in all other groups (HCC/cirrhosis (21%), CC (22%), CLD (12%) and R (3)).

Mentions: Figure 2 shows the proportions of subjects for each study group with detectable R249S-mutated DNA at 6 cutoff concentrations from 67 to 160 copies/mL plasma). At the method’s limit of determination (67 copies/mL), the 4 liver disease groups had similar proportions of patients positive for R249S-mutated DNA (53–64%), clearly separated from the R group, for which only 19% of subjects were positive. Increasing the cutoff concentration better resolved the 5 study groups. We thus selected a lower cutoff concentration of 150 copies/mL for further comparisons of R249S-mutated DNA concentrations between the 4 liver disease groups and the reference group (Figure 3).


Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis.

Villar S, Ortiz-Cuaran S, Abedi-Ardekani B, Gouas D, Nogueira da Costa A, Plymoth A, Khuhaprema T, Kalalak A, Sangrajrang S, Friesen MD, Groopman JD, Hainaut P - PLoS ONE (2012)

Distribution of the liver disease and reference groups at different cutoffs of positivity of TP53 R249S mutation.At 150 copies/mL there is a clear distinction among the three liver cancer groups the chronic liver disease subjects and the reference group. The proportion of patients at this cut-off is higher in HCC/no cirrhosis (44%) than in all other groups (HCC/cirrhosis (21%), CC (22%), CLD (12%) and R (3)).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366967&req=5

pone-0037707-g002: Distribution of the liver disease and reference groups at different cutoffs of positivity of TP53 R249S mutation.At 150 copies/mL there is a clear distinction among the three liver cancer groups the chronic liver disease subjects and the reference group. The proportion of patients at this cut-off is higher in HCC/no cirrhosis (44%) than in all other groups (HCC/cirrhosis (21%), CC (22%), CLD (12%) and R (3)).
Mentions: Figure 2 shows the proportions of subjects for each study group with detectable R249S-mutated DNA at 6 cutoff concentrations from 67 to 160 copies/mL plasma). At the method’s limit of determination (67 copies/mL), the 4 liver disease groups had similar proportions of patients positive for R249S-mutated DNA (53–64%), clearly separated from the R group, for which only 19% of subjects were positive. Increasing the cutoff concentration better resolved the 5 study groups. We thus selected a lower cutoff concentration of 150 copies/mL for further comparisons of R249S-mutated DNA concentrations between the 4 liver disease groups and the reference group (Figure 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: International Agency for Research on Cancer, Lyon, France.

ABSTRACT
Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3(rd) 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.

Show MeSH
Related in: MedlinePlus