Evidence for association with hepatocellular carcinoma at the PAPSS1 locus on chromosome 4q25 in a family-based study

Abstract

A region on chromosome 4q25 has recently been highlighted as linked to hepatocellular carcinoma (HCC). In this study, we performed a family-based association analysis with 67 single-nucleotide polymorphisms (SNPs) to map this linkage region in 240 families with HCC, 212 (88.3%) of which were ascertained through hepatitis B virus surface antigen (HBsAg)-positive index cases. Individual SNP analysis with correction for multiple testing identified 10 SNPs in two correlated haplotype blocks, located in or around the 3 0 -phosphoadenosine 5 0 -phosphosulfate synthetase-1 (PAPSS1) gene (all P-values: o0.0075). Our linkage data and GIST (Genotype identity-by-descent sharing test) indicate that 6 of these 10 SNPs contributed to the linkage signal. The haplotype block of the strongest association with HCC extended from the intron 5 to the 3 0 -flanking region of PAPSS1; multiple consecutive three-SNP haplotypes in this region were significant. The most significant haplotype showed odd ratios of 3.41 (95% confidence interval (CI) ¼ 1.36 -8.53) for homozygous individuals in a case-unaffected sibling analysis. This haplotype also revealed an association with elevated serum a-fetoprotein and with poor survival in familial cases and an independent series of HBsAg-positive cases with small tumor present at the time of hospital admission. These results implicate PAPSS1 as a candidate HCC-susceptibility gene in hepatitis B carriers.

Risk of HCC: Genetic heterogeneity and complex genetics

“…The single genetic defects and the polygenic conditions cause liver damage and necrosis, resulting in liver cirrhosis that favors accumulation and/or promotion of somatic mutations and of genetic damage and thus representing the ultimate risk factor for HCC. studies suggest that a genetic locus on chromosome 4, encoding the candidate PAPSS1 gene, may modulate individual risk of HCC in HBV-positive subjects of the Chinese population [50]. The role of PAPSS1 genetic variants in HCC risk in the general population, in other countries, and in the absence of HBV infection remains to be established.…”

“…A subsequent family-based association analysis to finely map this linkage region in these families with HCC and HBV surface antigen (HBsAg)-positive index cases pointed to a linkage near the 3'-phosphoadenosine 5 0 -phosphosulfate syntase-1 (PAPSS1) gene [50] (Table 1). Functional characterization of the PAPSS1 candidate gene and identification of functional variants await further studies.…”

The IL-8 Gene Polymorphisms and the Risk of the Hepatitis B Virus/Infected Patients

“…It is also the second most common cause of cancer death in China (Poon et al, 1999). More than half of the HCC cases worldwide occur in Southeast Asia and sub-Saharan Africa (Shih et al, 2009), where it is attributed to the hepatitis B virus (HBV) that was recognized as a established risk factor for HCC development. Although HBV is known as a major cause of HCC, only a few of patients with chronic HBV infection develop HCC during their lifetime, revealing that genetic and environmental factors are important in determining individuals' susceptibility to HCC (Wu and Lin, 2007).…”

Genotype–phenotype analysis of 4q deletion syndrome: Proposal of a critical region

“…In brain and skin, PAPSS1 is the major expressed isoform [Venkatachalam, 2003]. PAPSS1 is implicated to be a candidate hepatocellular carcinomasusceptibility gene in hepatitis B carriers [Shih et al, 2009]. The effect of hemizygosity for PAPSS1 on this patient's phenotype is not clear.…”