Risk Of CCA Research Articles

Pancreatic cancer risk variantABO rs505922in patients with cholangiocarcinoma

The aim of this study was to investigate an association between the development of cholangiocarcinoma (CCA) and the ABO variant rs505922 (known to increase pancreatic cancer risk) in a large cohort of European individuals with CCA. In total, 180 individuals with CCA and 350 CCA-free controls were included. The ABO variant rs505922 was genotyped using a polymerase chain reaction-based assay. Association between this single nucleotide polymorphism (SNP) and CCA was tested in contingency tables. Neither allele distributions nor association tests and regression analysis provided evidence for an increased risk of CCA among carriers of the ABO variant (all P > 0.05). Nevertheless, we documented a deviation from Hardy-Weinberg equilibrium in the entire CCA cohort (P = 0.028) and for patients with intrahepatic (P = 0.037) but not extrahepatic tumor localization (P > 0.05). The association tests did not provide evidence for a prominent role of the investigated SNP in the genetic risk of CCA. However, Hardy-Weinberg disequilibrium in the entire cohort and the intrahepatic CCA subgroup warrants future studies investigating a potential CCA risk modulation by individual blood groups.

Cancer risk in DES daughters.

ObjectiveWe examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero.MethodsA total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population.ResultsA total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer.ConclusionsExcept for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently.Electronic supplementary materialThe online version of this article (doi:10.1007/s10552-010-9526-5) contains supplementary material, which is available to authorized users.

Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma

The human hMYH and NEIL1 genes encode DNA glycosylases involved in repair of oxidative base damage and mutations in these genes are associated with certain cancers. Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease characterized by inflammatory destruction of the biliary tree, is often complicated by the development of cholangiocarcinoma (CCA). Here, we aimed to investigate the influence of genetic variations in the hMYH and NEIL1 genes on risk of CCA in PSC patients. The hMYH and NEIL1 gene loci in addition to the DNA repair genes hOGG1, NTHL1 and NUDT1 were analyzed in 66 PSC patients (37 with CCA and 29 without cancer) by complete genomic sequencing of exons and adjacent intronic regions. Several single-nucleotide polymorphisms and mutations were identified and severe impairment of protein function was observed for three non-synonymous variants. The NEIL1 G83D mutant was dysfunctional for the major oxidation products 7,8-dihydro-8-oxoguanine (8oxoG), thymine glycol and dihydrothymine in duplex DNA, and the ability to perform δ-elimination at abasic sites was significantly reduced. The hMYH R260Q mutant had severe defect in adenine DNA glycosylase activity, whereas hMYH H434D could excise adenines from A:8oxoG pairs but not from A:G mispairs. We found no overall associations between the 18 identified variants and susceptibility to CCA in PSC patients; however, the impaired variants may be of significance for carcinogenesis in general. Our findings demonstrate the importance of complete resequencing of selected candidate genes in order to identify rare genetic variants and their possible contribution to individual susceptibility to cancer development.

High lifetime risk of cancer in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) patients are at risk for developing cholangiocarcinoma (CCA) and colorectal carcinoma (CRC). Our aim was to assess the risk of malignancies and their influence on survival. Data from PSC patients diagnosed between 1980 and 2006 in two university hospitals were retrieved. The Kaplan-Meier method and a time-dependent Cox regression model were used to calculate risks of malignancies and their influence on survival. Two hundred and eleven patients were included, 143 (68%) were male and 126 (60%) had inflammatory bowel disease (IBD). Median transplantation-free survival was 14 years. The risk of CCA after 10 and 20 years was 9% and 9%, respectively. In patients with concomitant IBD the 10-year and 20-year risks for CRC were 14% and 31%, which was significantly higher than for patients without IBD (2% and 2% (P=0.008)). CCA, cholangitis, and age at entry were independent risk factors for the combined endpoint death or liver transplantation. Risk factors for the endpoint death were CCA, CRC, age, and symptomatic presentation. Patients with PSC and IBD have a high long-term risk of developing CRC and this risk is about threefold higher than the risk for CCA. Both malignancies are associated with decreased survival.

Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms

Primary sclerosing cholangitis (PSC) is often complicated by the development of cholangiocarcinoma (CCA). Genetic variation of natural killer cell receptor G2D (NKG2D) has been associated with cancer susceptibility. An important ligand for NKG2D, major histocompatibility complex class I chain-related molecule A (MICA), serves as a marker of cellular stress. The 5.1 allele of the gene encoding MICA has been associated with PSC. In this study, we aimed to investigate the influence of genetic variations in the NKG2D-MICA receptor-ligand pair on the risk of CCA in patients with PSC. Seven single nucleotide polymorphisms (SNPs) covering the NKG2D gene were genotyped in 365 Scandinavian PSC patients and 368 healthy controls with TaqMan technology. Genotype data on the MICA 5.1 variant were available from previous studies. Forty-nine of the PSC patients (13.6%) had developed CCA at the time of study. Two of the NKG2D SNPs were associated with an increased risk of CCA: rs11053781 [odds ratio (OR) = 2.08, 95% confidence interval (CI) = 1.31-3.29, corrected P (P(c)) = 0.011] and rs2617167 (OR = 2.32, 95% CI = 1.47-3.66, P(c) = 0.0020). Carriership of the MICA 5.1 allele was associated with resistance against CCA (OR = 0.43, 95% CI = 0.20-0.95, not corrected P = 0.032). Our results show that genetic variants of the NKG2D receptor are associated with development of CCA in PSC patients. This suggests that interaction between NKG2D and MICA is involved in protection against CCA in PSC. Patients who are homozygous for the nonrisk alleles are unlikely to develop CCA; this finding could be helpful in identifying PSC patients with a low CCA risk.

In Brief

Cholangiocarcinoma (CCA) is a cancer arising from the intra- or extrahepatic bile ducts and mainly characterized by its late diagnosis and fatal outcome. CCA is the second most common primary liver tumour and accounts for approximately 10–15% of all hepatobiliary malignancies. The development of CCA is linked to a wide spectrum of conditions causing biliary inflammation, cholestasis and inflammation of the liver. The geographic diversity of risk factors is reflected in considerable differences in incidence worldwide. Although data are not consistent, incidence seems to be rising in the Western World. Given the limited opportunities of treating advanced CCA, surveillance has been suggested as a strategy for detection of early disease in the high-risk group of patients with primary sclerosing cholangitis (PSC). In this review we present an updated overview of the epidemiology of CCA. We also highlight the risk of CCA in PSC with special focus on surveillance strategies.

Advances in the diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis

Advances in the diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis

Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis.

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0-16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p= 0.01), and lack of symptoms (p= 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p= 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3-67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.