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Background & Aims Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival. Methods We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases. Results Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features. Conclusion These data suggest that the tumour micro-environment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles. Lay summary Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival.

Gallbladder dysplasia can progress to cancer and may be associated with increased cancer risk at other biliary tract sites. Thus, its accurate identification is relevant both for etiologic understanding and for clinical purposes. Data on the frequency and distribution of gallbladder dysplasia are lacking due to limited gallbladder sampling and inability to visualize dysplasia grossly. An expert pathology group used consensus criteria to review 140 totally sampled consecutive cholecystectomy specimens from Chilean women. Three cases (2%) revealed incidental invasive carcinoma, all T2, along with high-grade dysplasia (HGD). The surface area covered by dysplasia or cancer in these cases was 9%, 37%, and 87%. Although the first longitudinal (“diagnostic”) section of the whole gallbladder captured HGD or cancer in all three cases, the deepest focus of invasive carcinoma was not present in this section. Fourteen additional cases (10%) had low-grade dysplasia (LGD), which was typically very focal (covering

We examined inflammation as a mediator of associations between bacterial infection markers and gallbladder cancer (GBC).Bacterial response proteins (lipopolysaccharide [LPS], soluble cluster of differentiation 14 [sCD14], and LPS-binding protein [LBP]) were measured in 40 GBC cases and 126 gallstone controls with data on 63 serum inflammation markers. The relationships of LPS, LBP, and sCD14 with GBC were examined by logistic regression, which also was used to evaluate whether these associations are influenced by systemic inflammation as measured by a combinatorial inflammation score.The third versus the first tertiles of sCD14 and of LBP were associated with an increased GBC risk (odds ratio [95% confidence interval]: 5.41 [2.00-16.75] for sCD14, and 6.49 [2.24-23.79] for LBP). sCD14 and LBP were strongly associated with inflammation score (above vs. below the median), which itself was associated with a more than 21-fold increased risk of GBC for the third versus first tertiles. Associations between GBC and sCD14 and LBP were markedly attenuated when the inflammation score was included in the model. While LPS was not associated with GBC or inflammation, only 35% of cases and 22% of controls had detectable levels.These findings suggest that these LPS-pathway proteins are associated with GBC via inflammation-related pathways.

Most gallbladder cancer (GBC) cases arise in the context of gallstones, which cause inflammation, but few gallstone patients develop GBC. We explored inflammation/immune-related markers measured in bile and serum in GBC cases compared to gallstone patients to better understand how inflammatory patterns in these two conditions differ. We measured 65 immune-related markers in serum and bile from 41 GBC cases and 127 gallstone patients from Shanghai, China, and calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GBC versus gallstones. We then focused on the markers that were significantly elevated in bile and serum to replicate the findings in serum from 35 GBC cases and 31 gallstone controls from Chile. Comparing the highest versus lowest quantile, 15 markers (23%) were elevated in both serum and bile from GBC versus gallstone patients in the Shanghai study (p

Increasing evidence suggests that altered immunity and chronic inflammation play a key role in the etiology of many malignancies, but the underlying biological mechanisms involved remain unclear. Systemic markers of immunity may not represent the clinically relevant, site-specific immune response, whereas tissue-based markers may more accurately reflect the local immunologic mechanisms by which precursor lesions develop into cancer. Tissues are often only available in individuals with disease. Previous studies have measured tumor-infiltrating lymphocytes to predict prognosis and survival, but it can be challenging to use tissue-based markers to study the natural history of cancer due to limitations with regard to temporality, the availability of appropriate comparison groups, and other epidemiologic issues. In this commentary, we discuss several epidemiologic study design and study population considerations to address these issues, including the strengths and limitations of using tissue-based markers to study immune response and cancer development. We also discuss how the use of tissue-based immune markers fits into the greater context of molecular epidemiology, which encompasses multiple technologies and techniques, and how implementation of tissue-based immune markers will provide an increased understanding of site-specific biological mechanisms involved in carcinogenesis.

Background If women who receive the human papillomavirus (HPV) vaccine are unduly reassured about the cancer prevention benefits of vaccination, they may choose not to participate in screening, thereby increasing their risk for cervical cancer. This study assesses adult women's knowledge of the need to continue cervical cancer screening after HPV vaccination, describes Pap test intentions of vaccinated young adult women, and evaluates whether knowledge and intentions differ across groups at greatest risk for cervical cancer. Methods Data were from the 2008 Health Information National Trends Survey (HINTS) and the 2008 National Health Interview Survey (NHIS), which initiated data collection approximately 18 months after the first FDA approval of an HPV vaccine. We calculated associations between independent variables and the outcomes using chi-square tests. Results Of 1586 female HINTS respondents ages 18 through 74, 95.6% knew that HPV-vaccinated women should continue to receive Pap tests. This knowledge did not vary significantly by race/ethnicity, education, income, or healthcare access. Among 1101 female NHIS respondents ages 18–26 who had ever received a Pap test, the proportion (12.7%; n = 139) who reported receipt of the HPV vaccine were more likely than those not vaccinated to plan to receive a Pap test within three years (98.1% vs. 92.5%, p Conclusions US adult women possess high knowledge and intention to participate in Pap testing after HPV vaccination. The vast majority of young adult women who received the HPV vaccine within its first two years on the market intend to participate in cervical cancer screening in the near future. Future studies are needed to examine whether those vaccinated in adolescence will become aware of, and adhere to, screening guidelines as they become eligible.

Background & Aims Studies of liver cancer risk in recipients of solid organ transplants generally have been small, yielding mixed results, and little is known about biliary tract cancers among transplant recipients. Methods We identified incident hepatobiliary cancers among 201,549 US recipients of solid organs, from 1987 through 2008, by linking data from the US transplant registry with 15 cancer registries. We calculated standardized incidence ratios (SIRs), comparing risk relative to the general population. We also calculated incidence rate ratios (RRs), comparing risk for hepatocellular carcinoma (HCC) and total (intrahepatic and extrahepatic) cholangiocarcinoma among subgroups of recipients. Results Of transplant recipients, 165 developed hepatobiliary cancers (SIR, 1.2; 95% confidence interval [CI], 1.0–1.4). HCC risk was increased among liver recipients (SIR, 1.5; 95% CI, 1.0–2.2), especially 5 or more years after transplant (SIR, 1.8; 95% CI, 1.0–3.0). Cholangiocarcinoma was increased among liver (SIR, 2.9; 95% CI, 1.6–4.8) and kidney recipients (SIR, 2.1; 95% CI, 1.3–3.1). HCC was associated with hepatitis B virus (RR, 3.2; 95% CI, 1.3–6.9), hepatitis C virus (RR, 10; 95% CI, 5.9–16.9), and non–insulin-dependent diabetes (RR, 2.5; 95% CI, 1.2–4.8). Cholangiocarcinoma was associated with azathioprine maintenance therapy (RR, 2.0; 95% CI, 1.1–3.7). Among liver recipients, primary sclerosing cholangitis was associated with an increased risk of cholangiocarcinoma, compared with the general population (SIR, 21; 95% CI, 8.2–42) and compared with liver recipients without primary sclerosing cholangitis (RR, 12.3; 95% CI, 4.1–36.4). Conclusions Risks for liver and biliary tract cancer are increased among organ transplant recipients. Risk factors for these cancers include medical conditions and potentially medications taken by recipients.