Browsing by Author "Hildesheim, Allan"

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    Association of inflammatory and other immune markers with gallbladder cancer: Results from two independent case-control studies
    (2016) Koshiol, Jill; Castro, Felipe; Kemp, Troy J.; Gao, Yu-Tang; Carlos Roa, Juan; Wang, Bingsheng; Nogueira, Leticia; Carlos Araya, Juan; Shen, Ming-Chang; Rashid, Asif; Hsing, Ann W.; Hildesheim, Allan; Ferreccio, Catterina; Pfeiffer, Ruth M.; Pinto, Ligia A.
    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 <0.05). The strongest OR was for CXCL8 (interleukin-8) in serum (96.8, 95% CI: 11.9-790.2). Of these 15 markers, 6 were also significantly elevated in serum from Chile (CCL20, C -reactive protein, CXCL8, CXCL10, resistin, serum amyloid A). Pooled ORs from Shanghai and Chile for these 6 markers ranged from 7.2 (95% CI: 2.8-18.4) for CXCL10 to 58.2 (95% CI: 12.4-273.0) for CXCL8. GBC is associated with inflammation above and beyond that generated by gallstones alone. This local inflammatory process is reflected systemically. Future longitudinal studies are needed to identify the key players in cancer development, which may guide translational efforts to identify individuals at high risk of developing GBC. Published by Elsevier Ltd.
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    Gallbladder cancer mortality in Chile: Has the government program targeting young gallstone patients had an impact?
    (2024) Cid, Vicente; Vargas, Claudio; Delgado, Iris; Apablaza, Mauricio; Shiels, Meredith S.; Hildesheim, Allan; Koshiol, Jill; Ferreccio, Catterina
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    Inflammatory profiles in Chilean Mapuche and non-Mapuche women with gallstones at risk of developing gallbladder cancer
    (2021) Jackson, Sarah S.; Van De Wyngard, Vanessa; Pfeiffer, Ruth M.; Cook, Paz; Hildesheim, Allan; Pinto, Ligia A.; Jackson, Sharon H.; Choi, Kelvin; Verdugo, Ricardo A.; Cuevas, Mara; Yanez, Cristian; Tobar-Calfucoy, Eduardo; Retamales-Ortega, Rocio; Araya, Juan Carlos; Ferreccio, Catterina; Koshiol, Jill
    Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P=0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P=0.03 and P<0.001). SDR analysis confirmed correlation between the biomarkers and ethnicity. We found higher IL-8 levels among Mapuche than non-Mapuche women. Novel inflammatory biomarkers were correlated with ethnicity and should be studied further for their role in gallbladder disease. These findings may elucidate underlying ethnic disparities in gallstones and carcinogenesis among Amerindians.
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    Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes
    (2021) Nepal, Chirag; Zhu, Bin; O'Rourke, Colm J.; Bhatt, Deepak Kumar; Lee, Donghyuk; Song, Lei; Wang, Difei; Van Dyke, Alison L.; Choo-Wosoba, Hyoyoung; Liu, Zhiwei; Hildesheim, Allan; Goldstein, Alisa M.; Dean, Michael; LaFuente-Barquero, Juan; Lawrence, Scott; Mutreja, Karun; Olanich, Mary E.; Bermejo, Justo Lorenzo; Ferreccio, Catterina; Roa, Juan Carlos; Rashid, Asif; Hsing, Ann W.; Gao, Yu-Tang; Chanock, Stephen J.; Araya, Juan Carlos; Andersen, Jesper B.; Koshiol, Jill
    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 TP53was themostmutated gene. The overallmutation ratewas low(median 0.82Mut/Mb). APOBECmediated 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 95gene 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 microenvironment 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. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.