Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes

Nepal, Chirag; Zhu, Bin; O’Rourke, Colm J.; Bhatt, Deepak; Lee, Donghyuk; Song, Lei; Wang, Difei; Dyke, Alison L. Van; Choo‐Wosoba, Hyoyoung; Liu, Zhiwei; Hildesheim, Allan; Goldstein, Alisa M.; Dean, Michael; Lafuente-Barquero, Juan; Lawrence, Scott M.; 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, J. C.; Andersen, Jesper B.; Koshiol, Jill

doi:10.1016/j.jhep.2020.11.033

Cited by 49 publications

(37 citation statements)

References 35 publications

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“…In contrast, poor prognosis GBC were associated with dysregulation of immune-related pathways, including dysfunctional T cells and T cell exclusion. 5 In agreement with the presence of an immunosuppressive microenvironment, poor prognosis GBC also exhibited expression of markers linked to the activation of transforming growth factor beta (TGFb), a potent immunosuppressive cytokine (Fig. 1).…”

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confidence: 55%

“…The work of Nepal and colleagues, aiming at deciphering the different TIME present in GBC, could thus represent a major step forward for future clinical trial development. 5 Similar analyses were previously done in CCA, highlighting clinically relevant subgroups of patients who may benefit from immunotherapies based on specific TIME. 17 The subgroup of GBC with a better prognosis identified by Nepal and colleagues would, at first glance, appear to be a good target for evaluating ICIs.…”

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confidence: 64%

“…Histomorphological analysis by Nepal and colleagues showed an enrichment of biliary, gastric foveolar and intestinal growth patterns in subtype 1, subtype 2 and subtype 3, respectively. 5 Interestingly, this morpho-molecular subtyping resembles the pattern of intracholecystic papillary neoplasm, the known premalignant lesion of the gallbladder, raising interesting questions regarding the processes of tumor differentiation and malignant transformation. However, independent validation of this finding and identification of tissue biomarkers associated with these histological subtypes would provide additional support for an association of gastric foveolar GBC with good prognosis.…”

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confidence: 89%

“…4 In this issue of Journal of Hepatology, Nepal and colleagues address this issue by establishing a comprehensive landscape of genetic, epigenetic and transcriptomic alterations in a large cohort of patients with GBC. 5 Importantly, by integrating various data from DNA methylation changes, copy number analysis, RNA sequencing and whole exome sequencing, they highlight clinically relevant tumor subgroups associated with prognosis (Fig. 1).…”

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confidence: 99%

“…1). 5 MDSCs have been shown to exhibit strong immunosuppressive effects by upregulating regulatory T cells and immune suppressive cytokines, as well as supporting the conversion of fibroblasts to CAFs. 14 Therefore, the study by Nepal and colleagues sheds new light on the tumor microenvironment of GBC in poor and good outcome subgroups, supporting the hypothesis that immunosuppression and microenvironment remodeling may account for poor patient survival and possibly poor response to immune checkpoint inhibitors (ICIs) (Fig.…”

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confidence: 99%

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Integrative genomics highlights opportunities for innovative therapies targeting the tumor microenvironment in gallbladder cancer

Roessler

Edeline²,

Schirmacher³

et al. 2021

Journal of Hepatology

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confidence: 55%

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confidence: 64%

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confidence: 89%

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confidence: 99%

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confidence: 99%

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Integrative genomics highlights opportunities for innovative therapies targeting the tumor microenvironment in gallbladder cancer

Roessler

Edeline²,

Schirmacher³

et al. 2021

Journal of Hepatology

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Super‐Enhancer Reprograming Driven by SOX9 and TCF7L2 Represents Transcription‐Targeted Therapeutic Vulnerability for Treating Gallbladder Cancer

Yan,

Liu,

Wang

et al. 2024

Advanced Science

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Gallbladder cancer (GBC) is a highly aggressive malignancy lacking clinically available targeted therapeutic agents. Super‐enhancers (SEs) are crucial epigenetic cis‐regulatory elements whose extensive reprogramming drives aberrant transcription in cancers. To study SE in GBC, the genomic distribution of H3K27ac is profiled in multiple GBC tissue and cell line samples to establish the SE landscape and its associated core regulatory circuitry (CRC). The biliary lineage factor SOX9 and Wnt pathway effector TCF7L2, two master transcription factor (TF) candidates identified by CRC analysis, are verified to co‐occupy each other's SE region, forming a mutually autoregulatory loop to drive oncogenic SE reprogramming in a subset of GBC. The SOX9/TCF7L2 double‐high GBC cells are highly dependent on the two TFs and enriched of SE‐associated gene signatures related to stemness, ErbB and Wnt pathways. Patients with more such GBC cells exhibited significantly worse prognosis. Furthermore, SOX9/TCF7L2 double‐high GBC preclinical models are found to be susceptible to SE‐targeted CDK7 inhibition therapy in vitro and in vivo. Together, this study provides novel insights into the epigenetic mechanisms underlying the oncogenesis of a subset of GBCs with poorer prognosis and illustrates promising prognostic stratification and therapeutic strategies for treating those GBC patients in future clinical trials.

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Association of aflatoxin with gallbladder cancer in a case‐control study nested within a Chinese cohort

Koshiol,

Zhu,

Wang

et al. 2023

Intl Journal of Cancer

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We evaluated whether aflatoxin B1 (AFB1) exposure was associated with later risk of developing gallbladder cancer (GBC). We measured AFB1‐lysine albumin adducts in baseline samples from the Shanghai Cohort Study of 18 244 men aged 45 to 64 years (recruited 1986‐1989). We included 84 GBC cases with sufficient serum and 168 controls matched on age at sample collection, date of blood draw and residence. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for detectable vs non‐detectable AFB1‐lysine albumin adducts and gallbladder cancer. AFB1‐lysine albumin adducts were detected in 50.0% of GBC cases, and risk of GBC was twice as high in those with detectable vs undetectable levels (OR = 2.0, 95% CI = 1.0‐3.9). ORs ranged from 1.8 (95% CI = 0.75‐4.3) for 0.5 to <1.75 pg/mg vs undetectable adduct levels to 2.2 (95% CI = 0.91‐5.6) for >3.36 pg/mg vs undetectable, suggesting a dose‐response (Ptrend = .05). When restricted to cases diagnosed before the median time to diagnosis after blood draw (18.4 years), results were similar (OR = 2.2, 95% CI = 0.80‐5.8) to those for the entire follow‐up duration. The OR was 9.4 (95% CI = 1.7‐51.1) for individuals with detectable AFB1‐lysine albumin adducts and self‐reported gallstones compared to individuals with neither. Participants with detectable AFB1‐lysine albumin adducts at baseline had increased risk of developing GBC, replicating the previously observed association between AFB1 exposure and providing the first evidence of temporality.

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Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes

Cited by 49 publications

References 35 publications

Integrative genomics highlights opportunities for innovative therapies targeting the tumor microenvironment in gallbladder cancer

Integrative genomics highlights opportunities for innovative therapies targeting the tumor microenvironment in gallbladder cancer

Super‐Enhancer Reprograming Driven by SOX9 and TCF7L2 Represents Transcription‐Targeted Therapeutic Vulnerability for Treating Gallbladder Cancer

Association of aflatoxin with gallbladder cancer in a case‐control study nested within a Chinese cohort

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