1.
Rapid emergence and predominance of a broadly recognizing and fast-evolving norovirus GII.17 variant in late 2014
Chan, Martin C W; Lee, Nelson; Hung, Tin-Nok ...
Nature communications,
12/2015, Volume:
6, Issue:
1
Journal Article
Norovirus genogroup II genotype 4 (GII.4) has been the predominant cause of viral gastroenteritis since 1996. Here we show that during the winter of 2014-2015, an emergent variant of a previously ...
rare norovirus GII.17 genotype, Kawasaki 2014, predominated in Hong Kong and outcompeted contemporary GII.4 Sydney 2012 in hospitalized cases. GII.17 cases were significantly older than GII.4 cases. Root-to-tip and Bayesian BEAST analyses estimate GII.17 viral protein 1 (VP1) evolves one order of magnitude faster than GII.4 VP1. Residue substitutions and insertion occur in four of five inferred antigenic epitopes, suggesting immune evasion. Sequential GII.4-GII.17 infections are noted, implicating a lack of cross-protection. Virus bound to saliva of secretor histo-blood groups A, B and O, indicating broad susceptibility. This fast-evolving, broadly recognizing and probably immune-escaped emergent GII.17 variant causes severe gastroenteritis and hospitalization across all age groups, including populations who were previously less vulnerable to GII.4 variants; therefore, the global spread of GII.17 Kawasaki 2014 needs to be monitored.
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2.
MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non-Small Cell Lung Carcinoma with Poor Prognosis
Tong, Joanna H; Yeung, Sai F; Chan, Anthony W H ...
Clinical cancer research,
06/2016, Volume:
22, Issue:
12
Journal Article
Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the ...
clinicopathologic correlations in a large cohort of treatment-naïve non-small cell lung carcinoma (NSCLC).
Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively.
METΔ14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). METΔ14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis.
The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048-56. ©2016 AACRSee related commentary by Drilon, p. 2832.
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3.
Genomic landscape of lymphoepithelioma‐like hepatocellular carcinoma
Chan, Anthony W‐H; Zhang, Zhe; Chong, Charing C‐N ...
The Journal of pathology,
October 2019, 2019-10-00, 20191001, Volume:
249, Issue:
2
Journal Article
Lymphoepithelioma‐like hepatocellular carcinoma (LEL‐HCC) is a distinct variant of HCC that is characterized by dense tumor‐infiltrating lymphocytes (TILs). Patients with LEL‐HCC also show better ...
clinical outcomes compared to conventional HCC (c‐HCC), which is commonly presented with low TIL. Emerging evidence has begun to highlight tumor‐intrinsic genetic abnormalities in the tumor–host immune interfaces. However, genome‐wide characterization of LEL‐HCC remains largely unexplored. Here, we defined the genomic landscape of 12 LEL‐HCC using whole‐exome sequencing, and further underpinned those genetic alterations related to an immune active microenvironment by comparing findings to 15 c‐HCC that were sequenced in parallel. Overall, the mutational load between LEL‐HCC and c‐HCC was similar. Interestingly, SNV incidences of specific genes (CTNNB1, AXIN1, NOTCH1, and NOTCH2) were significantly higher in c‐HCC than LEL‐HCC, suggesting a plausible link between activated Wnt/β‐catenin and Notch signaling pathways and immune avoidance. Marked focal amplification of chromosome 11q13.3 was prevalent in LEL‐HCC. Using The Cancer Genome Atlas dataset, we further established oncogenes expressed from chromosome 11q13.3 (CCND1, FGF19, and FGF4) to be strongly associated with the immune checkpoint signature (CD274, PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3). Our results have illustrated for the first time the somatic landscape of LEL‐HCC, and highlighted molecular alterations that could be exploited in combinatory therapy with checkpoint inhibitors in targeting HCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
4.
EBV‐encoded miRNAs target ATM‐mediated response in nasopharyngeal carcinoma
Lung, Raymond W‐M; Hau, Pok‐Man; Yu, Ken H‐O ...
The Journal of pathology,
April 2018, Volume:
244, Issue:
4
Journal Article
Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein–Barr virus (EBV) ...
infection. In NPC, miR‐BARTs, the EBV‐encoded miRNAs derived from BamH1‐A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV‐encoded miRNAs in a panel of NPC patient‐derived xenografts and an EBV‐positive NPC cell line by small RNA sequencing. Among the 40 miR‐BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV‐miRNAs, BART5‐5p, BART7‐3p, BART9‐3p, and BART14‐3p could negatively regulate the expression of a key DNA double‐strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'‐UTR. Notably, the expression of these four miR‐BARTs represented more than 10% of all EBV‐encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT‐PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5‐5p, BART7‐3p, BART9‐3p, and BART14‐3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR‐BARTs in EBV‐positive NPC cells, we further demonstrated the novel function of miR‐BARTs in inhibiting Zta‐induced lytic reactivation. These findings imply that the four viral miRNAs work co‐operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
5.
Receptor tyrosine kinase fusions act as a significant alternative driver of the serrated pathway in colorectal cancer development
Chan, Anthony W‐H; Pan, Yi; Tong, Joanna H‐M ...
The Journal of pathology,
20/May , Volume:
251, Issue:
1
Journal Article
Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the ...
development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4–RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4–RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen‐activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
6.
Steatotic hepatocellular carcinoma: a variant associated with metabolic factors and late tumour relapse
Chan, Anthony W H; Yu, Shuangni; Yu, Yau-Hei ...
Histopathology,
12/2016, Volume:
69, Issue:
6
Journal Article
Aims
Steatosis in hepatocellular carcinoma (HCC) has been recognized for decades and found most commonly in small, well‐differentiated HCC. However, the clinicopathological features and pathogenesis ...
of HCC with steatosis is not well characterized. There are few data concerning whether HCC with steatosis should be regarded a distinct histological variant, steatotic HCC.
Methods and results
A retrospective cohort of 516 patients undergoing curative surgery for primary HCC was recruited. The median follow‐up was 45.5 (range: 0.2–166.0) months. Steatotic HCC was defined as HCC with significant steatosis (≥5% of tumour cells). Associations with immunohistochemical expression of fatty acid binding protein‐1 (FABP1), sonic hedgehog (SHH) and gene polymorphism of patatin‐like phospholipase 3 (PNPLA3) were analysed. Steatotic HCC was found in 21.1% of patients and was associated with higher metabolic risks diabetes mellitus (36.7% versus 18.2%) and hypertension (44.0% versus 28.7%), underlying fatty liver (60.6% versus 37.8%), steatohepatitis (30.3% versus 13.0%), smaller tumour size, lower frequency of major vessel (1.8% versus 11.3%) and microvascular invasion (20.2% versus 32.4%), earlier tumour stages and lower serum alpha‐fetoprotein. It was associated with developing late tumour relapse (hazard ratio 2.15, P = 0.002) independently of underlying cirrhosis and non‐anatomical excision. Steatotic HCC did not differ from HCC without significant steatosis in immunohistochemical expression of FABP1 and SHH and PNPLA3 gene polymorphism.
Conclusion
Steatotic HCC is a common histological variant of HCC with distinct association with underlying fatty liver, steatohepatitis and metabolic risks. Despite more favourable baseline tumour features, it was associated with late tumour relapse.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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