Whole-exome sequencing identifies
            <i>MST1R</i>
            as a genetic susceptibility gene in nasopharyngeal carcinoma

Dai, Wei; Zheng, Hong; Cheung, Arthur Kwok Leung; Tang, Clara S.; Ko, Josephine Mun Yee; Wong, Bonnie Wing Yan; Leong, Merrin Man-Long; Sham, Pak C.; Cheung, Florence; Kwong, Dora Lai-Wan; Ngan, Roger K.C.; Ng, Wai Tong; Yau, Chun Chung; Pan, Jianji; Peng, Xingxing; Tung, Stewart Y.; Zhang, Zengfeng; Ji, Mingfang; Chiang, Alan Kwok Shing; Lee, Anne W.M.; Lee, Victor Ho-fun; Lam, Ka-On; Au, Kwok Hung; Cheng, Hoi Ching; Yiu, Harry; Lung, Maria Li

doi:10.1073/pnas.1523436113

Cited by 80 publications

(70 citation statements)

References 42 publications

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“…Further studies utilizing long‐range sequencing platforms will help to interrogate the association between variations in repetitive regions and NPC. Third, interaction between host genetics, environmental exposures and viral variants has not been explored. A joint study of EBV and host genomics may provide new insights into such interactions.…”

Section: Discussionmentioning

confidence: 99%

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

Hui

Chan

Yang

et al. 2019

Intl Journal of Cancer

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Whether certain variants of Epstein–Barr virus (EBV) are linked to the pathogenesis of nasopharyngeal carcinoma (NPC), which shows a marked geographic restriction, remains an unresolved issue. We performed a case–control study comparing genomic sequences of EBV isolated from saliva samples of 142 population carriers with those from primary tumour biopsies derived from 62 patients with NPC of Hong Kong. Cluster analysis discovered five EBV subgroups 1A‐C and 2A‐B amongst the population carriers in contrast to the predominance of 1A and ‐B in the majority of NPC. Genome‐wide association study (GWAS) identified a panel of NPC‐associated single nucleotide polymorphisms (SNPs) and indels in the EBER locus. The most significant polymorphism, which can be found in 96.8% NPC cases and 40.1% population carriers of Hong Kong, is a four‐base‐deletion polymorphism downstream of EBER2 (EBER‐del) from coordinates 7188–7191 (p = 1.91 × 10−7). In addition, the predicted secondary structure of EBER2 is altered with likely functional consequence in nearly all NPC cases. Using the SNPs and indels associated with NPC, genetic risk score is assigned for each EBV variant. EBV variants with high genetic risk score are found to be much more prevalent in Hong Kong Chinese than individuals of other geographic regions and in NPC than other EBV‐associated cancers. We conclude that high risk EBV variants with polymorphisms in the EBER locus, designated as HKNPC‐EBERvar, are strongly associated with NPC. Further investigation of the biological function and potential clinical application of these newly identified polymorphisms in NPC and other EBV‐associated cancers is warranted.

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Section: Discussionmentioning

confidence: 99%

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

Hui

Chan

Yang

et al. 2019

Intl Journal of Cancer

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“…2Germline variants of 338 ESCC cases in total consisting of 296 DNA extracted from blood detected by target capture and 42 normal esophageal tissues of Hong Kong ESCC patients detected by exome sequencing for somatic mutational landscape in Hong Kong ESCC patients were included.…”

Section: Resultsmentioning

confidence: 99%

“…Results were independently validated in Henan cohort (1,935 cases and 1,168 controls) and Hong Kong cohort (338 cases and 890 controls). The samples in the validation phase were all sequenced using a 598 gene‐based capture design, except 42 Hong Kong ESCC cases and 890 Hong Kong non‐cancer controls, which are from our previous genomic exome studies …”

Section: Methodsmentioning

confidence: 99%

“…The samples in the validation phase were all sequenced using a 598 gene-based capture design, except 42 Hong Kong ESCC cases and 890 Hong Kong non-cancer controls, which are from our previous genomic exome studies. 18,19 Library preparation and sequencing details are described in the supplementary methods. Briefly, genomic DNA was fragmented by sonication before library preparation using the KAPA HTP Library Prep Kit.…”

Section: Study Of Familial Escc: Discovery By Exome Sequencing and Twmentioning

confidence: 99%

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BRCA2 loss‐of‐function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese

Ning

Zhao

et al. 2019

Intl Journal of Cancer

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Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole‐exome sequencing (WES) included 186 familial ESCC patients from high‐risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate‐risk Hong Kong Chinese. A WES approach identified BRCA2 loss‐of‐function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10−10). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild‐type somatic allelic loss via loss of heterozygosity. Gene‐based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10−5), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.

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“…The SNRPN encoded protein has a role in the processing of pre-mRNA and possibly governs alternative splicing events in tissue-specific manner [104]. MST1R ’s promoter methylation leading to decreased expression has also been reported in cancers other than prostate [105]. Further, stromal cell expression of MST1R within the prostate tumor microenvironment has been observed to drive tumor growth [106].…”

Section: Epigenetics In Cancer Health Disparitiesmentioning

confidence: 99%

Epigenetic basis of cancer health disparities: Looking beyond genetic differences

Ahmad

Azim

Zubair

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Despite efforts at various levels, racial health disparities still exist in cancer patients. These inequalities in incidence and/or clinical outcome can only be explained by a multitude of factors, with genetic basis being one of them. Several investigations have provided convincing evidence to support epigenetic regulation of cancer-associated genes, which results in the differential transcriptome and proteome, and may be linked to a pre-disposition of individuals of certain race/ethnicity to early or more aggressive cancers. Recent technological advancements and the ability to quickly analyze whole genome have aided in these efforts, and owing to their relatively easy detection, methylation events are much well-characterized, than the acetylation events, across human populations. The early trend of investigating a pre-determined set of genes for differential epigenetic regulation is paving way for more unbiased screening. This review summarizes our current understanding of the epigenetic events that have been tied to the racial differences in cancer incidence and mortality. A better understanding of the epigenetics of racial diversity holds promise for the design and execution of novel strategies targeting the human epigenome for reducing the disparity gaps.

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Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma

Cited by 80 publications

References 42 publications

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

High risk Epstein‐Barr virus variants characterized by distinct polymorphisms in the EBER locus are strongly associated with nasopharyngeal carcinoma

BRCA2 loss‐of‐function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese

Epigenetic basis of cancer health disparities: Looking beyond genetic differences

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