A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis

Mengyuan Yang; Yingxin Zhao; Yuwei Ding; Juan Wang; Yinuo Tan; Dong Xu; Ying Yuan

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A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis

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Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.Methods:Adenomatous polyposis coli(APC)negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification.Then,whole-exome sequencing(WES)was used to determine candidate genes harboring pathogenic variants.Functional experiments were performed to explore their effects.Subsequently,using Sanger sequencing,we found other polyposis patients carrying variants of the DUOX2 gene,encoding dual oxidase 2,and analyzed them.Results:From 88 patients with suspected familial adenomatous polyposis,25 unrelated APC negative polyposis patients were identified.Based on the WES results of 3 patients and 2 healthy relatives from a family,the germline nonsense variant(c.1588 A>T;p.K530 X)of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis.During functional experiments,we observed that the truncated protein,h Duox2 K530,was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant,causing abnormal cell proliferation through endoplasmic reticulum(ER)retention.In addition,we found two unrelated APC negative patients carrying DUOX2 missense variants(c.3329 G>A,p.R1110 Q;c.4027 C>T,p.L1343 F).Given the results of the in silico analysis,these two missense variants might exert a negative influence on the function of h Duox2.Conclusions:To our knowledge,this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis.With an autosomal dominant inheritance,it causes ER retention,inducing an unfolded protein response.

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《癌症生物学与医学（英文版）》 |2021年第1期|215-226|共12页
作者
Mengyuan Yang; Yingxin Zhao; Yuwei Ding; Juan Wang; Yinuo Tan; Dong Xu; Ying Yuan;
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作者单位

Department of Medical Oncology Zhejiang University School of Medicine Hangzhou 310009 China;

Cancer Institute Zhejiang University School of Medicine Hangzhou 310009 China;

Department of Medical Oncology Zhejiang University School of Medicine Hangzhou 310009 China;

Cancer Institute Zhejiang University School of Medicine Hangzhou 310009 China;

Department of Medical Oncology Zhejiang University School of Medicine Hangzhou 310009 China;

Department of Medical Oncology Zhejiang University School of Medicine Hangzhou 310009 China;

Cancer Institute Zhejiang University School of Medicine Hangzhou 310009 China;

Department of Medical Oncology Zhejiang University School of Medicine Hangzhou 310009 China;

Cancer Institute Zhejiang University School of Medicine Hangzhou 310009 China;

Department of Colorectal Surgery and Oncology Key Laboratory of Cancer Prevention and Intervention Ministry of Education The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 China;

Department of Medical Oncology Zhejiang University School of Medicine Hangzhou 310009 China;

Cancer Institute Zhejiang University School of Medicine Hangzhou 310009 China;

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A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis

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