文档库

最新最全的文档下载
当前位置:文档库 > Germline Mutations in MSR1, ASCC1

Germline Mutations in MSR1, ASCC1

Germline Mutations in MSR1, ASCC1

PRELIMINARY

COMMUNICATION

Germline Mutations in MSR1,ASCC1,and CTHRC1in Patients With Barrett Esophagus and Esophageal Adenocarcinoma

Mohammed Orloff,PhD

Charissa Peterson,MS

Xin He,MD,PhD

Shireen Ganapathi

Brandie Heald,MS,CGC

Yi-ran Yang,MD

Gurkan Bebek,PhD

Todd Romigh,MS

Jee Hoon Song,BS

Wenjing Wu,BS

Stefan David,MD

Yulan Cheng,MD

Stephen J.Meltzer,MD

Charis Eng,MD,PhD

T HE INCIDENCE OF ESOPHAGEAL

adenocarcinoma(EAC)in the

United States and Europe has

increased350%since1970,

with uncertain etiology.1Although

early-stage EAC is curable,most cases

are detected at an advanced stage with

poor survival.Esophageal adenocarci-

noma is believed to be preceded by

Barrett esophagus(BE),a premalig-

nant metaplasia caused by chronic

gastroesophageal reflux disease

(GERD).2-6GERD-related inflamma-

tion and the transforming growth fac-

tor␤(TGFB)pathway have been implicated in sporadic BE and EAC, just as the role of inflammation has become prominent in a range of human cancers.7Although acknowl-edged,the role of inflammation in BE and EAC has not been thoroughly Author Affiliations:Genomic Medicine Institute(Drs Or-

loff,He,Yang,Bebek,and Eng and Mss Peterson,Ga-

napathi,and Heald and Mr Romigh),Taussig Cancer

Institute(Drs Orloff and Eng and Ms Heald),and Stan-

ley Shalom Zielony Institute for Nursing Excellence

(Dr Eng),Cleveland Clinic,Cleveland,Ohio;Center

for Proteomics and Bioinformatics(Dr Bebek),Depart-

ment of Genetics(Dr Eng),and CASE Comprehensive

Cancer Center(Drs Bebek and Eng),Case Western

Reserve University School of Medicine,Cleveland,Ohio;

and Department of Medicine and Sidney Kimmel Com-

prehensive Cancer Center,Johns Hopkins University

School of Medicine,Baltimore,Maryland(Drs David,

Cheng,and Meltzer and Messrs Song and Wu).

Corresponding Author:Charis Eng,MD,PhD,Ge-

nomic Medicine Institute,Cleveland Clinic,9500

Euclid Ave,Mailstop NE-50,Cleveland,OH44195

(engc@http://www.wendangku.net/doc/3f9d7e25c5da50e2534d7f03.html ).

Context Barrett esophagus(BE)occurs in1%to10%of the general population and is believed to be the precursor of esophageal adenocarcinoma(EAC).The incidence of EAC has increased350%in the last3decades without clear etiology.Finding pre-disposition genes may improve premorbid risk assessment,genetic counseling,and management.Genome-wide multiplatform approaches may lead to the identification of genes important in BE/EAC development.

Objective To identify risk alleles or mutated genes associated with BE/EAC. Design,Setting,and Patients Model-free linkage analyses of21concordant-affected sibling pairs with BE/EAC and11discordant sibling pairs(2005-2006).Sig-nificant germline genomic regions in independent prospectively accrued series of176 white patients with BE/EAC and200ancestry-matched controls(2007-2010)were validated and fine mapped.Integrating data from these significant genomic regions with somatic gene expression data from19BE/EAC tissues yielded12“priority”can-didate genes for mutation analysis(2010).Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued vali-dation series of58cases(2010).

Main Outcome Measures Identification of germline mutations in genes associ-ated with BE/EAC cases.Functional interrogation of the most commonly mutated gene.

Results Three major genes,MSR1,ASCC1,and CTHRC1were associated with BE/ EAC(all PϽ.001).In addition,13patients(11.2%)with BE/EAC carried germline mu-tations in MSR1,ASCC1,or CTHRC1.MSR1was the most frequently mutated,with 8of116(proportion,0.069;95%confidence interval[CI],0.030-0.130;PϽ.001)cases with c.877CϾT(p.R293X).An independent validation series confirmed germline MSR1 mutations in2of58cases(proportion,0.035;95%CI,0.004-0.120;P=.09).MSR1 mutation resulted in CCND1up-regulation in peripheral-protein lysate.Immunohis-tochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expres-sion of CCND1.

Conclusion MSR1was significantly associated with the presence of BE/EAC in deri-vation and validation samples,although it was only present in a small percentage of the cases.

JAMA.2011;306(4):http://www.wendangku.net/doc/3f9d7e25c5da50e2534d7f03.html

410JAMA,July27,2011—Vol306,No.4©2011American Medical Association.All rights

Germline Mutations in MSR1, ASCC1

reserved.

免费下载Word文档免费下载: Germline Mutations in MSR1, ASCC1

(共10页)