A Fazeli

A Pavlicek

AR Clarke

AR Moser

AR Shoemaker

C Greenman

Chinnambally Venkataramu

CM Caldwell

Dana Busam

DJ Askew

DL Stoler

ER Fearon

G Voidonikolas

GJ Riggins

GP Boivin

H Rajagopalan

International Human Genome Sequencing Consortium

J Camps

J Massague

J Tang

JC Pole

JC Venter

Jie Tang

JK Habermann

K Takaku

KM Haigis

KW Kinzler

M Bienz

M Grade

M Peifer

Maria Marjorette O Peña

NJ Toft

NS Fearnhead

OA Hampton

P Pevzner

PL Deininger

PM Haverty

R Beroukhim

RB Halberg

Richard Halberg

S Jones

S Kaiser

S Thiagalingam

S Zhao

SA Hahn

Shaying Zhao

Steve Ferriera

T Hinoi

T Reichling

T Sjöblom

Timothy J Yeatman

WM Clements

X Ji

Xinglai Ji

Y Shi

BMC Cancer

English

PubMed

Springer - Publisher Connector

Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study

Abstract
          
            Background
            We are developing a cross-species comparison strategy to distinguish between cancer driver- and passenger gene alteration candidates, by utilizing the difference in genomic location of orthologous genes between the human and other mammals. As an initial test of this strategy, we conducted a pilot study with human colorectal cancer (CRC) and its mouse model C57BL/6J Apc
              Min/+, focusing on human 5q22.2 and 18q21.1-q21.2.
          
          
            Methods
            We first performed bioinformatics analysis on the evolution of 5q22.2 and 18q21.1-q21.2 regions. Then, we performed exon-targeted sequencing, real time quantitative polymerase chain reaction (qPCR), and real time quantitative reverse transcriptase PCR (qRT-PCR) analyses on a number of genes of both regions with both human and mouse colon tumors.
          
          
            Results
            These two regions (5q22.2 and 18q21.1-q21.2) are frequently deleted in human CRCs and encode genuine colorectal tumor suppressors APC and SMAD4. They also encode genes such as MCC (mutated in colorectal cancer) with their role in CRC etiology unknown. We have discovered that both regions are evolutionarily unstable, resulting in genes that are clustered in each human region being found scattered at several distinct loci in the genome of many other species. For instance, APC and MCC are within 200 kb apart in human 5q22.2 but are 10 Mb apart in the mouse genome. Importantly, our analyses revealed that, while known CRC driver genes APC and SMAD4 were disrupted in both human colorectal tumors and tumors from Apc
              Min/+ mice, the questionable MCC gene was disrupted in human tumors but appeared to be intact in mouse tumors.
          
          
            Conclusions
            These results indicate that MCC may not actually play any causative role in early colorectal tumorigenesis. We also hypothesize that its disruption in human CRCs is likely a mere result of its close proximity to APC in the human genome. Expanding this pilot study to the entire genome may identify more questionable genes like MCC, facilitating the discovery of new CRC driver gene candidates.
          </jats:sec

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Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study

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