A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC.
Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinicopathologic staging for decades. There is a need to stratify subpopulations of CRC on a molecular basis to better predict outcome and assign therapies. Here we report targeted exome-sequencing of 1,321 cancer-related genes on 468 tumour specimens, which identified a subset of 17 genes that best classify CRC, with APC playing a central role in predicting overall survival. APC may assume 0, 1 or 2 truncating mutations, each with a striking differential impact on survival. Tumours lacking any APC mutation carry a worse prognosis than single APC mutation tumours; however, two APC mutation tumours with mutant KRAS and TP53 confer the poorest survival among all the subgroups examined. Our study demonstrates a prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Michael J
MJ
Schell
Gibbs Cancer Center and Research Institute, 380 Serpentine Drive, Spartanburg, South Carolina 29303, USA.
Mingli
M
Yang
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Jamie K
JK
Teer
Genomic Services, LabCorp Clinical Trials, 401 Terry Avenue North, Suite 200, Seattle, Washington 98109, USA.
Fang Yin
FY
Lo
Genomic Services, LabCorp Clinical Trials, 401 Terry Avenue North, Suite 200, Seattle, Washington 98109, USA.
Anup
A
Madan
Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Domenico
D
Coppola
Department of Epidemiology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Alvaro N A
AN
Monteiro
Genetics and Pharmacogenomics, Merck, Sharp and Dohme, PO Box 4, 770 Sumneytown Pike, Building 53, West Point, Pennsylvania 19486, USA.
Michael V
MV
Nebozhyn
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Binglin
B
Yue
Genetics and Pharmacogenomics, Merck, Sharp and Dohme, PO Box 4, 770 Sumneytown Pike, Building 53, West Point, Pennsylvania 19486, USA.
Andrey
A
Loboda
Molecular Health, 2700 Technology Forest Boulevard, The Woodlands, Texas 77381, USA.
Gabriel A
GA
Bien-Willner
Genetics and Pharmacogenomics, Merck, Sharp and Dohme, PO Box 4, 770 Sumneytown Pike, Building 53, West Point, Pennsylvania 19486, USA.
Danielle M
DM
Greenawalt
Gibbs Cancer Center and Research Institute, 380 Serpentine Drive, Spartanburg, South Carolina 29303, USA.
Timothy J
TJ
Yeatman
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D052138:Genes, Neoplasm; D006801:Humans; D053208:Kaplan-Meier Estimate; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D013194:Staining and Labeling; D018709:Statistics, Nonparametric; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D051176:beta Catenin