TY - JOUR
T1 - A new polygenic model for nonfamilial colorectal cancer inheritance based on the genetic architecture of the azoxymethane-induced mouse model
AU - Bissahoyo, Anika C.
AU - Xie, Yuying
AU - Yang, Lynda
AU - Pearsall, R. Scott
AU - Lee, Daekee
AU - Elliott, Rosemary W.
AU - Demant, Peter
AU - McMillan, Leonard
AU - de Villena, Fernando Pardo Manuel
AU - Angel, Joe M.
AU - Threadgill, David W.
N1 - Funding Information:
We thank the many members of the Threadgill laboratory who assisted with mouse husbandry and necropsies throughout the project, and for suggestions and comments on the manuscript. This work was supported by National Cancer Institute grants (CA079869, CA105417, and CA106991 to D.W.T.) and a National Institute of Environmental Health Sciences fellowship (ES012354 to A.C.B.). Author contributions: D.W.T. and R.S.P. designed the study concept and experiments; R.W.E. and P.D. provided mouse strains and advised on study design; A.C.B., R.S.P., D.K., and D.W.T performed the study; Y.X., L.Y., L.M., F.P-M.deV, and D.W.T. performed data analysis; A.C.B. and D.W.T. wrote the manuscript; J.M.A. edited the manuscript, and all authors read the manuscript.
Publisher Copyright:
Copyright © 2020 by the Genetics Society of America.
PY - 2020
Y1 - 2020
N2 - The azoxymethane model of colorectal cancer (CRC) was used to gain insights into the genetic heterogeneity of nonfamilial CRC. We observed significant differences in susceptibility parameters across 40 mouse inbred strains, with 6 new and 18 of 24 previously identified mouse CRC modifier alleles detected using genome-wide association analysis. Tumor incidence varied in F1 as well as intercrosses and backcrosses between resistant and susceptible strains. Analysis of inheritance patterns indicates that resistance to CRC development is inherited as a dominant characteristic genome-wide, and that susceptibility appears to occur in individuals lacking a large-effect, or sufficient numbers of small-effect, polygenic resistance alleles. Our results suggest a new polygenic model for inheritance of nonfamilial CRC, and that genetic studies in humans aimed at identifying individuals with elevated susceptibility should be pursued through the lens of absence of dominant resistance alleles rather than for the presence of susceptibility alleles.
AB - The azoxymethane model of colorectal cancer (CRC) was used to gain insights into the genetic heterogeneity of nonfamilial CRC. We observed significant differences in susceptibility parameters across 40 mouse inbred strains, with 6 new and 18 of 24 previously identified mouse CRC modifier alleles detected using genome-wide association analysis. Tumor incidence varied in F1 as well as intercrosses and backcrosses between resistant and susceptible strains. Analysis of inheritance patterns indicates that resistance to CRC development is inherited as a dominant characteristic genome-wide, and that susceptibility appears to occur in individuals lacking a large-effect, or sufficient numbers of small-effect, polygenic resistance alleles. Our results suggest a new polygenic model for inheritance of nonfamilial CRC, and that genetic studies in humans aimed at identifying individuals with elevated susceptibility should be pursued through the lens of absence of dominant resistance alleles rather than for the presence of susceptibility alleles.
KW - Cancer susceptibility
KW - Genetic architecture
KW - Heterogeneity
KW - Mouse models
UR - http://www.scopus.com/inward/record.url?scp=85081085478&partnerID=8YFLogxK
U2 - 10.1534/genetics.119.302833
DO - 10.1534/genetics.119.302833
M3 - Article
C2 - 31879319
AN - SCOPUS:85081085478
SN - 0016-6731
VL - 214
SP - 691
EP - 702
JO - Genetics
JF - Genetics
IS - 3
ER -