TY - JOUR
T1 - The Genomics of Colorectal Cancer in Populations with African and European Ancestry
AU - Myer, Parvathi A.
AU - Lee, Jessica K.
AU - Madison, Russell W.
AU - Pradhan, Kith
AU - Newberg, Justin Y.
AU - Isasi, Carmen R.
AU - Klempner, Samuel J.
AU - Frampton, Garrett M.
AU - Ross, Jeffery S.
AU - Venstrom, Jeffrey M.
AU - Schrock, Alexa B.
AU - Das, Sudipto
AU - Augenlicht, Leonard
AU - Verma, Amit
AU - Greally, John M.
AU - Raj, Srilakshmi M.
AU - Goel, Sanjay
AU - Ali, Siraj M.
N1 - Funding Information:
J.K. Lee reports personal fees from Foundation Medicine and Roche during the conduct of the study. R.W. Madison reports personal fees from Foundation Medicine and other support from Roche Holding AG during the conduct of the study. J.Y. Newberg reports personal fees from Foundation Medicine and Roche during the conduct of the study. S.J. Klempner reports personal fees from Foundation Medicine, Astellas, Merck, Bristol Myers Squibb, Daiichi Sankyo, Sanofi-Aventis, Eli Lilly, Pieris, and Natera, and other support from Turning Point Therapeutics outside the submitted work. G.M. Frampton is an employee of Foundation Medicine and a shareholder in Roche AG. J.S. Ross reports personal fees from Foundation Medicine during the conduct of the study. J.M. Venstrom reports other support from Foundation Medicine and Roche during the conduct of the study, as well as other support from Roche outside the submitted work. A.B. Schrock reports personal fees from Foundation Medicine and Roche during the conduct of the study. S. Das reports grants from Science Foundation Ireland outside the submitted work. A. Verma reports personal fees and other support from Stelexis, and grants from Janssen, Bristol Myers Squibb, Prelude, and Curis outside the submitted work. S.M. Ali reports other support from EQRx and personal fees from Elevation Oncology, Pillar Biosciences, Droplet Biosciences, and IN8bio outside the submitted work; genomics patents with Foundation Medicine pending and issued; and is a former employee of Foundation Medicine (no longer holds equity interest). No disclosures were reported by the other authors.
Funding Information:
We acknowledge the mentorship of Dr. I. David Goldman, Dr. Roman Perez-Soler, and Dr. Allan Wolkoff. This work was supported by NIH grant 5K12CA13278312 and the Paul Calabresi K12 Career Development Award (awarded to P.A. Myer).
Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - Black people have a higher incidence of colorectal cancer and worse survival rates when compared with white people. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer microsatellite instability–high (MSI-H) tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations, specifically KRASG12D and KRASG13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, and RET). In patients with young-onset colorectal cancer (<50 years), AFR and EUR had a similar frequency of MSI-H and tumor mutational burden–high (TMB-H) tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of the diverse U.S. population. SIGNIFICANCE: KRAS (particularly KRASG12D/G13), APC, and PIK3CA were more frequently altered in AFR who had a lower frequency of MSI-H tumors. There were no differences in actionable kinase driver alterations. In young-onset colorectal cancer, both ancestries had a similar frequency of MSI-H/TMB-H tumors, but strikingly different trends in APC.
AB - Black people have a higher incidence of colorectal cancer and worse survival rates when compared with white people. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer microsatellite instability–high (MSI-H) tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations, specifically KRASG12D and KRASG13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, and RET). In patients with young-onset colorectal cancer (<50 years), AFR and EUR had a similar frequency of MSI-H and tumor mutational burden–high (TMB-H) tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of the diverse U.S. population. SIGNIFICANCE: KRAS (particularly KRASG12D/G13), APC, and PIK3CA were more frequently altered in AFR who had a lower frequency of MSI-H tumors. There were no differences in actionable kinase driver alterations. In young-onset colorectal cancer, both ancestries had a similar frequency of MSI-H/TMB-H tumors, but strikingly different trends in APC.
UR - http://www.scopus.com/inward/record.url?scp=85129780792&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129780792&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-21-0813
DO - 10.1158/2159-8290.CD-21-0813
M3 - Article
C2 - 35176763
AN - SCOPUS:85129780792
SN - 2159-8274
VL - 12
SP - 1282
EP - 1293
JO - Cancer Discovery
JF - Cancer Discovery
IS - 5
ER -
