Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review

Yu Imamura; Paul Lochhead; Mai Yamauchi; Aya Kuchiba; Zhi R. Qian; Xiaoyun Liao; Reiko Nishihara; Seungyoun Jung; Kana Wu; Katsuhiko Nosho; Yaoyu E. Wang; Shouyong Peng; Adam J. Bass; Kevin M. Haigis; Jeffrey A. Meyerhardt; Andrew T. Chan; Charles S. Fuchs; Shuji Ogino

doi:10.1186/1476-4598-13-135

Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review

Yu Imamura, Paul Lochhead, Mai Yamauchi, Aya Kuchiba, Zhi R. Qian, Xiaoyun Liao, Reiko Nishihara, Seungyoun Jung, Kana Wu, Katsuhiko Nosho, Yaoyu E. Wang, Shouyong Peng, Adam J. Bass, Kevin M. Haigis, Jeffrey A. Meyerhardt, Andrew T. Chan, Charles S. Fuchs, Shuji Ogino

Department of Nutritional Science & Food Management

Research output: Contribution to journal › Article › peer-review

121 Scopus citations

Abstract

Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI.Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation].Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.

Original language	English
Article number	135
Journal	Molecular Cancer
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/1476-4598-13-135
State	Published - 31 May 2014

Bibliographical note

Funding Information:
ATC previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, and Pfizer Inc. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, or Pfizer Inc. No other conflict of interest exists.

Funding Information:
We deeply thank hospitals and pathology departments throughout the U.S. for generously providing us with tissue specimens. In addition, we would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. This work was supported by U.S. National Institute of Health (NIH) grants [P01 CA87969 to S.E. Hankinson; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to CSF; R01 CA137178 to ATC; and R01 CA151993 to SO]; and by grants from the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. ATC is a Damon Runyon Clinical Investigator. PL is a Scottish Government Clinical Academic Fellow and was supported by a Harvard University Frank Knox Memorial Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

Clinical outcome
Colon cancer
Genetic change
RAF
RAS

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Imamura, Y., Lochhead, P., Yamauchi, M., Kuchiba, A., Qian, Z. R., Liao, X., Nishihara, R., Jung, S., Wu, K., Nosho, K., Wang, Y. E., Peng, S., Bass, A. J., Haigis, K. M., Meyerhardt, J. A., Chan, A. T., Fuchs, C. S., & Ogino, S. (2014). Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review. Molecular Cancer, 13(1), Article 135. https://doi.org/10.1186/1476-4598-13-135

@article{ee0a46c8d3a44159a0a52692344d65b0,

title = "Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review",

abstract = "Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI.Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation].Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.",

keywords = "Clinical outcome, Colon cancer, Genetic change, RAF, RAS",

author = "Yu Imamura and Paul Lochhead and Mai Yamauchi and Aya Kuchiba and Qian, {Zhi R.} and Xiaoyun Liao and Reiko Nishihara and Seungyoun Jung and Kana Wu and Katsuhiko Nosho and Wang, {Yaoyu E.} and Shouyong Peng and Bass, {Adam J.} and Haigis, {Kevin M.} and Meyerhardt, {Jeffrey A.} and Chan, {Andrew T.} and Fuchs, {Charles S.} and Shuji Ogino",

note = "Funding Information: ATC previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, and Pfizer Inc. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, or Pfizer Inc. No other conflict of interest exists. Funding Information: We deeply thank hospitals and pathology departments throughout the U.S. for generously providing us with tissue specimens. In addition, we would like to thank the participants and staff of the Nurses{\textquoteright} Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. This work was supported by U.S. National Institute of Health (NIH) grants [P01 CA87969 to S.E. Hankinson; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to CSF; R01 CA137178 to ATC; and R01 CA151993 to SO]; and by grants from the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. ATC is a Damon Runyon Clinical Investigator. PL is a Scottish Government Clinical Academic Fellow and was supported by a Harvard University Frank Knox Memorial Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

year = "2014",

month = may,

day = "31",

doi = "10.1186/1476-4598-13-135",

language = "English",

volume = "13",

journal = "Molecular Cancer",

issn = "1476-4598",

publisher = "BioMed Central Ltd.",

number = "1",

}

Imamura, Y, Lochhead, P, Yamauchi, M, Kuchiba, A, Qian, ZR, Liao, X, Nishihara, R, Jung, S, Wu, K, Nosho, K, Wang, YE, Peng, S, Bass, AJ, Haigis, KM, Meyerhardt, JA, Chan, AT, Fuchs, CS & Ogino, S 2014, 'Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review', Molecular Cancer, vol. 13, no. 1, 135. https://doi.org/10.1186/1476-4598-13-135

TY - JOUR

T1 - Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer

T2 - Cohort study and literature review

AU - Imamura, Yu

AU - Lochhead, Paul

AU - Yamauchi, Mai

AU - Kuchiba, Aya

AU - Qian, Zhi R.

AU - Liao, Xiaoyun

AU - Nishihara, Reiko

AU - Jung, Seungyoun

AU - Wu, Kana

AU - Nosho, Katsuhiko

AU - Wang, Yaoyu E.

AU - Peng, Shouyong

AU - Bass, Adam J.

AU - Haigis, Kevin M.

AU - Meyerhardt, Jeffrey A.

AU - Chan, Andrew T.

AU - Fuchs, Charles S.

AU - Ogino, Shuji

N1 - Funding Information: ATC previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, and Pfizer Inc. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, or Pfizer Inc. No other conflict of interest exists. Funding Information: We deeply thank hospitals and pathology departments throughout the U.S. for generously providing us with tissue specimens. In addition, we would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. This work was supported by U.S. National Institute of Health (NIH) grants [P01 CA87969 to S.E. Hankinson; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to CSF; R01 CA137178 to ATC; and R01 CA151993 to SO]; and by grants from the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. ATC is a Damon Runyon Clinical Investigator. PL is a Scottish Government Clinical Academic Fellow and was supported by a Harvard University Frank Knox Memorial Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2014/5/31

Y1 - 2014/5/31

N2 - Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI.Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation].Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.

AB - Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI.Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation].Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.

KW - Clinical outcome

KW - Colon cancer

KW - Genetic change

KW - RAF

KW - RAS

UR - http://www.scopus.com/inward/record.url?scp=84902532849&partnerID=8YFLogxK

U2 - 10.1186/1476-4598-13-135

DO - 10.1186/1476-4598-13-135

M3 - Article

C2 - 24885062

AN - SCOPUS:84902532849

SN - 1476-4598

VL - 13

JO - Molecular Cancer

JF - Molecular Cancer

IS - 1

M1 - 135

ER -

Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review

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