Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women

Niloy Jewel Samadder, Robert A. Vierkant, Lori S. Tillmans, Alice H. Wang, Daniel J. Weisenberger, Peter W. Laird, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, John D. Potter, Susan L Slager, Thomas Christopher Smyrk, Stephen N Thibodeau, James R Cerhan, Paul John Limburg

Research output: Contribution to journalArticle

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Abstract

Background & Aims Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. Methods We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Results Patients' mean age (P =.03) and tumors' anatomic subsite (P =.0001) and grade (P =.0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). Conclusions We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.

Original languageEnglish (US)
JournalGastroenterology
Volume145
Issue number2
DOIs
StatePublished - Aug 2013

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CpG Islands
Colorectal Neoplasms
Microsatellite Instability
Mutation
Phenotype
Microsatellite Repeats
Clinical Pathology
Neoplasms
Women's Health
Proportional Hazards Models
Carcinogenesis
Confidence Intervals
Survival
Mortality

Keywords

  • Molecular Epidemiology Colon Cancer Prognostic Factor Integrated Pathways

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women. / Samadder, Niloy Jewel; Vierkant, Robert A.; Tillmans, Lori S.; Wang, Alice H.; Weisenberger, Daniel J.; Laird, Peter W.; Lynch, Charles F.; Anderson, Kristin E.; French, Amy J.; Haile, Robert W.; Potter, John D.; Slager, Susan L; Smyrk, Thomas Christopher; Thibodeau, Stephen N; Cerhan, James R; Limburg, Paul John.

In: Gastroenterology, Vol. 145, No. 2, 08.2013.

Research output: Contribution to journalArticle

Samadder, NJ, Vierkant, RA, Tillmans, LS, Wang, AH, Weisenberger, DJ, Laird, PW, Lynch, CF, Anderson, KE, French, AJ, Haile, RW, Potter, JD, Slager, SL, Smyrk, TC, Thibodeau, SN, Cerhan, JR & Limburg, PJ 2013, 'Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women', Gastroenterology, vol. 145, no. 2. https://doi.org/10.1053/j.gastro.2013.05.001
Samadder, Niloy Jewel ; Vierkant, Robert A. ; Tillmans, Lori S. ; Wang, Alice H. ; Weisenberger, Daniel J. ; Laird, Peter W. ; Lynch, Charles F. ; Anderson, Kristin E. ; French, Amy J. ; Haile, Robert W. ; Potter, John D. ; Slager, Susan L ; Smyrk, Thomas Christopher ; Thibodeau, Stephen N ; Cerhan, James R ; Limburg, Paul John. / Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women. In: Gastroenterology. 2013 ; Vol. 145, No. 2.
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abstract = "Background & Aims Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. Methods We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77{\%}), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Results Patients' mean age (P =.03) and tumors' anatomic subsite (P =.0001) and grade (P =.0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95{\%} confidence interval, 1.07-2.89, compared with the traditional pathway). Conclusions We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.",
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T1 - Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women

AU - Samadder, Niloy Jewel

AU - Vierkant, Robert A.

AU - Tillmans, Lori S.

AU - Wang, Alice H.

AU - Weisenberger, Daniel J.

AU - Laird, Peter W.

AU - Lynch, Charles F.

AU - Anderson, Kristin E.

AU - French, Amy J.

AU - Haile, Robert W.

AU - Potter, John D.

AU - Slager, Susan L

AU - Smyrk, Thomas Christopher

AU - Thibodeau, Stephen N

AU - Cerhan, James R

AU - Limburg, Paul John

PY - 2013/8

Y1 - 2013/8

N2 - Background & Aims Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. Methods We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Results Patients' mean age (P =.03) and tumors' anatomic subsite (P =.0001) and grade (P =.0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). Conclusions We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.

AB - Background & Aims Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. Methods We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Results Patients' mean age (P =.03) and tumors' anatomic subsite (P =.0001) and grade (P =.0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). Conclusions We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.

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