TY - JOUR
T1 - Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women
AU - Samadder, N. 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 C.
AU - Thibodeau, Stephen N.
AU - Cerhan, James R.
AU - Limburg, Paul J.
N1 - Funding Information:
Funding Supported by National Institutes of Health grants CA107333 and HHSN261201000032C .
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.
KW - Molecular Epidemiology Colon Cancer Prognostic Factor Integrated Pathways
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U2 - 10.1053/j.gastro.2013.05.001
DO - 10.1053/j.gastro.2013.05.001
M3 - Article
C2 - 23665275
AN - SCOPUS:84880632820
SN - 0016-5085
VL - 145
SP - 348-356.e2
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -
