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

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.

Keywords: CI; CIMP; CRC; Colon Cancer; CpG island methylator phenotype; IWHS; Integrated Pathways; Iowa Women’s Health Study; MSI; Molecular Epidemiology; PCR; Prognostic Factor; RR; SEER; Surveillance, Epidemiology, and End Results; colorectal cancer; confidence interval; microsatellite instability; polymerase chain reaction; relative risk.

Figure 1

Kaplan–Meier curves. All-cause mortality by independent marker status. (A) MSI; (B) CIMP; (C) BRAF mutation; and (D) KRAS mutation.

Figure 2

Kaplan–Meier curves. CRC mortality by independent marker status. (A) MSI; (B) CIMP; (C)BRAFmutation;and(D)KRAS mutation.

Figure 3

Kaplan–Meier curves. All-cause and CRC mortality by integrated pathway assignments. (A) All-cause mortality by traditional, alternate, serrated, or other (unassigned) pathways. (B) CRC mortality by traditional, alternate, serrated, or other (unassigned) pathways. (C) All-cause mortality in pathway unassigned cases (cluster A, cluster B, or other). (D) CRC mortality in pathway unassigned cases (cluster A, cluster B, or other).