Case Comprehensive Cancer Center CRC — African American Cohort (2015)

Overview

A single-institution cohort from Case Medical Center (northeastern Ohio) designed to characterize the somatic mutational landscape of microsatellite-stable (MSS) colorectal cancers in African American (AA) patients — the largest such cohort at the time of publication. All tumors were fresh-frozen, pathologist-confirmed ≥50% tumor cellularity, and MSS by five-marker panel (BAT26/BAT40/D2S123/D5S346/D17S250). The study was published in 2015 by Guda et al. in PNAS.

Composition

  • Discovery set: 29 informative MSS late-stage AA CRC tumor/normal pairs sequenced by whole-exome sequencing; one hypermutator excluded from the original 30 cases.
  • Validation set: 74 informative MSS AA CRC cases (predominantly early-stage) sequenced with a custom Agilent SureSelectXT bait library against 78 candidate genes; three hypermutators excluded from the original 77.
  • Comparator: 129 predominantly late-stage MSS Caucasian CRCs from the same institution, resequenced for the 20 significantly mutated AA genes.
  • Cancer type: COAD.
  • Samples drawn exclusively from fresh-frozen archive in northeastern Ohio.

Assays / panels (linked)

  • whole-exome-seq — 29 discovery AA CRC paired tumor/normal exomes.
  • targeted-dna-seq — custom Agilent SureSelectXT bait library (78 candidate genes) for 74 AA CRC validation cases; used for 129 Caucasian comparators (20-gene panel).
  • sanger-sequencing — orthogonal confirmation of candidate somatic variants.

Papers using this cohort

  • PMID:25583493 — Guda et al. (2015). Whole-exome and targeted sequencing of 103 AA and 129 Caucasian MSS CRCs; nominated 20 significantly mutated genes with a 15-gene subset preferentially targeted in AA patients.

Notable findings derived from this cohort

  • A 15-gene subset of the 20 newly identified significantly mutated genes is preferentially targeted in AA CRCs (~twofold more mutations per tumor than Caucasian CRCs; P = 1.8 × 10⁻⁸), accounting for 41% of AA cases vs 15% of Caucasian cases. PMID:25583493
  • EPHA6 mutations identified in 5.83% of AA CRCs (6/103) vs 0% of Caucasian CRCs (P = 0.007), proposed as an AA-specific CRC driver. PMID:25583493
  • FLCN mutations (two frameshifts, one nonsense) exclusive to AA cases (3/103 vs 0/129; P = 0.086), consistent with loss-of-function and proposed as an AA-specific driver. PMID:25583493
  • Classic CRC drivers (APC, TP53, KRAS, PIK3CA, SMAD4, BRAF, FBXW7) did not differ overall between AA and Caucasian CRCs; however, KRAS and FBXW7 individually showed significantly higher mutation rates in AA cases. PMID:25583493

Sources

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