Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers

Cancer. 2016 Sep 15;122(18):2828-35. doi: 10.1002/cncr.30082. Epub 2016 May 31.


Background: The incidence and outcomes of patients with colorectal cancer (CRC) varies by age. Younger patients tend to have sporadic cancers that are not detected by screening and worse survival. To understand whether genetic differences exist between age cohorts, the authors sought to characterize unique genetic alterations in patients with CRC.

Methods: In total, 283 patients who were diagnosed with sporadic CRC between 1998 and 2010 were identified and divided by age into 2 cohorts-ages ≤45 years (the younger cohort) and ≥65 years (the older cohort)-and targeted exome sequencing was performed. The Fisher exact test was used to detect differences in mutation frequencies between the 2 groups. Whole exome sequencing was performed on 21 additional younger patient samples for validation. Findings were confirmed in The Cancer Genome Atlas CRC data set.

Results: In total, 246 samples were included for final analysis (195 from the older cohort and 51 from the younger cohort). Mutations in the FBXW7 gene were more common in the younger cohort (27.5% vs 9.7%; P = .0022) as were mutations in the proofreading domain of polymerase ε catalytic subunit (POLE) (9.8% vs 1%; P = .0048). There were similar mutation rates between cohorts with regard to TP53 (64.7% vs 61.5%), KRAS (43.1% vs 46.2%), and APC (60.8% vs 73.8%). BRAF mutations were numerically more common in the older cohort, although the difference did not reach statistical significance (2% vs 9.7%; P = .082).

Conclusions: In this retrospective study, a unique genetic profile was identified for younger patients who have CRC compared with patients who are diagnosed at an older age. These findings should be validated in a larger study and could have an impact on future screening and treatment modalities for younger patients with CRC. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2828-2835. © 2016 American Cancer Society.

Keywords: F-box and WD repeat-containing protein 7 (FBXW7); adolescent and young adults; biomarkers; colorectal cancer.

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cohort Studies
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Polymerase II / genetics*
  • DNA Polymerase II / metabolism
  • F-Box Proteins / genetics*
  • F-Box Proteins / metabolism
  • F-Box-WD Repeat-Containing Protein 7
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mutation
  • Poly-ADP-Ribose Binding Proteins
  • Retrospective Studies
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism


  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Ubiquitin-Protein Ligases
  • DNA Polymerase II
  • POLE protein, human