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. Author manuscript; available in PMC: 2019 Sep 12.
Published in final edited form as: Nat Rev Cancer. 2016 Feb 12;16(3):173–186. doi: 10.1038/nrc.2016.4

Table 3 |.

Summary of promising molecular biomarkers associated with aspirin chemoprevention of adenoma or colorectal cancer

Biomarker Study population Study design Outcome Cases (n) Biomarker description RR (95% CI)* of outcome according to regular aspirin or NSAID use stratified by biomarker Refs
Germline genetic
rs6983267-T NHS and HPFS Nested case–control CRC 840 T allele of SNP

  • TT: 0.52 (0.35–0.78)

  • GT: 0.61 (0.47–0.79)

 GG: 0.99 (0.70–1.40) 115
rs2965667-TT 10 cohorts‡ GWAS§ CRC 8,634 TT genotype of SNP TT: 0.63 (0.59–0.68) TA or AA: 1.76 (1.16–2.66) 12
rs16973225-AA AA genotype of SNP AA: 0.63 (0.59–0.68) AC or CC: 0.93 (0.75–1.17)
rs2920421-GA CCFR Case–unaffected-sibling-control study CRC 1,621 GA genotype of SNP GA: 0.60 (0.45–0.80)

  • GG: 1.12 (0.86–1.46)

  • AA: 0.83 (0.45–1.51)

 94
rs2430420-GG AFPPS Nested cohort within an RCT Adenoma 370 GG genotype of SNP GG: 0.68 (0.50–0.94)∥ GA or AA: 0.95 (0.75–1.20)∥ 154
rs28362380-TT TT genotype of SNP TT: 0.75 (0.61–0.92)∥ TC or CC: 1.32 (0.85–2.06)∥
Colonic mucosa
HPGD NHS and HPFS Prospective cohort CRC 270 HPGD mRNA expression in normal mucosa High HPGD: 0.49 (0.34–0.71) Low HPGD: 0.90 (0.63–1.27) 65
Colorectal tumour
PIK3CA mutation NHS and HPFS Prospective cohort CRC 1,226 PIK3CA (exons 9 and 20) mt tumours PIK3CA mt: 0.66 (0.48–0.89) PIK3CA wt: 0.79 (0.69–0.90) 74,96
CRC-specific survival 964 PIK3CA mt: 0.18 (0.06–0.61) PIK3CA wt: 0.96 (0.69–1.32)
BRAF mutation NHS and HPFS Prospective cohort CRC 1,226 BRAFV600E mutation status of tumours BRAF wt: 0.73 (0.64–0.83) BRAF mt: 1.03 (0.76–1.38) 74
PTGS2 overexpression NHS and HPFS Prospective cohort CRC 632 Positive PTGS2 expression in tumour by IHC Positive PTGS2: 0.64 (0.52–0.78) Negative PTGS2: 0.96 (0.73–1.26) 66
Urine
PGE-M NHS Nested case–control Adenoma 420 Quartiles (Q) of urinary PGE-M High PGE-M (Q2–Q4): 0.61 (0.43–0.87) Low PGE-M (Q1): 1.05 (0.50–2.19) 86
AFPPS RCT Adenoma 328 Tertiles (T) of urinary PGE-M High PGE-M (T2 or T3):

  • 81 mg: 0.85 (0.67–1.08)

  • 325 mg: 1.03 (0.82–1.29)

 Low PGE-M (T1):

  • 81 mg: 0.62 (0.41–0.92)

  • 325 mg: 0.63 (0.43–0.91)

 87
Plasma
MIC1 NHS and HPFS Nested case–control CRC 618 Cohort-specific quintiles of plasma MIC1 High MIC1 and PTGS2 positive: 0.60 (0.41–0.88) High MIC1 and PTGS2 negative: 1.21 (0.71–2.07) 175
sTNFR2 NHS Nested case–control CRC 280 ≥Median plasma sTNFR2 sTNFR2 ≥ median: 0.39 (0.18–0.86) sTNFR2 < median: 0.86 (0.41–1.79) 119

AFPPS, Aspirin/Folate Polyp Prevention Study; CI, confidence interval; CRC, colorectal cancer; GWAS, genome-wide association study; HPGD, 15-hydroxyprostaglandin dehydrogenase; HR, hazard ratio; IHC, immunohistochemistry; MIC1, macrophage inhibitory cytokine 1; mt, mutant; NSAID, non-steroidal anti-inflammatory drug; PGE-M, major metabolite of prostaglandin E2; PIK3CA, PI3K catalytic subunit-α; PTGS2, prostaglandin-endoperoxide synthase 2; RCT, randomized clinical trial; RR, relative risk; SNP, single nucleotide polymorphism; sTNFR2, soluble tumour necrosis factor receptor 2; wt, wild-type.

*

All estimates are based on multivariable adjusted models.

‡

Ten cohorts: CCFR, Colon Cancer Family Registry; DACHS, Darmkrebs: Chancen der Verhütung durch Screening Study; DALS, Diet, Activity and Lifestyle Study; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; OFCCR, Ontario Familial Colorectal Cancer Registry; PMH-CCFR, Postmenopausal Hormone Study–CCFR; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; VITAL, Vitamins and Lifestyle; WHI, Women’s Health Initiative.

§

Case-only interaction analysis;

∥

RR represents 81 mg aspirin versus placebo. No significant effect was measured for 325 mg aspirin.