I’m continuing my deep dives into the genetic pathways to get actionable insights as the previous ones have been incredible precise and useful. This time I’m looking at Cancer Predisposition genetic pathways.
Here is the general description of the pathways and their variants. I will put the finding about my own genome below it as an example of what useful and actionable insights you can get.
Cancer_Predisposition_Pathway_Reference.pdf (472.2 KB)
Cancer Predisposition — Top 10 Actionable Findings
Summary card for discussion with treating physician · Date: April 2026 · Source: 60× WGS, GRCh38
Headline: No high-penetrance pathogenic findings. Dominant pattern is a moderate common-variant (polygenic) signal for colorectal and prostate cancer, an intact DNA repair apparatus, and a favorable TP53 Arg72 homozygous finding. Main actions cluster around screening intensity, filling a data gap, and reinforcing the existing antioxidant/Nrf2/one-carbon strategy.
1. Homozygous 8q24 rs6983267 + rs1447295 + 11q23 rs3802842 — moderate polygenic CRC + prostate signal
Three independent homozygous common risk variants at the most-replicated CRC and prostate cancer GWAS loci. Each OR ~1.2–1.3 per allele. Aggregate signal meaningful but not high-penetrance. Discuss: colonoscopy interval (earlier start and/or shorter interval), annual PSA with trajectory tracking, MRI-informed prostate approach.
2. Homozygous GSTP1 V/V (I105V) + homozygous NAT2 *5 slow acetylator — Phase II detox bottleneck
Reduced conjugation of PAH diolepoxides and aromatic amines. Gene-environment dependent — main action is avoidance of tobacco smoke and minimizing charred meat. Discuss: higher-dose NAC (600–1200 mg vs current 100 mg) and routine sulforaphane/broccoli sprout extract for Nrf2-mediated upregulation of residual Phase II enzymes.
3. GSTM1/GSTT1 null status — data gap (HIGH PRIORITY)
Single-SNP bcftools query cannot detect these copy-number deletions (~50% population null frequency). If null, would substantially strengthen the Phase II bottleneck. Request: structural-variant analysis from WGS provider, or dedicated GSTM1/GSTT1 PCR assay.
4. Homozygous VDR rs731236 (TaqI) + rs2228570 (FokI) — confirm vitamin D adequacy
Both VDR variants homozygous. Individual effects weak, but combined argue for confirmed 25-OH D 40–60 ng/mL. Discuss: annual serum 25-OH D. Your current D3 5000 IU EOD should achieve target.
5. Homozygous SRD5A2 L/L (V89L) — mildly protective for prostate cancer; converges with dutasteride
Reduced 5-alpha-reductase type 2 activity, pharmacologically synergistic with your current dutasteride 0.5 mg EOD. Gene-plus-drug convergence. Discuss: reassuring but does not replace PSA surveillance.
6. Heterozygous KLK3 rs2735839 — baseline PSA shifted
The KLK3 (PSA gene) risk allele modulates baseline PSA production. Discuss with urologist: interpret PSA values as a trajectory rather than against fixed cutoffs; small changes over time may be more informative than absolute numbers.
7. Homozygous TP53 Arg72/Arg72 (rs1042522) — favorable finding
More efficient mitochondrial apoptosis induction in response to DNA damage compared to Pro72. Partially offset by heterozygous MDM2 SNP309 (slightly raised MDM2 expression). Net: slightly favorable common polymorphism. Reassuring — no action required.
8. Aspirin 81 mg daily is already the single most evidence-based cancer chemopreventive in your regimen
CRC risk reduction ~20–40% with sustained use (Rothwell Lancet 2010–2012). Directly addresses the dominant 8q24/11q23 CRC polygenic signal. Continue. This is the highest-value single cancer-preventive intervention you are on.
9. One-carbon convergence: MTHFR C677T het + MTRR I22M het — confirm cofactor adequacy
Direct replication from Homocysteine Regulation report. Folate status links directly to uracil misincorporation and cancer risk. Verify: Momentous Multi contains methyl-folate (5-MTHF) not folic acid, and methyl-B12 + P5P + riboflavin. Check serum homocysteine, serum folate, and RBC folate annually.
10. Negative findings worth knowing
No BRCA1/2 pathogenic variants. No Lynch syndrome. No APC I1307K. No CHEK2 1100delC. No ATM V2424G. No MUTYH MAP variants. No PALB2. The high-penetrance cancer repair machinery is genetically intact. The moderate-penetrance DDR genes are clean. This is reassuring context for the polygenic common-variant signals above.
Additional items to discuss
- Formal polygenic risk score (PRS) for CRC and prostate cancer to quantify absolute risk increment
- Sulforaphane / broccoli sprout extract 10–50 mg SFN daily for Nrf2 induction (HIGH priority)
- Curcumin (bioavailable BCM-95 or Meriva) 500–1000 mg for CRC polyp reduction evidence
- Higher-dose NAC (up from 100 mg to 600–1200 mg) for glutathione precursor support
- DHEA 25 mg — mixed evidence vis-a-vis the hormonal GWAS findings; worth a conversation
- Annual dermatology exam — routine preventive (no strong genetic indication)
Tests to add to routine labs
- 25-OH vitamin D (annual)
- Serum homocysteine, folate, RBC folate (annual)
- hs-CRP, IL-6 (already tracked)
- PSA total + free with trajectory tracking (annual)
- FIT (between colonoscopies)
Full report: Cancer Predisposition Genetic Report (docx). Educational reference: Cancer Predisposition Pathway Reference (docx). Neither report constitutes a clinical diagnosis; all actions require physician discussion.