| Title: | APC I1307K and clinical management: insights from UK Biobank association analysis of colorectal and other cancer risks in Ashkenazi and non-Ashkenazi whites |
| Journal: | Journal of Medical Genetics |
| Published: | 27 Aug 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40866199/ |
| DOI: | https://doi.org/10.1136/jmg-2025-110911 |
| URL: | https://jmg.bmj.com/content/jmedgenet/early/2025/08/27/jmg-2025-110911.full.pdf |
Publication 19658
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Abstract
BACKGROUND: APC c.3920T>A; p.Ile1307Lys (I1307K), prevalent in individuals of Ashkenazi Jewish (AJ) origin, has been associated with a modestly increased colorectal cancer (CRC) risk. Clinical recommendations for I1307K heterozygotes vary across countries and expert groups, reflecting differences in population frequencies, modest risk estimates and limited data in non-AJ individuals.</p>
METHODS: We analysed UK Biobank data comprising 466 315 individuals (8944 with CRC), using genomic analysis to classify AJ and non-AJ ancestries.</p>
RESULTS: I1307K was identified in 7.1% of AJ and 0.08% of non-AJ white participants. No significant association with CRC was observed in AJ (OR: 0.71; 95% CI: 0.17 to 2.95) or non-AJ white individuals (OR: 1.05; 95% CI: 0.50 to 2.22). The previously established OR of 1.7-1.8 for AJ individuals lies within our 95% CI, indicating underpowered results due to limited CRC cases. No significant associations were detected for other cancers. Unbiased, adequately powered CRC case-control studies in non-AJ populations would require cohorts far larger than current resources for feasible analysis.</p>
CONCLUSION: Clinical actionability of I1307K should prioritise risk stratification based on overall CRC risk and ancestry-dependent variant detection rates. However, management strategies need not differ by ancestry once a carrier is identified, as the biological impact of I1307K should be consistent across populations.</p>
15 Keywords
- Adenomatous Polyposis Coli Protein
- Aged
- Biological Specimen Banks
- Colorectal Neoplasms
- Female
- Genetic Predisposition to Disease
- Humans
- Jews
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- UK Biobank
- United Kingdom
- White People
5 Authors
- Sophie Allen
- Charlie F Rowlands
- Andrew Latchford
- Clare Turnbull
- Laura Valle
1 Application
| Application ID | Title |
|---|---|
| 76689 | Cancer Genetics Variant Interpretation and Gene Discovery |
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