APC I1307K and clinical management: insights from UK Biobank association analysis of colorectal and other cancer risks in Ashkenazi and non-Ashkenazi whites.
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Embargo End Date
ICR Authors
Authors
Allen, S
Rowlands, CF
Latchford, A
Turnbull, C
Valle, L
Rowlands, CF
Latchford, A
Turnbull, C
Valle, L
Document Type
Journal Article
Date
2025-11-21
Date Accepted
2025-08-06
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. METHODS: We analysed UK Biobank data comprising 466 315 individuals (8944 with CRC), using genomic analysis to classify AJ and non-AJ ancestries. 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. 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.
Citation
Journal of Medical Genetics, 2025,
Source Title
Journal of Medical Genetics
Publisher
BMJ PUBLISHING GROUP
ISSN
0022-2593
eISSN
1468-6244
Collections
Research Team
Translational Genetics