APCI1307K and clinical management: insights from UK Biobank association analysis of colorectal and other cancer risks in Ashkenazi and non-Ashkenazi whites

ABSTRACT 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. We analyzed UK Biobank data comprising 466,315 individuals (8,727 with CRC), using genomic analysis to classify AJ and non-AJ ancestries. 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: 0.17–2.95) or non-AJ white individuals (OR: 1.05; 95%CI: 0.50– 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. Clinical actionability of I1307K should prioritize 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement SA and CFR were supported by CG-MAVE, Cancer Research UK Programme Award [EDDPGM-Nov22/100004]. LV's research activity is funded by the Spanish Ministry of Science and Innovation (Agencia Estatal de Investigacion), co-funded by FEDER funds-a way to build Europe- [PID2020-112595RB-I00, AEI/10.13039/501100011033], Instituto de Salud Carlos III [CIBERONC CB16/12/00234, PMP22/00064], and Government of Catalonia [AGAUR 2021_SGR_01112, CERCA Program for institutional support]. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the National Health Services National Research Ethics Service (16/NW/0274) and the North West Multi-Centre Research Ethics Committee as a Research Tissue Bank approval (11/NW/0382). Each participant provided written informed consent. Permission to access and analyze UK Biobank data (Project Application Number 76689) was approved by the UK Biobank according to their established access procedures. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes DATA AVAILABILITY STATEMENT All data used in the analyses are available from UK Biobank upon request (https://www.ukbiobank.ac.uk). Data and methods relevant to the study are included in the article or uploaded as supplementary information.