Abstract
It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.
Highlights
Nonsyndromic cleft lip/palate is a birth defect characterised by lack of fusion of structures in the upper lip and palate, with a complex aetiology influenced by both genetic and environmental factors (Dixon, Marazita, Beaty, & Murray, 2011; Mossey, Little, Munger, Dixon, & Shaw, 2009)
The combined summary statistics were not publicly available, so meta‐analysis summary statistics were reconstructed by the authors, this has been described in detail previously (Howe et al, 2018, 2019)
The Transmission Disequilibrium Test (TDT) results were meta‐analysed with genome‐wide association study (GWAS) summary results on 399 cases and 1,318 controls from the Bonn‐II study, of European descent (Mangold et al, 2010)
Summary
Nonsyndromic cleft lip/palate (nsCL/P) is a birth defect characterised by lack of fusion of structures in the upper lip and palate, with a complex aetiology influenced by both genetic and environmental factors (Dixon, Marazita, Beaty, & Murray, 2011; Mossey, Little, Munger, Dixon, & Shaw, 2009). Evidence from epidemiological population‐ based studies that individuals with birth defects have increased incidence of cancer (Bjørge, Cnattingius, Lie, Tretli, & Engeland, 2008; Carozza, Langlois, Miller, & Canfield, 2012; Fisher et al, 2012; Johnson et al, 2017) suggests that birth defects, including nsCL/P, may have shared aetiology with cancer. For nsCL/P the evidence for increased incidence of cancers among cases and unaffected first degree relatives is largely inconsistent, with findings limited by available sample sizes (Bille et al, 2005; Bjørge et al, 2008; Carozza et al, 2012; Johnson et al, 2017; Vieira, Khaliq, & Lace, 2012; Zhu et al, 2002). Syndromic and nonsyndromic forms of CL/P have different aetiologies and can be difficult to distinguish, suggesting that combining them together could be problematic if they have differences in cancer risk
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