Relationship between non-syndromic oral clefts and cancer: A systematic review and meta-analysis

To summarize the clinical evidence on the relationship between cancer and non-syndromic oral cleft (NSOC).

The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist, and a literature search was conducted in six databases and gray literature. Studies published in any language mentioning cancer in patients with NSOC and their relatives and NSOC in patients with cancer and their relatives were included. Risk of bias was assessed using the Joanna Briggs Institute appraisal tool. The certainty of the evidence was evaluated using the GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) assessment. After a 2-step selection process, 33 studies were included: 17 case-control studies, 13 cross-sectional studies, and 3 case reports.

The study evaluated 206,096 patients from 20 countries. Of these, 0.35% of patients with cancer (95% CI: 0.0%-1.1%; I²  = 86%), 3.0% of relatives of patients with cancer (95% CI: 1.19%-5.46%; I²  = 55%), and 0.26% of controls (95% CI: 0.0%-0.83%; I²  = 87%) had NSOC. Among the studies that examined the prevalence of cancer, 2.4% (95% CI: 0.0%-19.3%; I²  = 99%) of patients with NSOC, 15.4% of relatives of patients with NSOC (95% CI: 2.0%-37.6%; I²  = 99%), and 5.3% of controls (95% CI: 0.0%-22.8%; I²  = 99%) had cancer. Although no relationship was observed between the risk of cancer in patients with NSOC and the risk of NSOC in patients with cancer, there was an association for an increased risk of cancer in relatives of patients with NSOC (OR: 9.96, 95% CI: 1.55-63.99; p = 0.01) and a significant association for the NSOC risk in relatives of patients with leukemia (OR: 9.31; 95% CI: 1.13-76.67; p = 0.03).

Our findings demonstrate an increased risk of cancer in relatives of patients with NSOC and that relatives of patients with leukemia were more frequently affected by NSOC. Together, these findings can help guide cancer screening in patients with NSOC and their relatives and shed light on the risk of NSOC in families with a history of cancer.