AXIN2, Orofacial Clefts and Positive Family History for Cancer

Objectives: Craniofacial anomalies are the most common birth defects in newborns. It has been proposed that cancer and congenital malformations may occasionally have a common etiology. The goal of this study is to investigate if families segregating orofacial clefting, specifically cleft lip with or without cleft palate (CL/P) have increased cancer occurrence. Methods: First, history of cancer was analyzed in 168 families (75 CL/P families and 93 control families) of Caucasian ethnicity from Pittsburgh. Secondly, genes in which mutations have been independently associated with both cancer and craniofacial anomalies were studied in a total of 90 families (356 individuals) segregating CL/P from Pittsburgh. Fourteen SNPs in nine candidate genes were genotyped using Taqman chemistry. Results: CL/P families reported increased rates of any type of cancer when compared to control families (p=0.0002), and also increased rates of specific cancer types, including colon (p=0.0009), brain (p=0.003), leukemia (p=0.005), breast (p=0.009), prostate (p=0.01), skin (p=0.01), lung (p=0.02), and liver (0.02). Using transmission disequilibrium tests we found an association between CL/P and AXIN2 (p=0.04). Conclusion: Our results indicate that families segregating CL/P may have an increased susceptibility for cancer, notably colon cancer. AXIN2, a gene that when mutated increases the susceptibility to colon cancer, is associated with CL/P. NIH grants: R01-DE16148, P50-DE16215.