**8. Cleft palate and cancer**

Several studies from different countries (USA, Latvia, Denmark, and Brazil) have identified an association between cleft palate and cancer [90–95]. The first epidemiological studies addressed the presence of cancer in cleft lip/palate subjects and their families. Parents of kids with sporadic CL/P have a higher risk of developing cancer than control families [96], and increased risk of cancer in adulthood can be seen in a Danish population-based cohort of CL/P subjects [97]. Such studies suggested that the association was most frequent for breast cancer but also colorectal, gastric, prostate, and uterus cancers. In a large study, 313 families segregating cases of isolated CL/P, including information of 13,879 individuals, were analyzed by Vieira [93]. The study brings further evidence that individuals born with CL/P and their family members have a higher prevalence of cancer than the general population. This risk is three times higher in first- and second-degree relatives and decreases to 1.5 times in third-degree relatives.

A possible genetic link was identified in two families with mutations in the E-cadherin gene CDH1 with CL/P and hereditary diffuse gastric cancer [98]. CDH1 is highly expressed in the palate. Vogelaar et al. also identified germline mutations multiple families with gastric cancer and orofacial clefts [99]. One concern in interpreting these studies is that cleft lip/palate patients tend to have a higher prevalence of behavioral risk factors, such as smoking and drinking because of their limited social interactions as adolescents, thus are at higher risk of tobacco and alcohol-related cancers independently from their initial malformation.

What is lacking is a study of cancer cases and the risk of cleft palate in their family members. Such studies are limited by the fact that the genetic defect is still a rare event, and the number of cancer cases necessary to address the problem would be extremely large. A study conducted on family members of cancer patients (Taioli et al. [95]) involved an epidemiological questionnaire including family history of cancer and congenital oral cleft malformations that was administered to 168 cancer survivors and a population-based sample of 170 healthy subjects. In the control group, 1.2% reported a family member with CL/P; among cancer survivors, the figure was 4.2% (odds ratio: 3.7; 95% confidence interval: 0.75–17.8; *p* = .07). Among cancer survivors with a family member with CL/P, there was an apparent excess of testicular cancer and melanoma in comparison with the cancer survivors with no family history of CL/P. These preliminary results suggest a common etiologic background for cancer and CL/P.

Taken all together, the data suggest that there are shared environmental and genetic factors in families that predispose to both cleft palate and cancer.
