Nucleotide variants of the cancer predisposing gene CDH1 and the risk of non-syndromic cleft lip with or without cleft palate

Abstract

The CDH1 gene plays an important role during carcinogenesis and craniofacial morphogenesis. Germline mutations in this gene have been described in families presenting syndromic diffuse gastric cancer and orofacial clefts. The aim of this study was to evaluate the association between nucleotide variants of CDH1 and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Six single nucleotide polymorphisms (SNPs) of the CDH1 gene (rs16260, rs9929218, rs7186053, rs4783573, rs16958383, and rs1801552) were genotyped using the TaqMan SNP genotyping assays in 250 patients with NSCL/P and 540 controls from the Polish population. Comparison between patient and control groups showed that the CDH1 rs1801552 variant, under the assumption of recessive model, was associated with a two-fold decrease in the risk of NSCL/P (ORTT vs CT + CC = 0.481, 95 % CI 0.281–0.824, p = 0.007). This association remained statistically significant even after the multiple testing correction. No significant associations with NSCL/P risk were found for the other five tested SNPs. We found a strong association between the cancer predisposing gene CDH1 and the risk of NSCL/P in the Polish population. This result, together with previous observations of co-occurrence of orofacial clefts and a variety of cancer types, suggests the need for replication studies testing rs1801552 in NSCL/P cohorts with a known cancer history.

Clinical relevance of breast and gastric cancer-associated polymorphisms as potential susceptibility markers for oral clefts in the Brazilian population

“…Many reports showed that rs16260 is associated with the development of gastric cancer [45, 48], but it is controversial its association with craniofacial development [39, 40]. Similarly, rs9929218 was shown to have a borderline association with unilateral NSCL/P in Brazilian population [37] as well as the haplotype composed of rs9929218, rs7186053, rs4783573 and rs16958383 to NSCL/P in the population of Warsaw [40]. CDH1 plays a key role in cell adhesion, which is vital to normal development, including craniofacial morphogenesis and palatal fusion [49].…”

“…Genotyping analyses were randomly repeated in 10% of the samples, and the concordance rate was 100%. These SNPs were selected based on their minor allele frequencies (www.ncbi.nlm.nih.gov) and because they were described as risk factors for oral cleft and breast and gastric cancer [29, 37, 39, 40, 43–46]. The study was approved by the ethics review board of each of the centers or hospitals affiliated with the collaborative study.…”

“…Germline CDH1 mutations confer an increased risk of developing both gastric and breast cancer [34]. Genetics studies revealed that polymorphic variants in AXIN2 and CDH1 are risk factors for NSCL ± P and tooth agenesis [35–40]. In this study, we postulated that single nucleotide polymorphisms (SNP) in genes associated with breast and gastric pathogenesis ( AXIN2 and CDH1 ) might be related to the risk of NSCL ± P. Thus, we evaluated the association of 9 SNPs in CDH1 and AXIN2 with the risk of NSCL ± P using a family-based study design (case-parent trios).…”

Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate

“…These findings suggest that the most noteworthy CDH1 etiological contribution to NSOFC arises from the fraction of NSCL/P cases involving moderate penetrance, which is best represented by familial cases. Since the previously suggested association between common variants and NSCL/P [Letra et al., ; Hozyasz et al., ] has not been supported by a large meta‐analysis with GWAS data [Ludwig et al., ], rare variants seem to be the major contribution of CDH1 to NSCL/P etiology.…”

Nonsyndromic Oral Cleft in First-Degree Relatives of Patients with Acute Lymphoblastic Leukemia

“…The concept is that genes acting during the normal development may also have an important role in malignancies [6]. Over the past years, epidemiological studies have investigated the association of cancer with NSOC in different populations, including those from the United States, Southeast Asia, Denmark, Latvia, India, the Netherlands, Turkey, France, Poland, Pakistan, and Brazil [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26], and the results are controversial. Thus, the aim of this study was to determine the frequency of NSOC in families of patients with a diagnosis of ALL.…”