Risk of Breast Cancer in Families with Cleft Lip and Palate

Purpose

To test whether female subjects in families with cleft lip and/or palate (CL/P) have an increased risk of breast cancer.

Methods

By using the Danish Facial Cleft Registry, we identified female subjects with CL/P, mothers of children with CL/P, and sisters to CL/P cases for the Danish birth cohorts 1911–1975. These subjects were compared with a 5% random sample of these cohorts regarding the incidence and age of onset for breast cancer registered in the Danish Hospital Discharge Register 1977–2005.

Results

Examining 48,404 person-years for 1809 female CL/P cases (49 breast cancer cases) and 212,795 person-years for 7935 female relatives (188 breast cancer cases), we found no increased breast cancer risk for either CL/P cases (hazard ratio [HR], 1.23; 95% confidence interval (CI), 0.92–1.63), mothers of children with CL/P (HR, 0.93; 95% CI, 0.80–1.08), or sisters of CL/P cases (HR, 0.94; 95% CI, 0.55–1.60), nor was there any significant differences in age of onset.

Conclusion

Both epidemiological and genetic studies have suggested common etiological factors for breast cancer and CL/P. However, in this population-based study we were not able to confirm a general increase in the risk of breast cancer among female subjects in families with CL/P.

Introduction

Congenital malformations and cancer may share common etiological factors 1, 2, 3. Co-occurrences of malformations and cancers have been seen in children as the result of both genetic and environmental causes. Genetic links between malformations and cancer include mutations in the Patched Homolog 1 (PTCH) gene, which produce physical anomalies such as rib and craniofacial abnormalities, and basal cell carcinoma or medulloblastoma 4, 5, 6. Mutations in the Wilms Tumor 1 (WT1) gene or Paired Box 6 (PAX6) gene can lead to WAGR syndrome, which is characterized by Wilm’s tumor associated with genitourinary, diaphragmatic, and ocular physical abnormalities (7). Another well-studied example is between Down syndrome and leukemia 8, 9.

Cleft lip and/or palate (CL/P) is a common congenital malformation, with a frequency of approximately 1 per 700 births, but varying widely by race 2, 10. CL/P can be divided into subphenotypes on the basis of their anatomical location with common subdivisions, including cleft lip only (CL), cleft lip with cleft palate (CLP), and cleft palate only (CP) 11, 12. Although CL and CLP have been commonly lumped into cleft lip with or without cleft palate, evolving evidence suggests they can have distinct and independent risks 13, 14, 15. Studies in Danish twins have found a monozygotic twin concordance rate between 40% and 60% for CL/P, whereas dizygotic twins have a concordance rate of approximately 5%–10% with heritability estimates of 70%-90% 16, 17, 18, 19, suggesting that genetic factors play a major role in the susceptibility to CL/P.

The authors of several studies have found associations between CL/P and various cancers for affected individuals 20, 21, 22, 23 and in their families 24, 25. Others have failed to find an association between CL/P and cancer (26). A general problem for many previous studies is small sample sizes of both cancer and CL/P cases. A previous study in Denmark in which the authors examined the co-incidence of CL/P with all types of cancers reported an increased breast cancer occurrence in female CL/P cases (20). This observation is particularly interesting because recent findings suggest common underlying genes for craniofacial development and breast cancer risk.

Breast cancers have been found to express high levels of fibroblast growth factor 2 (FGFR2), and certain genetic variants of FGFR2 predispose an individual to cancer 27, 28, 29, 30, 31, 32. FGFR2 is also important in craniofacial development and has been implicated in the development of CL/P 33, 34, 35. Furthermore, some FGFR2 mutations have been associated with CP in patients with Apert syndrome (36). The authors of a recent genome-wide association study of CL/P also identified the MAFB gene as having alleles contributing to CL/P (37), and MAFB has also been associated with certain hematologic malignancies (38). In this study we examine the association between CL/P and breast cancer in more than 1800 female CL/P cases and nearly 8000 first-degree female relatives to CL/P cases, accounting for more than 250,000 follow-up years.