The current proposal seeks activation of tlie ROO phase of a K99R00 award (1K99/R00-DE018413). The PI has completed his K99 main goals: to understand the etiology, epidemiology and phenotypes of oral clefts and to gain expertise in statistical genetics. Also, career development was one ofthe main objectives explored during the K99 phase, with emphasis in Responsible Conduct of Research, Scientific Management Leadership and Ethics. The University of Pittsburgh environment and the infrastructure of the School of Dental Medicine have been essential for the PI progress as an independent scientist. Craniofacial birth defects are the most common type of congenital anomaly in newborns. The etiology of oral clefting is complex, with multiple genetic and environmental influences. It has been proposed in the literature that cancer and congenital malformations may occasionally have a common etiology.
The aim of this project is to identify genes that can contribute to both craniofacial anomalies and cancer, and contribute to the better understanding of complex craniofacial and dental genetic disorders. The proposed K99 research aims were well-handled by the PI according to the planned time frame. The preliminary results recently published (Menezes et al;2009) have motivated the PI to go further in the investigation ofthe cancer/craniofacial anomalies relationship during the ROO phase, the PI will continue to investigate the possible association between cancer and craniofacial anomalies, expanding the studies to include additional genes/loci previously associated with craniofacial anomalies and independentiy with some types of cancer. In additional, new genes and chromosome regions previous reported to be associated with several types of cancers, have been reported to be associated with craniofacial anomalies in the literature. More recently, the PI contributed to a study where the 8q24 (a region previous related to colon and prostate cancer) was also associated with oral clefts (Beaty et al., 2010). The main aproach will continue to be genotyping and sequencing procedures together with statistical genetics analysis. The PI has also started training in cell/tissue culture and is planning to start doing some functional studies to complement his preliminary findings. This will help him accomplish the specific aims proposed for the ROO phase and enable the acquisition of more preliminary data for a stronger ROI application.
Cancer and congenital malformations may occasionally have a common etiology. The underlying concept is that the same genes act in normal and malignant development. If our hypothesis is confirmed our results may aid for future development of new personalized treatment strategies. The main objective is to collect enough and consistent data for a future ROI application.
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|Letra, Ariadne; Silva, Renato M; Motta, Luise G et al. (2012) Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts. Birth Defects Res A Clin Mol Teratol 94:540-8|
|Letra, Ariadne; Silva, Renato M; Rylands, Ryan J et al. (2012) MMP3 and TIMP1 variants contribute to chronic periodontitis and may be implicated in disease progression. J Clin Periodontol 39:707-16|
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|Letra, Ariadne; Menezes, Renato; Cooper, Margaret E et al. (2011) CRISPLD2 variants including a C471T silent mutation may contribute to nonsyndromic cleft lip with or without cleft palate. Cleft Palate Craniofac J 48:363-70|
|Menezes, Renato; Letra, Ariadne; Kim, Ana H et al. (2010) Studies with Wnt genes and nonsyndromic cleft lip and palate. Birth Defects Res A Clin Mol Teratol 88:995-1000|
|Letra, A; Menezes, R; Fonseca, R F et al. (2010) Novel cleft susceptibility genes in chromosome 6q. J Dent Res 89:927-32|
|Beaty, Terri H; Murray, Jeffrey C; Marazita, Mary L et al. (2010) A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet 42:525-9|
|Menezes, Renato; Marazita, Mary Louise; Goldstein McHenry, Toby et al. (2009) AXIS inhibition protein 2, orofacial clefts and a family history of cancer. J Am Dent Assoc 140:80-4|