Genetic heterogeneity and enrichment of variants in DNA-repair genes in ameloblastoma.

OBJECTIVE: Ameloblastomas are a group of relatively common odontogenic tumors that frequently originate from the dental epithelium. These tumors are aggressive in nature and present as slow-growing painless cortical expansion of the jaw. Histologically, the follicular and plexiform subtypes constitute two-thirds of solid/multicystic ameloblastomas. The objective of this study was to understand the genetic architecture of follicular and plexiform ameloblastomas using deep whole-exome sequencing. METHODS: Archived formalin-fixed paraffin-embedded tissue blocks of follicular (n = 4) and plexiform (n = 6) ameloblastomas were retrieved and genomic DNAs were isolated from the tumor tissue dissected from the formalin-fixed paraffin-embedded block. The exomes were enriched using the Integrated DNA Technologies Exome Research Panel (IDT, Coralville, IA) and paired-end sequencing was completed on an Illumina NovaSeq 6000 with an average output of 20 GB of data resulting in a mean coverage of 400×. Variant analysis was completed using custom-developed software: Rapid Understanding of Nucleotide variant Effect Software and variant integration and knowledge interpretation in genomes. RESULTS: Our analyses focused on examining somatic variants (gnomAD minor allele frequency ≤1%) in genes found on an Food and Drug Administration -approved clinical cancer sequencing panel (FoundationOne®CDx). In follicular tumors, variants (>20% of the reads) were identified in BRAF, KMT2D, and ABL1 genes. In plexiform tumors, variants (>20% of the reads) were identified in ALK, BRAF, KRAS, KMT2D, SMO, KMT2A, and BRCA2 genes. Enrichment analysis showed a significant role of DNA repair genes in the development of these tumors. CONCLUSION: The variants identified in follicular and plexiform ameloblastomas were enriched in DNA-repair genes. The observed genetic heterogeneity in these ameloblastomas may contribute to the aggressive nature and recurrence risk of these tumors.

Replication of GWAS significant loci in a sub-Saharan African Cohort with early childhood caries: a pilot study.

BACKGROUND: Early childhood caries (ECC) is a rapidly progressing form of dental infection and a significant public health problem, especially among socially and economically disadvantaged populations. This study aimed to assess the risk factors for ECC among a cohort of Sub-Saharan African children and to determine the role of genetics in the etiology of ECC. METHODS: A sample of 691 children (338 with ECC, 353 without ECC, age < 6 years) was recruited from schools in Lagos, Nigeria. Socio-demographic, dental services utilization and infant dietary data were obtained with interviewer-administered questionnaire. Oral examination was conducted using the WHO oral health diagnostic criteria. Saliva samples were collected from the children for genetic analysis. Single nucleotide polymorphisms were selected from previous study for genotyping. Genetic association analyses to investigate the role of genetics in the etiology of ECC was done. Bivariate comparisons and Multivariate logistic regression analyses were conducted to assess associations between ECC and predictor variables, p < 0.05. RESULTS: Of the 338 children with ECC, 64 (18.9%) had Severe-Early Childhood Caries (S-ECC). Children aged 48-59 months comprised the highest proportion of subjects with ECC (165; 48.8%) and S-ECC (24; 37.5%) while female subjects had higher dt (3.13 ± 2.56) and dmft values 3.27 ± 2.64. ECC was significantly more prevalent among children who were breastfed at night ≥ 12 months (OR 3.30; CI 0.39, 4.75), those with no previous dental visit (OR 1.71; CI 0.24, 2.77), those who used sweetened pacifiers (OR 1.85; CI 0.91, 3.79) and those who daily consumed sugar-sweetened drinks/snacks (OR 1.35; CI 0.09, 18.51). A suggestive increased risk for ECC (OR 1.26, p = 0. 0.0397) was observed for the genetic variant rs11239282 on chromosome 10. We also observed a suggestive reduced risk for ECC (OR 0.80, p = 0.03) for the rs131777 on chromosome 22. None of the genetic variants were significant after correction for multiple testing (Bonferroni p value p = 0.004). CONCLUSIONS: Prolonged night-time breastfeeding, poor utilization of dental services and daily consumption of sugar were risk factors for ECC. Larger sample size is needed to confirm the results of the genetic analysis and to conduct genome wide studies in order to discover new risk loci for ECC.