Colorectal Cancer-Associated Genes Are Associated with Tooth Agenesis and May Have a Role in Tooth Development (original) (raw)

Colorectal Cancer-Associated Genes Are Associated with Tooth Agenesis and May Have a Role in Tooth Development OPEN

Previously reported co-occurrence of colorectal cancer (CRC) and tooth agenesis (TA) and the overlap in disease-associated gene variants suggest involvement of similar molecular pathways. Here, we took an unbiased approach and tested genome-wide significant CRC-associated variants for association with isolated TA. Thirty single nucleotide variants (SNVs) in CRC-predisposing genes/loci were genotyped in a discovery dataset composed of 440 individuals with and without isolated TA. Genome-wide significant associations were found between TA and ATF1 rs11169552 (P = 4.36 × 10 −10) and DUSP10 rs6687758 (P = 1.25 × 10 −9), and positive association found with CASC8 rs10505477 (P = 8.2 × 10 −5). Additional CRC marker haplotypes were also significantly associated with TA. Genotyping an independent dataset consisting of 52 cases with TA and 427 controls confirmed the association with CASC8. Atf1 and Dusp10 expression was detected in the mouse developing teeth from early bud stages to the formation of the complete tooth, suggesting a potential role for these genes and their encoded proteins in tooth development. While their individual contributions in tooth development remain to be elucidated, these genes may be considered candidates to be tested in additional populations. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world and a leading cause of cancer-related deaths 1. Its etiology is multifactorial and ~33% of all cases are attributed to genetic factors 2. Tooth agenesis (TA), the congenital absence of one or more permanent teeth, results from disturbances occurring during tooth development, and represents one of the most common craniofacial anomalies in humans 3. Over a decade ago, Lammi et al. 4 reported that mutations in the tumor suppressor gene AXIN2 were found co-segregating with colorectal cancer and tooth agenesis in a large multiplex family. Moreover, these authors showed the expression of AXIN2 in developing mouse teeth and suggested that genes involved in colorectal cancer could also be involved in tooth development 4. Tooth development requires a sophisticated series of signaling interactions between the oral epithelium and mesenchyme under strict genetic control by a number of signaling molecules and their downstream signal-ing pathways 5. Any alteration of the epithelial-mesenchymal interactions can have deleterious effects on tooth

Unbiased association and expression studies identify novel genes for tooth development

Signature of genetic associations in oral cancer

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2017

Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based approaches. A systematic literature search was performed in the PubMed database to identify the loci associated with oral cancer by exclusive candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based study approaches. The information of loci associated with oral cancer is made online through the resource "ORNATE." Next, screening of the loci validated by candidate gene studies and next-generation sequencing approach or by two indepen...

Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

Journal of Dental Research

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of ...

Association between tooth agenesis and cancer: a systematic review

Journal of Applied Oral Science, 2021

The congenital absence of multiple teeth may share the same genetic background of the development of some types of cancer. Objective: This systematic review aimed to investigate the possible association between dental agenesis and cancer, and the perspective of agenesis as an early predictor for cancer risk. Methodology: The electronic databases PubMed, Scopus, Web of Science, Cochrane Library, LILACS, and OpenGrey were searched and the risk of bias was evaluated using the Newcastle-Ottawa tool. The GRADE tool was used to evaluate the certainty of the evidence. Results: Six studies met the eligibility criteria. A positive co-occurrence between ovarian cancer and hypodontia was found in two articles. Three studies evaluated the association between dental agenesis and colorectal cancer and only one showed common genes for these conditions. One paper found individuals with hypodontia had a higher risk of family history of cancer. Five studies had a fair quality and one a good quality. The certainty of evidence was classified as very low. Conclusion: Notwithstanding the limited scientific evidence, there may be a possible association between dental agenesis and cancer due to genes involved in both conditions. Agenesis of multiple teeth could be an early indicator of cancer risk. Nevertheless, studies with a better level of evidence are needed to confirm this possible association.

Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Human Genetics, 2019

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10 − 4 , replication P = 0.01), and PYGL (discovery P = 2.3 × 10 − 4 , replication P = 6.7 × 10 − 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up-and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to Stephanie A. Bien and Yu-Ru Su contributed equally to this work.

Genomic imbalances in precancerous tissues signal oral cancer risk

Molecular Cancer, 2009

Oral cancer develops through a series of histopathological stages: through mild (low grade), moderate, and severe (high grade) dysplasia to carcinoma in situ and then invasive disease. Early detection of those oral premalignant lesions (OPLs) that will develop into invasive tumors is necessary to improve the poor prognosis of oral cancer. Because no tools exist for delineating progression risk in low grade oral lesions, we cannot determine which of these cases require aggressive intervention. We undertook whole genome analysis by tiling-path array comparative genomic hybridization for a rare panel of early and late stage OPLs (n = 62), all of which had extensive longitudinal follow up (>10 years). Genome profiles for oral squamous cell carcinomas (n = 24) were generated for comparison. Parallel analysis of genome alterations and clinical parameters was performed to identify features associated with disease progression. Genome alterations in low grade dysplasias progressing to invasive disease more closely resembled those observed for later stage disease than they did those observed for non-progressing low grade dysplasias. This was despite the histopathological similarity between progressing and nonprogressing cases. Strikingly, unbiased computational analysis of genomic alteration data correctly classified nearly all progressing low grade dysplasia cases. Our data demonstrate that high resolution genomic analysis can be used to evaluate progression risk in low grade OPLs, a marked improvement over present histopathological approaches which cannot delineate progression risk. Taken together, our data suggest that whole genome technologies could be used in management strategies for patients presenting with precancerous oral lesions.

Rare and Common Variants Conferring Risk of Tooth Agenesis

Journal of Dental Research, 2018

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

Colorectal Cancer-Associated Genes Are Associated with Tooth Agenesis and May Have a Role in Tooth Development (original) (raw)

Related papers