Download Naturally Missing Teeth are Associated with an Ovarian Cancer

OVERVIEW
1 1 3 th A A O A n n u a l S e s s i o n
OUTLINE
U n rave l i n g a n A s s o c i at i o n b et we e n H y p o d o nt i a a n d
E p i t h e l i a l O va r i a n C a n c e r
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Anna N Vu, DMD, MS
Division of Orthodontics
May 2013
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HYPODONTIA
REVIEW
HYPODONTIA
& CANCER
HYPODONTIA
Defined as the developmental absence of one or more teeth as well as variations in size,
shape, rate of dental development and eruption time.
•
Over 300 genes are involved in odontogenesis including MSX1, PAX9, and AXIN2
•
Genes involved in dental development also have roles in other organs of the body
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Mutation in several genes governing tooth development have already been associated with
cancer
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Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer7
• AXIN2 gene is highly expressed in ovarian tissue so may play a role in epithelial ovarian cancer (EOC)8
Hypodontia is the agenesis of 6 or less teeth.
Oligodontia is the agenesis of 6 or more teeth.
Anodontia is the agenesis of all teeth.
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Reduced expression of PAX9 can lead to hypodontia and has been correlated with increased
malignancy of dysplastic and cancerous esophageal epithelium9
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RUNX transcription factor family (RUNX1, 2, and 3) are involved in odontogenesis and has been
the most targeted genes in acute myeloid leukemia and acute lymphoblastic leukemia10
78
2.6-11.3% reported prevelance worldwide.
Women are affected more than males at a ratio of 3:2.
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Both genetic and environmental explanations for hypodontia have been reported.
RUNX2 is amplified in various cancers including osteosarcoma and may play a role in breast and
prostate cancer
WHAT IS
OVARIAN CANCER?
WHAT IS
OVARIAN CANCER?
OVARIAN CANCER
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Mainly affects women over the age of 40
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Symptoms include:
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•
•
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Ovarian cancer is a gynecological cancer that begin in the ovaries.
70%
Although ovarian cancer only ranks
8th in most common cancer in
women….
Introduction
Background
Purpose
Materials and Methods
Results
Discussion
Conclusion
of women
diagnosed with
ovarian cancer
do not survive.
…it is the 5th leading cause of cancer
death in women.
•
Vaginal bleeding
Pain or pressure in pelvic region or abdominal area
Back pain
Bloating
Change in bathroom habits
Increased risk of EOC is correlated with:
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•
•
•
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Family history of ovarian cancer
Increasing age
History of breast, uterine, or colorectal cancer
Infertility
Endometriosis
Inside Knowledge: Ovarian Cancer. Atlanta, GA: Center for Disease Control and Prevention, May 2010.
OVARIAN CANCER
IN THE LITERATURE
OVARIAN CANCER
IN THE LITERATURE
PURPOSE
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Supports a possible association between hypodontia and EOC
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Suggests hypodontia may potentially become a risk marker for future cancer development
JADA 2008; 139(2): 163-9.
FINDINGS
• Prevalence of hypodontia was 20% for EOC subjects (p< .001)
• Reported family hx of hypodontia and ovarian cancer was higher in
EOC subjects
• EOC subjects were 8.1 times more likely to have hypodontia than
women without EOC
• Compare prevalence rates
of hypodontia among
epithelial ovarian cancer
(EOC) subjects and control
subjects
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Improved genetic screenings to identify persons at high risk for developing EOC
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Refer female patients to get earlier screenings for EOC
Earlier EOC diagnosis and treatment could save many lives
• Explore the possible
genetic association
between the two
phenotypes
GENE SELECTION:
Locus 8q24
PURPOSE
Susceptibility Loci for Ovarian Cancer
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Previous genome wide association study (GWAS) identified a ovarian cancer susceptiblity loci at
9q22 and found a 20% reduction in risk with each copy of the minor alleles23
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Most recent GWAS identified two new susceptibility loci for ovarian cancer
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2q31 (p= 3.8 x 10-14): rs2072590
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8q24 (p= 8.0 x 10-15): rs10088218, rs1519682 and rs10098821
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SNPs at these two loci showed strong support for an association with ovarian cancer with p-values
< 0.001.
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At locus 8q24, minor allele (A) of SNP rs10088218 was associated with a decreased risk for ovarian
cancer
PURPOSE
To investigate whether SNP rs10088218 is genetically associated with hypodontia.
NULL
Hypothesis
(HO)
SNP rs10088218 is NOT associated with hypodontia.
SNP rs10088218 is associated with hypodontia.
ALTERNATIVE
Hypothesis
(HA)
Goode EL, et al. Genome wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 2010; 42(10): 874-81.
MATERIALS
AND METHODS
Subject Population
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110 Caucasian subjects were recruited from the orthodontic clinic at the University of
Kentucky College of Dentistry
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67 females, 43 males
Subjects were classified into two research groups:
• Controls: patients without hypodontia
• Subjects: patients with hypodontia
MATERIALS
AND METHODS
Saliva Collection
• 2-4 mm of saliva was collected from all study participants
• Oragene-DNA Collection Kits (DNA Genotek Inc., Ottawa, Ontario, Canada)
• Preservatives in container will preserve DNA for 5+ years
DNA Isolation
• Genomic DNA extracted and resuspended in 10 mM Tris-HCl, 1 mM EDTA pH 8.0, and stored at 20° C
• DNA isolated and purified via ethanol precipitation
• DNA concentrations measured on the NanoDrop-1000 spectrophotometer (Thermo Fischer Scientific, Wilmington, DE)
Ta q m a n ® G e n e A s s a y K i t s
• Analysis of all SNPs were performed on the genomic DNA utilizing Taqman® Genotyping Assay Kits on Roche
LightCycler 480®
• Following RT-PCR amplification, each SNP allele was identified using allelic specific probes
• VIC or FAM fluorescence
• Analyze SNP rs10088218
MATERIALS
AND METHODS
RESULTS
SNP rs10088218
Statistical Methods
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• Genotyping of SNP rs10088218 was completed in all 30 subjects with
NMT and 80 controls.
The Chi-Square (x2) Analysis
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Used to evaluate the potential association of each SNP with hypodontia
Co-dominant mode on inheritance was utilized for potential association
Significance set at an alpha of 5% (p<0.05)
• No deviation from HWE was observed in either the controls or the
entire cohort.
• SNP rs10088218 was significantly associated with the presence of
hypodontia in 25 individuals versus 80 controls (p=0.019) with an
odds ratio (OR) of 11.51 (95% confidence interval (CI) 1.49-88.98)
under an additive mode of inheritance (MOI).
• SNP rs10088218 was also significantly associated with the presence
of hypodontia in 30 individuals versus 80 controls (p=0.021; OR=4.37
n= 3 MOI.
n= 0
95%CI: 1.25-15.35) under an additive
Frequency of Missing
Teeth
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Same as previously
reported
• Maxillary lateral incisor
was the most commonly
missing tooth
• The next most commonly
missing tooth type
included the mandibular
second premolars
followed by maxillary
second premolars
• Females affected more
than males at a ratio of
3:1
RESULTS
DISCUSSION
& CONCLUSIONS
SNP rs10088218
Number of individuals within the group with
a given genotype
(% of the total group)
Group
GG
(%)
AG
(%)
AA
(%)
Hypodontia
Subjects Only
n=25
24
(96.0)
1
(4.0)
0
(0)
Controls
n=80
54
(67.5)
23
(28.75)
3
(3.75)
Hypodontia
and
Oligodontia
Subjects
n=30
27
(90.0)
3
(10.0)
0
(0)
Controls
n=80
54
(67.5)
23
(28.75)
3
(3.75)
OR*
(95% Confidence
Interval)
11.51
(95% CI:1.49-88.98 )
Conclusions
p-Value
0.019
• Hypodontia patients
are 11.5x more likely
to be homozygous for
the G allele than
controls
• Odds ratio reduces
with addition of
oligodontia patients
4.37
(95% CI: 1.25-15.35)
•
Hypodontic teeth reported in this study are consistent with those previously
reported missing in women diagnosed with EOC and hypodontia
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The null hypothesis was rejected
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SNP rs10088218 is significantly associated with the occurrence of hypodontia
(p= 0.019)
0.021
FUTURE
DIRECTION
REFERENCES
1.
2.
• Continue to expand the sample size in order to increase the power of the study
• Test for association of SNP rs10088218 with ovarian cancer in EOC patients
• Look at other potential markers
• SNP rs2072590 that has been associated with an increased risk for ovarian caner
• WNT 10A which has been associated with hypodontia and has a presence in ovarian tissue
• Test these SNPs in ovarian cancer patients to find a common gene involved with both hypodontia
and ovarian cancer
Arte S and S Pirinen. Hypodontia. Orphanet Encyclopedia. 2004.
Peck S et al. Site –specificity of tooth agenesis in subjects with maxillary canine malpositions. Angle Orthod 1996; 66: 473476.
3. Al-Nimri KS and E Bsoul. Maxillary palatal canine impaction displacement in subjects with congenitally missing maxillary
lateral incisors. Am J Orthod Dentofacial Orthop 2011; 140(1): 81-86.
4. Jena AK and R Duggal. The pattern of maxillary canine impaction in relation to anomalous lateral incisors. J Clin Pediatr
Dent 2010; 35(1): 37-40.
5. DeCoster PJ et al. Dental Agenesis: Genetic and Clinical Perspectives. J Oral Pathol Med (2009). 38: 1-17.
6. Beeman CS. Prevalence of hypodontia in north america: regional and international comparisons. University of Kentucky.
Lexington, KY 2009. Lecture.
7. Lammi L, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet
2004; 74(5): 1043-50.
8. Dong X, et al. Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. Cytogenet Cell
Genet 2001; 93 (1-2): 26-8.
9. Gerber JK, et al. Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous
epithelium of the human esophagus. J Pathol 2002; 197(3): 293-7.
10. Song H et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet
2009; 41: 996-1000.
REFERENCES
11. Ohno K and Ohmori I. Anodontia with hypohidrotic ectodermal dysplasia in a young female: a case report. Pediatric
Dentistry 2000; 22(1): 49-52.
12. Fleischmannova J et al. Formation of the tooth-bone interface. J Dent Res 2010;89:108-115.
13. Inside Knowledge: Ovarian Cancer. Atlanta, GA: Center for Disease Control and Prevention, May 2010.
14. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2007 Incidence and Mortality Web-based
Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National
Cancer Institute; 2010.
15. Hoskins WJ. Prospective on ovarian cancer: why prevent? J Cell Biochem. 1995. S23: 189-99.
16. Chalothorn LA et al. Hypodontia as a risk marker for epithelial ovarian cancer: a case-controlled study. JADA 2008; 139(2):
163-169.
17. White SP. Evaluation of a common genetic etiology in ovarian cancer and tooth agenesis. Master’s Thesis, Texas A&M
University System Health Sciences Center. Ann Arbor: ProQuest/UMI, 2008. (Publication No. UMI 1457516)
18. Venkatesh K et al. Regulation of bone mass by Wnt signaling. J Clin Invest 2006; 116(5): 1202-1209.
19. Kimori T et al. Targeted disruption of Cbfa1 results in complete lack of bone formation owing to maturational arrest of
osteoblasts. Cell 1997; 89(5): 755-764.
20. Camilleri S et al. Runx2 and dental development. European Journal of Oral Sciences 2006; 114(5): 361-373.
21. Aberg T et al. Phenotypic changes in dentition of Runx2 homozygote-null mutant mice. J Histochem Cytochem 2004; 52(1):
131-139.
22. Goode EL et al. Genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet
2010; 42(10): 874-81.
23. Meyer KB et al. Allele-specific up-regulation of FGFR2 increases susceptiblity to breast cancer. PLoS Biol 2008; 6(5): 1098103.
RESEARCH
SUPPORT
American Association of Women Dentists/Proctor & Gamble Research Scholarship Award
Southern Association of Orthodontists
E. Preston Hicks Endowed Chair (JKH)