Original Article
Hypodontia prevalence and pattern in women with epithelial ovarian cancer ˇ retnikb; Iztok Takacˇc Anita Fekonjaa; Andrej C ABSTRACT Objective: To analyze the possible association between hypodontia and epithelial ovarian cancer (EOC), with the special interest in hypodontia pattern. Materials and Methods: One hundred twenty women with EOC treated at the Department of Gynecologic and Breast Oncology at the University Clinical Centre and 120 gynecologically healthy women of the same average age were reviewed for the presence and pattern of hypodontia. Collected data were analyzed for frequency, tooth type, location per jaw and side, number of missing teeth per person, and family history of hypodontia. Results: The results of the study showed prevalence of hypodontia in 19.2% of women with EOC and in 6.7% of women in the control group (P 5 .004). The most frequently missing teeth for women with EOC and women in the control group were maxillary second premolars and maxillary lateral incisors, respectively. Unilateral occurrence of hypodontia was more common than bilateral occurrence in women with EOC (P 5 .034). Of women with EOC and hypodontia, 21.7% reported a positive family history of hypodontia compared with no report in the control group of women with hypodontia (P 5 .150). Conclusions: The results statistically support possible association between EOC and hypodontia. Because hypdontia can be recognized early in life, this finding could possibly help in earlier detection of EOC, resulting in better prognosis and treatment in earlier stages of the disease. Earlier EOC diagnosis and treatment could save many lives. (Angle Orthod. 2014;84:810–814.) KEY WORDS: Hypodontia; Tooth agenesis; Ovarian cancer; Neoplasms
INTRODUCTION
Numerous studies have been published on the prevalence of hypodontia (excluding third molars) in various populations.2–4 The reported hypodontia rates range from 2.6% in the Mexican population5 to 10.1% in the Norwegian population,4 both sexes combined. According to literature data, hypodontia can be found more frequently in women than in men.3,4,6–8 The majority of previous studies have revealed that the most common congenitally missing teeth in the white population are the mandibular second premolar, followed by the maxillary lateral incisor3,4 and the maxillary second premolar.8 Both genetic and environmental factors have been found to contribute to the etiology of tooth agenesis, with many theories having been suggested to explain their affects, particularly prior to the intensive genetic studies performed in recent years.1,4 Hypodontia has been identified as both nonsyndromic, where it is an independent congenital oral trait, or syndromic, where it is acquired as part of a specific disease.9 It is an associated finding in at least 49 syndromes listed in the Online Mendelian Inheritance in Man database, implying that some factors involved in tooth development have a wider role within the human body.10 The
By definition, congenitally missing teeth are those that fail to erupt in the oral cavity and remain invisible in a radiograph, which implies that this is caused by disturbances during the early stages of tooth development.1 Hypodontia, defined as congenital absence of one to five teeth, is a dental disability that affects a patient’s function and esthetics.
a Department Head, Department of Orthodontics, Health Centre Maribor, Maribor, Slovenia. b Associate Professor, Medical Faculty, University of Maribor, Maribor, Slovenia. c Professor and Department Head, Department of Gynecologic and Breast Oncology, Clinical Department of Gynecology and Perinatology, University Clinical Centre Maribor, Medical Faculty, University of Maribor, Maribor, Slovenia. Corresponding author: Dr Anita Fekonja, Department of Orthodontics, Health Centre Maribor, Partizanska 14a, 2000 Maribor, Slovenia (e-mail: [email protected])
Accepted: January 2014. Submitted: November 2013. Published Online: April 1, 2014 G 2014 by The EH Angle Education and Research Foundation, Inc. Angle Orthodontist, Vol 84, No 5, 2014
810
DOI: 10.2319/112813-876.1
811
HYPODONTIA IN WOMEN WITH EPITHELIAL OVARIAN CANCER
nonsyndromic form of hypodontia can be sporadic or familial, and it has been most frequently reported as inherited in an autosomal dominant fashion, where it displays phenotypic heterogeneity as measured by the nature of the missing teeth and other alterations in the teeth.9,11 However, X-linked and polygenic inheritance has also been reported.12 Tooth development is a complex process of reciprocal interactions that has become known only recently. With the large number of genes involved in the odontogenic process, the opportunity for mutations to disrupt this process is high. Recent advances in genetic techniques have allowed us to begin to understand the genetic processes that underlie the odontogenic process and to identify the mechanisms responsible for tooth agenesis. To date, two genes have been identified by mutational analysis as the major causes of nonsyndromic hypodontia: PAX9 and MSX1.11,13,14 Several studies reported a higher presence of cancer in people with hypodontia.15–18 Chalothorn et al.18 reported that women with EOC are 8.1 times more likely to have hypodontia and microdontia than women without EOC. Furthermore, we found a more positive self-reported family history of some diseases like colorectal cancer, ovarian cancer, and thyroid disease in individuals with hypodontia than in those without it, while collecting anamnestic data in our dental practice. Ovarian cancer represents the seventh most common cancer among women in the Western world. It is also the fourth leading cause of cancer death in women.19 The lifetime risk of developing ovarian cancer for the general population is 1.6%.20 Spread of the disease within the peritoneal cavity is associated with nonspecific clinical symptoms that are often mistaken for other gastrointestinal or reproductive diseases. Consequently, 75%–80% of patients are not being diagnosed with the disease until the cancer has metastasized beyond the ovaries and is at stage III or IV.21 Most ovarian cancers occur because of gene changes that develop during a woman’s life and are not inherited. But, about 1 in 10 ovarian cancers (10%) are caused by an inherited faulty gene.20,21 Relationships among hypodontia and other pathological conditions, such as colorectal cancer,15 and between hypodontia and microdontia and EOC18 have already been reported. The purpose of the present study was to analyze the relationship between hypodontia (without microdontia) prevalence and patterns and EOC. Therefore, this study sought to evaluate and compare the specific type of missing teeth, the location per jaw and side of missing teeth, number of missing teeth, and family history of hypodontia between women with and without EOC.
MATERIALS AND METHODS The study included 120 white women who were diagnosed with epithelial ovarian cancer and were treated at the Department of Gynecologic and Breast Oncology at the University Clinical Centre, and 120 gynecologically healthy women of the same average age (control group). The health of the control group was confirmed by general gynecologic examination, which included transvaginal ultrasound, so that women with any ovarian abnormality, which is an indication of a potential malignancy, were excluded. The ovarian cancer group included patients with all cell types of epithelial ovarian cancer. Diagnosis was confirmed histologically. Ethical approval for the study was obtained from the Slovenian National Medical Ethics Committee. Prior to participation in the study, all subjects gave their informed consent after receiving an explanation of the aim of this study. The participants of both groups were sent to the Department of Orthodontics, Health Centre, where their dental status and dental history were recorded on a form prepared for this purpose. The diagnosis of hypodontia was confirmed by the same orthodontist based on clinical examination and panoramic radiographic analysis. Additional panoramic radiographs were taken, if necessary for diagnosis. Information on hypodontia was confirmed from documents, radiographs, and dental files at a general dentist and by collected questionnaires. Hypodontia was recorded in the case of absent tooth on the panoramic radiograph; furthermore, dental records excluded a history of tooth loss due to trauma, caries, periodontal disease, or orthodontic extraction. The dental history data were obtained from the general dentist. All permanent teeth were investigated, excluding third molars. The type of the missing tooth was marked with the international two-digit notation (according to the World Dental Federation system).22 Women with dentures or women in whom the cause of missing teeth could not be determined were excluded. No person had any associated syndrome. We reviewed each subject’s dental histories and recorded any possible family history of teeth agenesis. The analyses focused on the type and number of missing teeth, the average number of missing teeth per patient, unilateral vs bilateral agenesis, maxillary vs mandibular agenesis, and family history of dental agenesis. All descriptive and comparative statistical analyses were performed using the Statistical Package for the Social Sciences (version 20.0, SPSS Inc, Chicago, Ill). Unpaired (two-sample) t-test at a significance level of ,.05 was used to assess the differences in ages Angle Orthodontist, Vol 84, No 5, 2014
ˇ RETNIK, TAKAC ˇ FEKONJA, C
812 Table 1. Hypodontia Prevalence in Ovarian Cancer and Control Groupa Examined Sample, N
Affected Sample, N (%)
120 120
23 (19.2) 8 (6.7)
Ovarian cancer group Control group a
x2 5 8.33; P 5 .004.
RESULTS The mean (SD) age of the EOC patients at time of diagnosis was 53.05 (11.11) years; mean (SD) age of the control group was 53.27 (10.70) years (P 5 .878). The prevalence of hypodontia in women with EOC and in the control group is shown in Table 1. The difference between the two groups was statistically significant (P 5 .004); the crude OR was 3.30 (95% CI, 0.12–7.01). Women with ovarian cancer were 2.87 times (19.2%–6.7%) more likely to have hypodontia than healthy women. Thirty-one permanent teeth were found to be congenitally absent in patients with EOC; 14 permanent teeth were absent in the control group. The number of missing teeth in each case ranged from one to three, with an average of 1.35 missing teeth for women with EOC, and 1.75 missing teeth for women in the control group. The distribution of missing teeth by tooth type is shown in Table 2. The maxillary second premolars Table 2. Distribution of Hypodontia in the Maxilla and the Mandible in Both Groupsa
Total maxillary arch Maxillary lateral incisor Maxillary second premolar
Ovarian Cancer Group N (%)
Control Group N (%)
24 (77.4) 10 (32.3) 14 (45.1)
7 (50) 5 (35.7) 2 (14.3)
7 (22.6) 2 (6.5) 5 (16.1)
7 (50) 3 (21.4) 4 (28.6)
31 (100)
14 (100)
Total mandibular arch Mandibular central incisor Mandibular second premolar Total a
Ovarian cancer group Control group a
between the EOC patients and the control group. A chi-square or Fisher exact test was used to determine difference in prevalence rates of hypodontia between the ovarian cancer group and the control group. The differences in the type of missing tooth, location per jaw and side, number of missing teeth, and family history of hypodontia between both groups were also observed and determined; a P value ,.05 was considered statistically significant. To determine the relationship between hypodontia and ovarian cancer we used a logistic regression model. The results were presented as odds ratios (OR) with corresponding 95% confidence interval (CI).
Jaw
Table 3. Distribution of Hypodontia According to Its Presence Unilaterally or Bilaterallya
x2 5 3.38; P 5 .066.
Angle Orthodontist, Vol 84, No 5, 2014
Unilaterally N (%)
Bilaterally N (%)
Total N (%)
18 (78.3) 3 (37.5)
5 (21.7) 5 (62.5)
23 (100) 8 (100)
x2 5 4.51; P 5 .034.
were the most frequently (45.1%) missing teeth, followed by the maxillary lateral incisors (32.3%), the mandibular second premolars (16.1%), and mandibular central incisors (6.5%) in women with EOC. In the control group, the maxillary lateral incisors (35.7%) and mandibular second premolars (28.6%) are the most frequently missing teeth. However, the difference was not statistically significant (P 5 .124). At least one missing upper maxillary premolar was found in 52.2% of the women with EOC and in 12.8% of the women in the control group. Hypodontia was more commonly seen in the maxilla (77.4%) than in the mandible (22.6%) in patients with EOC, but without statistically significant difference (P 5 .066). The distribution of hypodontia according to its presence unilaterally or bilaterally (P 5 .034) and to the number of missing teeth per person (P 5 .049) is shown in Tables 3 and 4. Unilateral hypodontia was observed in 18 (78.3%) women with EOC and 37.5% of those in the control group. The maxillary second premolar was the most frequent unilaterally missing tooth (50%), followed by the maxillary lateral incisor (27.8%). Of the women with EOC and hypodontia, 21.7% reported having a family history of hypodontia compared with no report in the control group of women with hypodontia (P 5 .150) (Table 5). DISCUSSION Tooth morphogenesis is a complex process that involves epithelial-ectomesenchymal interactions. Numerous transcription factors, growth factors, and their receptors, as well as extracellular matrix components, have been associated with early tooth development.23,24 The genetic basis of tooth development is supported by the identification of mutations in genes that participate in dental development (MSX1, PAX9, Table 4.
Number of Congenitally Missing Teeth per Persona Two One Teeth N Tooth N (%) (%)
Ovarian cancer group Control group a
16 (69.6) 2 (25)
x2 5 6.05; P 5 .049.
6 (26.1) 6 (75)
Three or More Teeth Total N (%) N (%) 1 (4.3) 0 (0)
23 (100) 8 (100)
HYPODONTIA IN WOMEN WITH EPITHELIAL OVARIAN CANCER Table 5. Family History of Hypodontia
Variable Total ovarian cancer group Total control group Ovarian cancer group with hypodontia Control group with hypodontia
Family History of Hypodontia N (%) 5/120 3/120 5/23 0/8
(4.2) (2.5) (21.7) (0)
P Value .472 .150
AXIN2).11,14,25 More recently, a mutation in the AXIN2 gene was identified in families with oligodontia and colorectal cancer, suggesting that tooth agenesis might be an indicator of colorectal cancer susceptibility.15 Hypodontia may also be present in certain syndromes (Down syndrome),26 ectodermal dysplasia.27 New research also reported a higher presence of cancer in family members of patients with hypodontia.17 In Slovenia, we have required dental examinations of children and young adolescents. Such knowledge is particularly important for the early detection of these diseases because dentist may be the first to detect hypodontia. The aim of this study was to assess a possible association between hypodontia and EOC in the Slovenian population. Prevalence of tooth agenesis has been addressed by numerous studies. In most populations, the reported hypodontia prevalence, excluding third molars, varies from 2.6% to 10.1%.2–5 In white populations the prevalence of hypodontia (excluding third molars) is generally in the range of 5% to 8%.3 Hypodontia prevalence (excluding third molars) in the Slovenian population is 6.9% (7.8% in women and 5.9% in men).28 Researchers from the University of Kentucky, Lexington,18 found 3% prevalence of hypodontia and microdontia in a control group, and 20% prevalence of hypodontia and microdontia in patients with EOC. In our study, only patients with hypodontia were included, giving 19.2% hypodontia prevalence in women with EOC, while the prevalence of the control group was very similar to the general population of Slovenia.28 Studies on European populations mostly reported a higher prevalence of the missing mandibular second premolar, followed by upper lateral incisors and upper second premolars.2–5 Agenesis of second premolars and upper lateral incisors accounts for 85% of all affected teeth among white populations.3 In the Slovenian population, the most common missing teeth are mandibular second premolars, followed by maxillary lateral incisors.28 Chalothorn et al.18 reported that maxillary lateral incisors were the most frequent missing teeth in patients with EOC. In our study, we found that the teeth missing most often in women with EOC were maxillary second premolars, followed by maxillary lateral incisors, mandibular second premolars, and
813 mandibular central incisors. This result was quite different from the study of Chalothorn et al.18 In the control group, we found the maxillary lateral incisors and mandibular second premolars were the most frequent missing teeth, similar to the reports of many authors who reported the prevalence of the hypodontia in the general white population.2–4 Hypodontia of the maxillary second premolar rarely occurs in the general population, but it occurs most frequently in patients with EOC. At least one missing upper maxillary premolar was found in 52.2% of women with EOC and in only 12.8% of the control group. Therefore, special attention should be recommended to women with this pattern of hypodontia. Ku¨cher et al.17 observed an increased frequency of family history of breast cancer and prostate cancer in individuals with at least one missing premolar as well as an increased frequency of all cancers in the group with at least one missing upper lateral incisor. According to the literature, there seems to be no overall significant difference between the prevalence of hypodontia in the maxilla and mandible in the general white population.2–4 Chalothorn et al.18 found the most missing teeth in the maxilla. In our study, we found that hypodontia was more common in the maxillary arch than in the mandibular arch in the EOC group too, but not in the control group. Some authors5,7 reported that bilateral missing teeth occurred most frequently. In the present study, women with EOC were four times more likely to have teeth missing unilaterally than bilaterally. In the group with bilateral missing teeth, maxillary lateral incisors were most commonly seen. No general difference in the frequency of agenesis between the left and right sides was found. Chalothorn et al.18 reported that in their ovarian cancer group, the most common number of teeth missing was one (on average 1.2 teeth were missing). In our study, the same pattern of missing one tooth occurred most frequently in women with EOC, followed by two and three teeth (on average 1.35 teeth were missing). In our study, we found a positive family history of hypodontia in women with EOC. With regular dental examinations being mandatory in Slovenia, hypodontia can be detected very early in childhood. Though hypodontia is not yet proven to be causally linked to EOC, more frequent preventive gynecologic examinations may be suggested for women with hypodontia. The study by Chalothorn et al.18 also reported the frequent presence of hypodontia in women with EOC. Therefore, it would be wise for a large, further study to be done to evaluate the role between hypodontia and epithelial ovarian cancer. Further research in this area will contribute to a better understanding of the links between EOC and hypodontia. Angle Orthodontist, Vol 84, No 5, 2014
814 Congenital absence of permanent teeth has direct clinical (visual) implication, and early evaluation of hypodontia phenotype could help us to identify patients at risk for EOC and serve as a possible marker for EOC detection. Identification of these high-risk individuals should result in earlier screening regimens for these individuals, an increased number of early diagnoses, and thus the potential to save many lives. Limitations of this study were the relatively small number of women with EOC and a certain anomaly, in this case hyypodontia, and the ability to follow subjects from only one clinical setting. Further research with a larger number of subjects and in other settings and countries could be of great interest as well as of great importance. CONCLUSIONS N The results statistically support the possible association between EOC and hypodontia phenotype. N As the ovarian cancer is difficult to detect in the early stages with no known specific screening markers, hypodontia could possibly serve as an early marker in identifying the risk of EOC. ACKNOWLEDGMENTS We thank the Department of Gynecologic and Breast Oncology, Clinical Department of Gynecology and Perinatology, University Clinical Centre, and the Department of Gynecology, Health Centre for help in collecting the participants. We would like to express our sincere gratitude to all participants.
REFERENCES 1. Malatova E, Fleischmannova J, Sharpe PT, Tucker AS. Tooth agenesis: from molecular genetics to molecular dentistry. J Dent Res. 2008;87:617–623. 2. Mattheeuws N, Dermaut L, Martens G. Has hypodontia increased in Caucasians during the 20th century? A metaanalysis. Eur J Orthod. 2004;26:99–103. 3. Polder BJ, Van’t Hof MA, Van der Linden FPGM, KuijpersJagtman AM. A meta-analysis of the prevalence of dental agenesis of permanent teeth. Community Dent Oral Epidemiol. 2004;32:217–226. 4. Pemberton TJ, Das P, Patel PI. Hypodontia: genes and future perspectives. Braz J Oral Sci. 2005;4:695–706. 5. Silva Meza R. Radiographic assessment of congenitally missing teeth in orthodontic patients. Int J Paediatr Dent. 2003;13:112–116. 6. Symons AL, Stritzel F, Stamation J. Anomalies associated with hypodontia of the permanent lateral incisor and second premolar. J Clin Pediatr Dent. 1993;17:109–111. 7. Altug-Atac AT, Erdem D. Prevalence and distribution of dental anomalies in orthodontic patient. Am J Orthod Dentofacial Orthop. 2007;131:510–504. 8. Ba¨ckman B, Wahlin YB. Variations in number and morphology of permanent teeth in 7-year-old Swedish children. Int J Paediatr Dent. 2001;11:11–17.
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9. Burzynski NJ, Escobar VH. Classification and genetics of numeric anomalies of dentition. Birth Defects Orig Artic Ser. 1983;19:95–106. 10. Online Mendelian Inheritance in Man, OMIM. Available at: http://www.ncbi.nlm.nih.gov/omim. Accessed October 10, 2004. 11. Vastardis H, Karimbux N, Guthua SW, Seidman JG, Seidman CE. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet. 1996; 13:417–421. 12. Peck L, Peck S, Attia Y. Maxillary canine-first premolar transposition, associated dental anomalies and genetic basis. Angle Orthod. 1993;63:99–109. 13. van den Boogaard MJ, Dorland M, Beemer FA, van Amstel HK. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet. 2000;24:342–343. 14. Stockton DW, Das P, Goldenberg M, D’Souza RN, Patel PI. Mutation of PAX9 is associated with oligodontia. Nat Genet. 2000;24:18–19. 15. Lammi L, Arte S, Somer M, et al. Mutation in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet. 2004;24:1043–1050. 16. Hattab FN, Angmar-Mansson B. Oligodontia of permanent dentition with polycystic ovarian syndrome: case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84: 368–371. 17. Ku¨cher EC, Lips A, Tannure PN, et al. Tooth agenesis association with self-reported family history of cancer. J Dent Res. 2013;92:149–155. 18. Chalothorn LA, Beeman CS, Ebersole JL, et al. Hypodontia as a risk marker for epithelial ovarian cancer. J Am Dent Assoc. 2008;139:163–169. 19. United States Cancer Statistics: 1999–2008 Incidence and Mortality. Available at: http://www.cdc.gov/uscs. Accessed January 5, 2010. 20. Bolton KL, Ganda C, Berchuck A, Pharaoh PD, Gayther SA. Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the Ovarian Cancer Association Consortium (OCAC). J Intern Med. 2012;271:366–378. 21. Lalwani N, Prasad SR, Vikram R, Shanbhoque AK, Huettner PC, Fasih N. Histologic, molecular, and cytogenetic features of ovarian cancers: implications for diagnosis and treatment. Radiographics. 2011;31:625–646. 22. Dofka CM. Competency skills for the dental assistant. In: Phinney DJ, Halstead JH, eds. Dental Assisting: A Comprehensive Approach. Albany, NY: Delmar; 2000:125. 23. Thesleff I, Nieminen P. Tooth morphogenesis and cell differentiation. Curr Opin Cell Biol. 1996;8:844–850. 24. Miletic´ I, Sharpe PT. Normal and abnormal dental development. Hum Mol Genet. 2003;12:69–73. 25. Mostowska A, Biedziak B, Jagodzinski PP. Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis. J Hum Genet. 2006;51:262–266. 26. Suri S, Tompson BD, Atenafu E. Prevalence and patterns of permanent tooth agenesis in Down syndrome and their association with craniofacial morphology. Angle Orthod. 2011;81:260–269. 27. Kere J, Srivastava AK, Montonen O, et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet. 1996;13:409–416. 28. Fekonja A. Hypodontia prevalence over four decades in a Slovenian population. J Esthet Restor Dent. 2013 Dec 17 [Epub ahead of print].
Hypodontia prevalence and pattern in women with epithelial ovarian cancer ˇ retnikb; Iztok Takacˇc Anita Fekonjaa; Andrej C ABSTRACT Objective: To analyze the possible association between hypodontia and epithelial ovarian cancer (EOC), with the special interest in hypodontia pattern. Materials and Methods: One hundred twenty women with EOC treated at the Department of Gynecologic and Breast Oncology at the University Clinical Centre and 120 gynecologically healthy women of the same average age were reviewed for the presence and pattern of hypodontia. Collected data were analyzed for frequency, tooth type, location per jaw and side, number of missing teeth per person, and family history of hypodontia. Results: The results of the study showed prevalence of hypodontia in 19.2% of women with EOC and in 6.7% of women in the control group (P 5 .004). The most frequently missing teeth for women with EOC and women in the control group were maxillary second premolars and maxillary lateral incisors, respectively. Unilateral occurrence of hypodontia was more common than bilateral occurrence in women with EOC (P 5 .034). Of women with EOC and hypodontia, 21.7% reported a positive family history of hypodontia compared with no report in the control group of women with hypodontia (P 5 .150). Conclusions: The results statistically support possible association between EOC and hypodontia. Because hypdontia can be recognized early in life, this finding could possibly help in earlier detection of EOC, resulting in better prognosis and treatment in earlier stages of the disease. Earlier EOC diagnosis and treatment could save many lives. (Angle Orthod. 2014;84:810–814.) KEY WORDS: Hypodontia; Tooth agenesis; Ovarian cancer; Neoplasms
INTRODUCTION
Numerous studies have been published on the prevalence of hypodontia (excluding third molars) in various populations.2–4 The reported hypodontia rates range from 2.6% in the Mexican population5 to 10.1% in the Norwegian population,4 both sexes combined. According to literature data, hypodontia can be found more frequently in women than in men.3,4,6–8 The majority of previous studies have revealed that the most common congenitally missing teeth in the white population are the mandibular second premolar, followed by the maxillary lateral incisor3,4 and the maxillary second premolar.8 Both genetic and environmental factors have been found to contribute to the etiology of tooth agenesis, with many theories having been suggested to explain their affects, particularly prior to the intensive genetic studies performed in recent years.1,4 Hypodontia has been identified as both nonsyndromic, where it is an independent congenital oral trait, or syndromic, where it is acquired as part of a specific disease.9 It is an associated finding in at least 49 syndromes listed in the Online Mendelian Inheritance in Man database, implying that some factors involved in tooth development have a wider role within the human body.10 The
By definition, congenitally missing teeth are those that fail to erupt in the oral cavity and remain invisible in a radiograph, which implies that this is caused by disturbances during the early stages of tooth development.1 Hypodontia, defined as congenital absence of one to five teeth, is a dental disability that affects a patient’s function and esthetics.
a Department Head, Department of Orthodontics, Health Centre Maribor, Maribor, Slovenia. b Associate Professor, Medical Faculty, University of Maribor, Maribor, Slovenia. c Professor and Department Head, Department of Gynecologic and Breast Oncology, Clinical Department of Gynecology and Perinatology, University Clinical Centre Maribor, Medical Faculty, University of Maribor, Maribor, Slovenia. Corresponding author: Dr Anita Fekonja, Department of Orthodontics, Health Centre Maribor, Partizanska 14a, 2000 Maribor, Slovenia (e-mail: [email protected])
Accepted: January 2014. Submitted: November 2013. Published Online: April 1, 2014 G 2014 by The EH Angle Education and Research Foundation, Inc. Angle Orthodontist, Vol 84, No 5, 2014
810
DOI: 10.2319/112813-876.1
811
HYPODONTIA IN WOMEN WITH EPITHELIAL OVARIAN CANCER
nonsyndromic form of hypodontia can be sporadic or familial, and it has been most frequently reported as inherited in an autosomal dominant fashion, where it displays phenotypic heterogeneity as measured by the nature of the missing teeth and other alterations in the teeth.9,11 However, X-linked and polygenic inheritance has also been reported.12 Tooth development is a complex process of reciprocal interactions that has become known only recently. With the large number of genes involved in the odontogenic process, the opportunity for mutations to disrupt this process is high. Recent advances in genetic techniques have allowed us to begin to understand the genetic processes that underlie the odontogenic process and to identify the mechanisms responsible for tooth agenesis. To date, two genes have been identified by mutational analysis as the major causes of nonsyndromic hypodontia: PAX9 and MSX1.11,13,14 Several studies reported a higher presence of cancer in people with hypodontia.15–18 Chalothorn et al.18 reported that women with EOC are 8.1 times more likely to have hypodontia and microdontia than women without EOC. Furthermore, we found a more positive self-reported family history of some diseases like colorectal cancer, ovarian cancer, and thyroid disease in individuals with hypodontia than in those without it, while collecting anamnestic data in our dental practice. Ovarian cancer represents the seventh most common cancer among women in the Western world. It is also the fourth leading cause of cancer death in women.19 The lifetime risk of developing ovarian cancer for the general population is 1.6%.20 Spread of the disease within the peritoneal cavity is associated with nonspecific clinical symptoms that are often mistaken for other gastrointestinal or reproductive diseases. Consequently, 75%–80% of patients are not being diagnosed with the disease until the cancer has metastasized beyond the ovaries and is at stage III or IV.21 Most ovarian cancers occur because of gene changes that develop during a woman’s life and are not inherited. But, about 1 in 10 ovarian cancers (10%) are caused by an inherited faulty gene.20,21 Relationships among hypodontia and other pathological conditions, such as colorectal cancer,15 and between hypodontia and microdontia and EOC18 have already been reported. The purpose of the present study was to analyze the relationship between hypodontia (without microdontia) prevalence and patterns and EOC. Therefore, this study sought to evaluate and compare the specific type of missing teeth, the location per jaw and side of missing teeth, number of missing teeth, and family history of hypodontia between women with and without EOC.
MATERIALS AND METHODS The study included 120 white women who were diagnosed with epithelial ovarian cancer and were treated at the Department of Gynecologic and Breast Oncology at the University Clinical Centre, and 120 gynecologically healthy women of the same average age (control group). The health of the control group was confirmed by general gynecologic examination, which included transvaginal ultrasound, so that women with any ovarian abnormality, which is an indication of a potential malignancy, were excluded. The ovarian cancer group included patients with all cell types of epithelial ovarian cancer. Diagnosis was confirmed histologically. Ethical approval for the study was obtained from the Slovenian National Medical Ethics Committee. Prior to participation in the study, all subjects gave their informed consent after receiving an explanation of the aim of this study. The participants of both groups were sent to the Department of Orthodontics, Health Centre, where their dental status and dental history were recorded on a form prepared for this purpose. The diagnosis of hypodontia was confirmed by the same orthodontist based on clinical examination and panoramic radiographic analysis. Additional panoramic radiographs were taken, if necessary for diagnosis. Information on hypodontia was confirmed from documents, radiographs, and dental files at a general dentist and by collected questionnaires. Hypodontia was recorded in the case of absent tooth on the panoramic radiograph; furthermore, dental records excluded a history of tooth loss due to trauma, caries, periodontal disease, or orthodontic extraction. The dental history data were obtained from the general dentist. All permanent teeth were investigated, excluding third molars. The type of the missing tooth was marked with the international two-digit notation (according to the World Dental Federation system).22 Women with dentures or women in whom the cause of missing teeth could not be determined were excluded. No person had any associated syndrome. We reviewed each subject’s dental histories and recorded any possible family history of teeth agenesis. The analyses focused on the type and number of missing teeth, the average number of missing teeth per patient, unilateral vs bilateral agenesis, maxillary vs mandibular agenesis, and family history of dental agenesis. All descriptive and comparative statistical analyses were performed using the Statistical Package for the Social Sciences (version 20.0, SPSS Inc, Chicago, Ill). Unpaired (two-sample) t-test at a significance level of ,.05 was used to assess the differences in ages Angle Orthodontist, Vol 84, No 5, 2014
ˇ RETNIK, TAKAC ˇ FEKONJA, C
812 Table 1. Hypodontia Prevalence in Ovarian Cancer and Control Groupa Examined Sample, N
Affected Sample, N (%)
120 120
23 (19.2) 8 (6.7)
Ovarian cancer group Control group a
x2 5 8.33; P 5 .004.
RESULTS The mean (SD) age of the EOC patients at time of diagnosis was 53.05 (11.11) years; mean (SD) age of the control group was 53.27 (10.70) years (P 5 .878). The prevalence of hypodontia in women with EOC and in the control group is shown in Table 1. The difference between the two groups was statistically significant (P 5 .004); the crude OR was 3.30 (95% CI, 0.12–7.01). Women with ovarian cancer were 2.87 times (19.2%–6.7%) more likely to have hypodontia than healthy women. Thirty-one permanent teeth were found to be congenitally absent in patients with EOC; 14 permanent teeth were absent in the control group. The number of missing teeth in each case ranged from one to three, with an average of 1.35 missing teeth for women with EOC, and 1.75 missing teeth for women in the control group. The distribution of missing teeth by tooth type is shown in Table 2. The maxillary second premolars Table 2. Distribution of Hypodontia in the Maxilla and the Mandible in Both Groupsa
Total maxillary arch Maxillary lateral incisor Maxillary second premolar
Ovarian Cancer Group N (%)
Control Group N (%)
24 (77.4) 10 (32.3) 14 (45.1)
7 (50) 5 (35.7) 2 (14.3)
7 (22.6) 2 (6.5) 5 (16.1)
7 (50) 3 (21.4) 4 (28.6)
31 (100)
14 (100)
Total mandibular arch Mandibular central incisor Mandibular second premolar Total a
Ovarian cancer group Control group a
between the EOC patients and the control group. A chi-square or Fisher exact test was used to determine difference in prevalence rates of hypodontia between the ovarian cancer group and the control group. The differences in the type of missing tooth, location per jaw and side, number of missing teeth, and family history of hypodontia between both groups were also observed and determined; a P value ,.05 was considered statistically significant. To determine the relationship between hypodontia and ovarian cancer we used a logistic regression model. The results were presented as odds ratios (OR) with corresponding 95% confidence interval (CI).
Jaw
Table 3. Distribution of Hypodontia According to Its Presence Unilaterally or Bilaterallya
x2 5 3.38; P 5 .066.
Angle Orthodontist, Vol 84, No 5, 2014
Unilaterally N (%)
Bilaterally N (%)
Total N (%)
18 (78.3) 3 (37.5)
5 (21.7) 5 (62.5)
23 (100) 8 (100)
x2 5 4.51; P 5 .034.
were the most frequently (45.1%) missing teeth, followed by the maxillary lateral incisors (32.3%), the mandibular second premolars (16.1%), and mandibular central incisors (6.5%) in women with EOC. In the control group, the maxillary lateral incisors (35.7%) and mandibular second premolars (28.6%) are the most frequently missing teeth. However, the difference was not statistically significant (P 5 .124). At least one missing upper maxillary premolar was found in 52.2% of the women with EOC and in 12.8% of the women in the control group. Hypodontia was more commonly seen in the maxilla (77.4%) than in the mandible (22.6%) in patients with EOC, but without statistically significant difference (P 5 .066). The distribution of hypodontia according to its presence unilaterally or bilaterally (P 5 .034) and to the number of missing teeth per person (P 5 .049) is shown in Tables 3 and 4. Unilateral hypodontia was observed in 18 (78.3%) women with EOC and 37.5% of those in the control group. The maxillary second premolar was the most frequent unilaterally missing tooth (50%), followed by the maxillary lateral incisor (27.8%). Of the women with EOC and hypodontia, 21.7% reported having a family history of hypodontia compared with no report in the control group of women with hypodontia (P 5 .150) (Table 5). DISCUSSION Tooth morphogenesis is a complex process that involves epithelial-ectomesenchymal interactions. Numerous transcription factors, growth factors, and their receptors, as well as extracellular matrix components, have been associated with early tooth development.23,24 The genetic basis of tooth development is supported by the identification of mutations in genes that participate in dental development (MSX1, PAX9, Table 4.
Number of Congenitally Missing Teeth per Persona Two One Teeth N Tooth N (%) (%)
Ovarian cancer group Control group a
16 (69.6) 2 (25)
x2 5 6.05; P 5 .049.
6 (26.1) 6 (75)
Three or More Teeth Total N (%) N (%) 1 (4.3) 0 (0)
23 (100) 8 (100)
HYPODONTIA IN WOMEN WITH EPITHELIAL OVARIAN CANCER Table 5. Family History of Hypodontia
Variable Total ovarian cancer group Total control group Ovarian cancer group with hypodontia Control group with hypodontia
Family History of Hypodontia N (%) 5/120 3/120 5/23 0/8
(4.2) (2.5) (21.7) (0)
P Value .472 .150
AXIN2).11,14,25 More recently, a mutation in the AXIN2 gene was identified in families with oligodontia and colorectal cancer, suggesting that tooth agenesis might be an indicator of colorectal cancer susceptibility.15 Hypodontia may also be present in certain syndromes (Down syndrome),26 ectodermal dysplasia.27 New research also reported a higher presence of cancer in family members of patients with hypodontia.17 In Slovenia, we have required dental examinations of children and young adolescents. Such knowledge is particularly important for the early detection of these diseases because dentist may be the first to detect hypodontia. The aim of this study was to assess a possible association between hypodontia and EOC in the Slovenian population. Prevalence of tooth agenesis has been addressed by numerous studies. In most populations, the reported hypodontia prevalence, excluding third molars, varies from 2.6% to 10.1%.2–5 In white populations the prevalence of hypodontia (excluding third molars) is generally in the range of 5% to 8%.3 Hypodontia prevalence (excluding third molars) in the Slovenian population is 6.9% (7.8% in women and 5.9% in men).28 Researchers from the University of Kentucky, Lexington,18 found 3% prevalence of hypodontia and microdontia in a control group, and 20% prevalence of hypodontia and microdontia in patients with EOC. In our study, only patients with hypodontia were included, giving 19.2% hypodontia prevalence in women with EOC, while the prevalence of the control group was very similar to the general population of Slovenia.28 Studies on European populations mostly reported a higher prevalence of the missing mandibular second premolar, followed by upper lateral incisors and upper second premolars.2–5 Agenesis of second premolars and upper lateral incisors accounts for 85% of all affected teeth among white populations.3 In the Slovenian population, the most common missing teeth are mandibular second premolars, followed by maxillary lateral incisors.28 Chalothorn et al.18 reported that maxillary lateral incisors were the most frequent missing teeth in patients with EOC. In our study, we found that the teeth missing most often in women with EOC were maxillary second premolars, followed by maxillary lateral incisors, mandibular second premolars, and
813 mandibular central incisors. This result was quite different from the study of Chalothorn et al.18 In the control group, we found the maxillary lateral incisors and mandibular second premolars were the most frequent missing teeth, similar to the reports of many authors who reported the prevalence of the hypodontia in the general white population.2–4 Hypodontia of the maxillary second premolar rarely occurs in the general population, but it occurs most frequently in patients with EOC. At least one missing upper maxillary premolar was found in 52.2% of women with EOC and in only 12.8% of the control group. Therefore, special attention should be recommended to women with this pattern of hypodontia. Ku¨cher et al.17 observed an increased frequency of family history of breast cancer and prostate cancer in individuals with at least one missing premolar as well as an increased frequency of all cancers in the group with at least one missing upper lateral incisor. According to the literature, there seems to be no overall significant difference between the prevalence of hypodontia in the maxilla and mandible in the general white population.2–4 Chalothorn et al.18 found the most missing teeth in the maxilla. In our study, we found that hypodontia was more common in the maxillary arch than in the mandibular arch in the EOC group too, but not in the control group. Some authors5,7 reported that bilateral missing teeth occurred most frequently. In the present study, women with EOC were four times more likely to have teeth missing unilaterally than bilaterally. In the group with bilateral missing teeth, maxillary lateral incisors were most commonly seen. No general difference in the frequency of agenesis between the left and right sides was found. Chalothorn et al.18 reported that in their ovarian cancer group, the most common number of teeth missing was one (on average 1.2 teeth were missing). In our study, the same pattern of missing one tooth occurred most frequently in women with EOC, followed by two and three teeth (on average 1.35 teeth were missing). In our study, we found a positive family history of hypodontia in women with EOC. With regular dental examinations being mandatory in Slovenia, hypodontia can be detected very early in childhood. Though hypodontia is not yet proven to be causally linked to EOC, more frequent preventive gynecologic examinations may be suggested for women with hypodontia. The study by Chalothorn et al.18 also reported the frequent presence of hypodontia in women with EOC. Therefore, it would be wise for a large, further study to be done to evaluate the role between hypodontia and epithelial ovarian cancer. Further research in this area will contribute to a better understanding of the links between EOC and hypodontia. Angle Orthodontist, Vol 84, No 5, 2014
814 Congenital absence of permanent teeth has direct clinical (visual) implication, and early evaluation of hypodontia phenotype could help us to identify patients at risk for EOC and serve as a possible marker for EOC detection. Identification of these high-risk individuals should result in earlier screening regimens for these individuals, an increased number of early diagnoses, and thus the potential to save many lives. Limitations of this study were the relatively small number of women with EOC and a certain anomaly, in this case hyypodontia, and the ability to follow subjects from only one clinical setting. Further research with a larger number of subjects and in other settings and countries could be of great interest as well as of great importance. CONCLUSIONS N The results statistically support the possible association between EOC and hypodontia phenotype. N As the ovarian cancer is difficult to detect in the early stages with no known specific screening markers, hypodontia could possibly serve as an early marker in identifying the risk of EOC. ACKNOWLEDGMENTS We thank the Department of Gynecologic and Breast Oncology, Clinical Department of Gynecology and Perinatology, University Clinical Centre, and the Department of Gynecology, Health Centre for help in collecting the participants. We would like to express our sincere gratitude to all participants.
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