Congenital Tooth Agenesis and Risk of Early-Onset Cancer

Key Points Question Is tooth agenesis associated with early-onset cancer? Findings In this population-based cohort study of 2.5 million live-born singletons with up to 40 years of follow-up, tooth agenesis was positively associated with several cancer types, including neuroblastoma, nephroblastoma, and hepatoblastoma in childhood; osteosarcoma in adolescence; and colorectal carcinomas and carcinomas of the bladder in young adulthood. Meaning These findings suggest that tooth agenesis is associated with specific cancer types, particularly in early childhood and early adulthood; further evaluation of these associations is needed to assess possible clinical implications.


eMethods 2: Detailed description of syndrome diagnosis
Two sources were used for identification of a known syndrome: The Danish Cytogenetic Central Register (1, 2) and the Danish National Patient Registry (3).
All individuals with an abnormal karyotype (except balanced translocations) or abnormal chromosomal microarray in the Danish Cytogenetic Central Register (described in eMethods1) were classified as having a syndrome diagnosis.Tooth agenesis in itself was not an indication for genetic screening within the study period.
We were not able to include information about single-gene tests and whole exome/whole genome sequencing, but instead used diagnoses by International Classification of Diseases (ICD) codes for further identification of syndromes.From the Danish National Patient Registry, we classified individuals as having a syndrome diagnosis, if they had been assigned any of the following ICD codes:

eMethods 3: Detailed description of statistical analyses
Survival time was calculated as days from date of birth until first diagnosis of cancer (registered in the Danish Cancer Registry) or censoring due to emigration, age 40 years, death, or end of the study period (registered in the Danish Civil Registration Registry), whichever came first.If cancer was diagnosed before birth, a risk time of 0.1 days was assigned.
Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to evaluate associations between tooth agenesis and each cancer type.Evaluation of the models were made by examination of plots of observed and fitted survival curves, and log-log survival curves, and showed non-proportionality.
To meet the assumption of proportional hazards, the analyses were split into age groups (<1 year, 1 to <3 years, 3 to <10 years, 10 to <20 years, 20 to <30 years and 30 to <40 years) (1, 2).This approach was chosen as the age groups also accommodate the natural biology of the outcome in questionspecific cancers occur at specific age windows.All individuals were right censored as described above, e.g., an individual with a survival time of 1500 days would contribute survival time to the analyses of the <1 year, 1 to <3 years, and 3 to <10 years age groups.
We assessed HRs for any cancer and specific cancer types before age 40 years.For each age group, analyses of specific cancer types were performed only if the number of cancer cases among the exposed was ≥5, in accordance with the Danish Health Data regulations.
Associations with non-syndromic tooth agenesis were evaluated by repeating the analyses after exclusion of individuals with a registered genetic syndrome, as defined in eMethods 2.
A sensitivity analysis was performed after further exclusion of cases where detection of the tooth agenesis could be related to the clinical workup at the time of or after cancer diagnosis, possibly leading to detection bias.This was defined as cases where 1. the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and 2. tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry) as this could be influenced by having a cancer diagnosis.This is in contrast to the municipal dental care system, were nearly all Danish children are evaluated at least yearly from age two years.
All analyses were performed using R, version 4.1.0,dplyr and survival packages.

Tooth agenesis population characteristics stratified on registry Tooth agenesis data source Danish Central Registry of Odontology n = 58,269 (82.9%) Danish National Patient Registry only n = 12,019 (17.1%)
The left tooth agenesis column includes those registered in the Danish Central Registry of Odontology (municipal dental care), with or without additional registration in the Danish National Patient Registry (specialized hospital setting).The right tooth agenesis column includes those registered in the Danish National Patient Registry without having been registered in the Danish Central Registry of Odontology.

Results by age groups, 0 to <1 years: HR and 95% CI for overall, non-syndromic and sensitivity analyses Analysis estimates, HR (95% CI)
Re-analysis after further exclusion of cases where the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry) © 2024 Eiset SE et al.JAMA Network Open.eTable 4.

Results by age groups, 1 to <3 years: HR and 95% CI for overall, non-syndromic and sensitivity analyses Analysis estimates, HR (95% CI)
Re-analysis after exclusion of individuals with known genetic syndromesSensitivity analysis: Re-analysis after further exclusion of cases where the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry) Abbreviations: HR, hazard ratio; CI, confidence interval; n, number of cancer cases in age group; AML, acute myeloid leukemia; CNS, central nervous system a Including intracranial and intraspinal tumors b and other nonepithelial renal tumors © 2024 Eiset SE et al.JAMA Network Open.eTable 5.

Results by age groups, 3 to <6 years: HR and 95% CI for overall, non-syndromic and sensitivity analyses Analysis estimates, HR (95% CI)
Re-analysis after further exclusion of cases where the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry) Abbreviations: HR, hazard ratio; CI, confidence interval; n, number of cancer cases in age group; AML, acute myeloid leukemia © 2024 Eiset SE et al.JAMA Network Open.eTable 6.

Results by age groups, 6 to <10 years: HR and 95% CI for overall, non-syndromic and sensitivity analyses Analysis estimates, HR (95% CI)
Re-analysis after exclusion of individuals with known genetic syndromesSensitivity analysis: Re-analysis after further exclusion of cases where the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry) Abbreviations: HR, hazard ratio; CI, confidence interval; n, number of cancer cases in age group; CNS, central nervous system a Including intracranial and intraspinal tumors © 2024 Eiset SE et al.JAMA Network Open.eTable 7.

Results by age groups, 10 to <20 years: HR and 95% CI for overall, non-syndromic and sensitivity analyses Analysis estimates, HR (95% CI)
Non-syndromic tooth agenesis: Re-analysis after exclusion of individuals with known genetic syndromes Sensitivity analysis: Re-analysis after further exclusion of cases where the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry) Abbreviations: HR, hazard ratio; CI, confidence interval; n, number of cancer cases in age group; AML, acute myeloid leukemia © 2024 Eiset SE et al.JAMA Network Open.eTable 8.

Results by age groups, 20 to <30 years: HR and 95% CI for overall, non-syndromic and sensitivity analyses Analysis estimates, HR (95% CI)
Re-analysis after further exclusion of cases where the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry)

Results by age groups, 30 to <40 years: HR and 95% CI for overall, non-syndromic and sensitivity analyses
Non-syndromic tooth agenesis: Re-analysis after exclusion of individuals with known genetic syndromes Sensitivity analysis: Re-analysis after further exclusion of cases where the date of tooth agenesis diagnosis came after the date of cancer diagnosis, and tooth agenesis was registered in the hospital system only (ICD codes obtained from the Danish National Patient Registry) Abbreviations: HR, hazard ratio; CI, confidence interval; n, number of cancer cases in age group.