Molecular biomarker-defined brain tumors: Epidemiology, validity, and completeness in the United States

Abstract

Background: Selected molecular biomarkers were incorporated into the US cancer registry reporting for patients with brain tumors beginning in 2018. We investigated the completeness and validity of these variables and described the epidemiology of molecularly defined brain tumor types.

Methods: Brain tumor patients with histopathologically confirmed diagnosis in 2018 were identified within the Central Brain Tumor Registry of the United States and NCI's Surveillance, Epidemiology, and End Results Incidence databases. The brain molecular markers (BMM) site-specific data item was assessed for coding completeness and validity. 1p/19q status, MGMT promoter methylation, WHO grade data items, and new ICD-O-3 codes were additionally evaluated. These data were used to profile the characteristics and age-adjusted incidence rates per 100 000 population of molecularly defined brain tumors with 95% confidence intervals (95% CI).

Results: BMM completeness across the applicable tumor types was 75%-92% and demonstrated favorable coding validity. IDH-wildtype glioblastomas' incidence rate was 1.74 (95% CI: 1.69-1.78), as compared to 0.14 for WHO grade 2 (95% CI: 0.12-0.15), 0.15 for grade 3 (95% CI: 0.14-0.16), and 0.07 for grade 4 (95% CI: 0.06-0.08) IDH-mutant astrocytomas. Irrespective of WHO grade, IDH mutation prevalence was highest in adolescent and young adult patients, and IDH-mutant astrocytomas were more frequently MGMT promoter methylated. Among pediatric-type tumors, the incidence rate was 0.06 for H3K27M-mutant diffuse midline gliomas (95% CI: 0.05-0.07), 0.03 for SHH-activated/TP53-wildtype medulloblastomas (95% CI: 0.02-0.03), and <0.01 for both C19MC-altered embryonal tumor with multilayered rosettes and RELA-fusion ependymomas.

Conclusions: Our findings illustrate the success of developing a dedicated, integrated diagnosis variable, which provides critical molecular information about brain tumors related to accurate diagnosis.

Keywords: CBTRUS; IDH; biomarkers; brain tumor; molecular epidemiology.

Figure 1.

Completeness of 1p/19q and MGMT promoter methylation statuses in adult-type diffuse gliomas from US central cancer registries for diagnosis year 2018. Completeness of 1p/19q loss of heterozygosity (black) data was defined as cases having a “present” or “not present” code for both 1p and 19q loss of heterozygosity site-specific data items. Completeness of MGMT promoter methylation (gray) data was defined as cases with codes 0-3. Other codes were considered as incomplete reporting. Completeness was assessed for adult-type diffuse gliomas, categorized both by (A) histology-based ICD-O-3 coding (WHO-CNS4) and (B) brain molecular marker-based integrated diagnosis classification (WHO-CNS5). Data provided by NCI’s SEER Program, November 2020 submissions.

Figure 2.

IDH mutation and MGMT promoter methylation statuses of adult-type diffuse astrocytic gliomas from US central cancer registries for diagnosis year 2018. The percentage of IDH mutation among adult-type diffuse astrocytic gliomas reported in CBTRUS data for 2018, as stratified by patients’ sex (A, B) and age (C, D), was determined using the brain molecular markers (BMM) site-specific data item. Additionally, the percentage of MGMT promoter methylation among cases, as stratified by IDH status (E, F), was assessed using the BMM and MGMT promoter methylation data items (SEER data only). Results are shown for categorization of tumor types by both the WHO-CNS4 (using histology-defined ICD-O-3 codes, upon which the BMM was developed; A, C, E) into “diffuse astrocytoma” (9400/3), “anaplastic astrocytoma” (9401/3), or “glioblastoma” (9440/3, 9445/3); and by the WHO-CNS5 (B, D, F). Because the WHO-CNS5 grading criteria had not yet been incorporated into registry reporting, the grades reported here were based on the revised WHO-CNS4 grading criteria and categorized using clinically relevant WHO pathological grades into WHO CNS grades 2, 3, or 4. In accordance with WHO-CNS5, cases reported as “grade 1” or “low-grade” were integrated into “WHO CNS grade 2.” Data provided by CDC’s National Program of Cancer Registries and NCI’s SEER Programs (2020).