Clinical Relevance of Chromosome 5p/9p/20q/8q Germline Alterations in Glioma
This project in the Mayo Clinic Brain Cancer SPORE proposes to further validate the germline alterations within or near the CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions that are associated with glioma development to correlate alteration status with somatic genetic and expression alterations, with pathological variables and with clinical parameters.
The development of glioblastoma has been hypothesized to be associated with relatively common germline alterations with limited penetrance. Two genome-wide association studies using various single nucleotide polymorphism (SNP) array platforms have been performed in gliomas.
Collaborating with the University of California, San Francisco (UCSF), the Mayo Clinic Brain Cancer SPORE project team reported that SNPs mapping near CDKN2A/B/ARF (9p21) and RTEL1 (20q13) are associated with the development of high-grade astrocytomas. Other researchers have also observed these associations, as well as associations near TERT (5p15) and CCDC26/MLZE (8q24).
A reanalysis of data from UCSF and Mayo Clinic suggests that the RTEL1 (20q13), TERT (5p15) and CCDC26/MLZE (8q24) associations are largely restricted to patients with glioblastoma multiforme, anaplastic astrocytoma and oligodendroglioma. This finding suggests that different germline polymorphisms are associated with the development of different glioma subtypes.
This project has two aims.
Aim 1: Germline genetic analysis
The Brain Cancer SPORE is performing detailed germline genetic analysis of the associated CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions using three cohorts of prospectively acquired glioma cases and controls to estimate the prevalence and relative risk of known polymorphisms and new alterations.
This aim has two sub-aims:
- Aim 1a. The project team is performing custom genotyping of up to 384 candidate SNPs/alterations and 150 other alterations identified by the American Recovery and Reinvestment Act RC1 grant using two case-control sets: 582 previously collected prospective cases and 532 controls, and 600 cases and 600 matched controls from the UCSF SPORE. The team will impute additional genotypes and haplotypes and assess association with glioma development.
- Aim 1b. The team is performing further replication and validation based on results from the germline genetic analysis through custom genotyping of up to 384 refined candidate SNPs/alterations, 150 other alterations in 450 new glioma cases and 450 new matched controls and in combined total samples (about 1,600 cases and 1,600 controls).
Aim 2: Histopathologic and molecular pathologic relevance of germline alterations
This aim is evaluating the clinical, histopathologic and molecular pathologic relevance of germline CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) alterations.
This aim has two sub-aims:
- Aim 2a. The project team is determining the associations of the germline alterations with the development of a specific genetic subclass of glioma: expression subclass (for example, proneural, neural, classical, mesenchymal), acquired copy number subclass (for example, +7, -10, -1p, -19q), and/or acquired mutation subclass (for example, PTEN, p53, IDH1/2, EGFR).
- Aim 2b. In addition, the research team is assessing and modeling the association of the germline alterations (Aim 1) and subclasses (Aim 2a) with grade (astrocytoma vs. anaplastic astrocytoma vs. glioblastoma multiforme), morphology (oligodendroglioma vs. malignant oligoastrocytoma vs. astrocytoma), Grade I vs. Grade II glioblastoma, and survival, adjusting for key clinical variables including age and gender.
Co-leaders of this Brain Cancer SPORE project are: