Association of chromosome 19 q-arm polymorphisms with glioma development, survival and response to therapy

Principal Investigator: Ping Yang, M.D., Ph.D.
Co-Principal Investigator: Robert Jenkins, M.D., Ph.D.

Deletions of the chromosome 1p and 19q arms have been associated with gliomas, especially oligodendrogliomas. Patients with oligodendrogliomas with these alterations have been observed to have a better survival and a better response to chemotherapy and/or radiation. Recent evidence suggests that, in addition to acquired alterations, germline polymorphisms mapped to19q13.3 are associated with cancer development (e.g. basal cell carcinoma, breast cancer, adenocarcinoma of the lung, and glioma) and with cancer aggressiveness (e.g. prostate cancer).

Our main hypothesis is that there is a gene (or genes) on 19q13.3 that increases the risk of glioma and predicts progression. We propose to employ two fundamental study designs to achieve three aims: a case control study design to identify single nucleotide polymorphisms (SNPs) associated with glioma risk, and a patient cohort study design to identify SNPs associated with survival and response to therapy.

Our aims are as follows:

1. Evaluate the association of 19q SNPs with the risk of oligodendroglioma, mixed oligodendroglioma, and astrocytoma; will stratify the association analysis by glioma 19q deletion status; and will determine which alleles are lost in gliomas.
2. Evaluate the association of 19q SNPs with glioma survival and response to therapy for each of the three morphologic subtypes; will stratify by glioma 19q deletion status; and will determine which alleles are lost.
3. Focus the investigation on the narrow regions surrounding the significant SNPs identified by Aim 1; these regions most likely contain the gene(s)/SNP(s) associated with glioma risk.

All three Aims have two evaluation tiers using two independent yet complementary study samples: the first to screen SNPs for associations, the second to replicate and validate these associations.

Aims 1 and 3 use cases and controls enrolled retrospectively (tier-1) and prospectively (tier-2) at Mayo Clinic; Aim 2 uses Mayo Clinic retrospective cases (tier-1) and the RTOG trial 9402 cohort (tier-2). The overall study design is efficient and internally controlled. The Mayo Clinic retrospective cases and controls and the RTOG 9402 cases are already enrolled and will be available for analysis; whereas the prospective cases and controls will be enrolled using established research infrastructure at Mayo Clinic. Our translational goal is to find 19q SNP markers that are useful and feasible in glioma risk assessment and survival prediction.