Question

Clinical Background: A 40-year-old male patient complained of a right frontal headache and right neck pain for the duration of 4 weeks. The pain was associated with intermittent blurred vision in the right eye and three episodes of morning emesis without nausea. The patient denied dizziness, fever, diplopia, change in hearing, tinnitus, vertigo, weakness, numbness, difficulty speaking or with language, swallowing, eating, or gait. He reported no recent travel and no ill contacts. A head CT scan showed a large, primarily cystic lesion within the right frontal lobe containing areas of calcification with surrounding vasogenic edema. There was significant mass effect on the right lateral ventricle with a shift of midline structures to the left and evidence of subfalcine herniation. The patient underwent exploratory craniotomy and a frozen section was diagnosed as high-grade glioma. A total resection of the tumor was performed. The final pathological diagnosis was anaplastic oligodendroglioma (Figure a). A hematoxylin and eosin stain of the patient's tumor revealed classical histological features of oligodendroglioma with round nuclei, perinuclear halos, and delicate capillaries. Glial tumors are classified based on their morphological resemblance to normal anatomic counterparts. Anaplastic oligodendrogliomas have aggressive behavior with early recurrence and progression and short overall survival. Loss of chromosome arms 1p and 197 is seen in 85% of oligodendrogliomas and 50-60% of anaplastic oligodendrogliomas. Generally, tumors with 1p/19q co-deletion have a good response to chemotherapy and radiotherapy and oligodendrogliomas with 1p/19 loss have significantly better progression free and overall survival than those without the co-deletion. Therefore, 1p/19q loss represents a reliable marker of biologic behavior and therapeutic response. The 1p/19 co-deletion is also strongly associated with tumor location. Oligodendrogliomas most commonly arise in the frontal lobe, less commonly in the occipital lobe. Almost 90% of oligodendroglial tumors arising in the frontal lobe have 1p/19q co- deletion.

1. List 3 different molecular methods that could be used to detect the 1p/19q deletion. Describe what would be seen for each method if 1p/19q co-deletion were present. NOTE: LIST ONLY MOLECULAR METHODS SUCH AS FISH AND PCR AND DESCRIBE WHAT WOULD BE SEEN.
2. The cells of oligodengroglioma do not grow well in culture. Of the three assays from question 2, which would you choose to diagnose the 1p/19q deletion? Why? AGAIN LIST ONE OF THE MOLECULAR METHODS, NO OTHER METHODS ARE ACCEPTABLE!!

Answer 1

Ans) The 1p 19q deletion status can be analyzed with various molecular-genetic methods including FISH, comparative genomic hybridization (CGH), chromogenic in situ hybridization (CISH), PCR-based microsatellite analysis, real-time comparative quantitative PCR and multiplex ligation-dependent probe amplification (MLPA)

- Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) (1p/19q co-deletion) is the molecular genetic signature of oligodendrogliomas, a subtype of primary brain tumours accounting for approximately ten to fifteen percent of all diffuse gliomas in adults. The loss of one hybrid chromosome results in 1p and 19q loss of heterozygosity (LOH) 3. This molecular alteration is the result of an unbalanced whole-arm translocation between chromosomes 1 and 19 3 with the loss of the derivative t(1p;19q), which occurs early in the pathogenesis of oligodendrogliomas. Initially described in 1994 4, the biologic effect of 1p/19q co-deletion remains unclear. 1p/19q co-deletion is a valuable diagnostic, prognostic and predictive biomarker for the management of oligodendroglial tumours.

- 1p/19q co-deletion as a diagnostic biomarker in glioma
1p/19q co-deletion is a pathognomonic biomarker that defines a distinct glioma entity 5 and is characteristic of oligodendrogliomas 6,7. Virtually, all 1p/19q co-deleted oligodendrogliomas have mutation in isocitrate dehydrogenase 1 (IDH1) at arginine 132 (R132) or the analogous residue arginine 172 in IDH2 (R172). Other common molecular alterations co-occuring with 1p/19q co-deletion include mutations in the telomerase reverse transcriptase (TERT) gene promoter, mutations in homolog of Drosophila capicua (CIC) and far upstream element binding protein (FUBP1) 9, and promoter methylation of the methyl-guanine methyl transferase (MGMT) gene 8,7. With very few exceptions, 1p/19q co-deletion is mutually exclusive with TP53 and ATRX mutation, which both characterize glial tumours of astrocytic lineage.

- Thereby, assessment of 1p/19q co-deletion, together with IDH mutation status and other molecular markers (e.g. ATRX and TP53 status), can help distinguish oligodendrogliomas which are IDH-mutant and 1p/19q-codeleted, from tumours of astrocytic lineage which are 1p/19q-non co-deleted.

- In some cases, an oligodendroglioma can be cured. Anaplastic oligodendroglioma (grade III): An anaplastic oligodendroglioma grows quickly and spreads into nearby tissues. The tumor cells look different from normal cells. This type of tumor usually cannot be cured.