Oligodendroglioma 1p/19q co-deletion [Neurosurgery Wiki]

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====== Oligodendroglioma 1p/19q co-deletion ======

In the [[2016]] WHO classification of diffuse glioma, the diagnosis of an (anaplastic) [[oligodendroglioma]] requires the presence of both an [[IDH mutation]] (mt) and [[1p/19q co-deletion]].
((van den Bent MJ, Chang SM. Grade II and III Oligodendroglioma and Astrocytoma.
Neurol Clin. 2018 Aug;36(3):467-484. doi: 10.1016/j.ncl.2018.04.005. Epub 2018
Jun 15. Review. PubMed PMID: 30072066.)).
----
Complete [[deletion]] of both the short arm of [[chromosome 1]] (1p) and the long arm of [[chromosome 19]] ([[19q]]) is pathognomonic for [[oligodendroglioma]]
((Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016; 131:803–820))
((Stupp R, Brada M, van den Bent MJ, et al. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3:iii93–ii101))
It is strongly associated with [[IDH mutation]] and is mutually exclusive of [[ATRX]] & [[TP53]] [[mutation]]s.
----
Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 genes, is the molecular diagnostic criterion for oligodendroglioma, IDH-mutant and 1p/19q-codeleted. 1p/19q codeletion is a diagnostic marker and allows prognostication and prediction of the best drug response within IDH-mutant tumors.
----
[[TERT promoter mutation]]s commonly occur concomitantly with [[1p/19q co-deletion]],
((Arita H, Narita Y, Fukushima S, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol. 2013; 126:267–276)) 
and are mutually exclusive in gliomas with TP53 mutations.
----
Loss of one arm of a hybrid chromosome is called [[loss of heterozygosity]] (LOH) for that chromosome region. LOH in 1p & 19q occurs as a result of unbalanced whole-arm [[translocation]]s between [[chromosome 1]] & [[chromosome 19]],
((Jenkins RB, Blair H, Ballman KV, et al. A t(1;19) (q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006; 66: 9852–9861))
which occurs early in the pathogenesis of [[oligodendroglioma]]s.

 It is often sent out, results typically take 3–7 days. Cost for FISH is on the order of $200 U.S., PCR is $300–500 U.S.

Less invasive method for prediction of pathological type-even gene status-is desired.

[[11C methionine positron emission tomography]]/MRI based texture analysis and conventional features may be a promising noninvasive predictor for differentiating the varied [[glioma]]s
((Zhao K, Yu P, Xue Z, Liu J, Yao A, Zhao Y, Yang F, Tian J, Xu B.
(11)C-Methionine Integrated PET/MRI-Based Texture Analysis Features May Have a
Potential Ability to Distinguish Oligodendroglioma (IDH-Mutant and
1p/19q-Codeleted) From Varied Gliomas. Acad Radiol. 2019 Oct 10. pii:
S1076-6332(19)30446-5. doi: 10.1016/j.acra.2019.09.013. [Epub ahead of print]
PubMed PMID: 31607471.
)).
----
In the revised 4th edition of the [[World Health Organization Classification of Tumors of the Central Nervous System 2016]], [[classification]] of especially [[diffuse glioma]]s has fundamentally changed: for the first time a large subset of these tumours is now defined based on presence/absence of [[IDH mutation]] and [[1p/19q co-deletion]]. Following this approach, the diagnosis of [[anaplastic oligoastrocytoma]] can be expected to largely disappear
((Wesseling P, Capper D. WHO 2016 Classification of Gliomas. Neuropathol Appl
Neurobiol. 2017 Aug 16. doi: 10.1111/nan.12432. [Epub ahead of print] PubMed
PMID: 28815663.
)).

While in cases of histologically classical oligodendroglioma 1p/19q analysis is essential for making the final (integrated) diagnosis, this is less clear for cases with less pronounced oligodendroglial differentiation or even for histologically astrocytic tumors. The WHO Classification states that the presence of an astrocytic component is compatible with the diagnosis of oligodendroglioma when molecular testing reveals the entity-defining combination of IDH mutation and 1p/19q co-deletion. This means that histologically pure astrocytomas do not need to be analyzed for 1p19q codeletion. On the other hand, in the review article written by the editors of the WHO Classification, it is stated that “genotype trumps histological phenotype”, i.e., a diffuse glioma that histologically appears astrocytic, but proves to have IDH mutation and 1p/19q co-deletion necessitates a diagnosis of oligodendroglioma, IDH-mutant, and 1p/19q-codeleted
((Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D,
Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health 
Organization Classification of Tumors of the Central Nervous System: a summary.
Acta Neuropathol. 2016 Jun;131(6):803-20. doi: 10.1007/s00401-016-1545-1. Review.
PubMed PMID: 27157931.
)).

This means that 1p/19q analysis would be required in all cases of diffuse glioma. The most appropriate practical approach may depend on the amount/representativeness of the material in the individual case as well as on systematic studies revealing the actual frequency of this kind of constellation, i.e., completely disparate genotype versus histotype. Some clarification and ideally consensus appears useful.
----
Otani et al. analyzed 170 WHO grade II to IV gliomas resected in there institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of the TCGA was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas: AA), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas: AO). Of the 88 IDH-wild type Glioblastomas, 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival (OS) compared to 19q-intact AAs (p=0.001). This tendency was observed in the TCGA Lower Grade Glioma dataset. In contrast, there was no difference in OS between the 19q-loss Glioblastoma and 19q-intact Glioblastoma (p=0.4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas
((Otani R, Uzuka T, Higuchi F, Matsuda H, Nomura M, Tanaka S, Mukasa A, Ichimura
K, Kim P, Ueki K. IDH-mutated astrocytomas with 19q-loss constitute a subgroup
that confers better prognosis. Cancer Sci. 2018 May 12. doi: 10.1111/cas.13635.
[Epub ahead of print] PubMed PMID: 29752851.
)).
----
In [[oligodendroglioma]]s, [[mutation]]s in [[IDH1]] and [[codeletion]] of chromosomes 1p and 19q are associated with improved survival with upfront use of combined chemotherapy and radiation, and these tumors also have unique mutations of CIC and FUBP1 genes

The 1p-/19q- combination appears to be an objective diagnosis marker of classic [[oligodendroglioma]]s, one that can be used, in combination with histological examination, to improve the diagnosis of oligodendroglioma. Fluorescence in situ hybridization on touch preparations is a simple way to obtain information on 1p-/19q- in 24 hours
((Gadji M, Fortin D, Tsanaclis AM, Drouin R. Is the 1p/19q deletion a diagnostic
marker of oligodendrogliomas? Cancer Genet Cytogenet. 2009 Oct;194(1):12-22. doi:
10.1016/j.cancergencyto.2009.05.004. PubMed PMID: 19737649.)).

Chromosome 1p/19q deletion is an established prognostic and predictive marker in the WHO grade III [[oligodendroglial tumors]] (OT).

[[Oligodendroglioma]] patients with 1p/19q LOH and Sox17 protein expression had a better prognosis. Thus, analysis of 1p/19q LOH and Sox17 protein expression could significantly enhance diagnostic accuracy, guide treatment, and improve the prognosis
((Li J, Miao N, Liu M, Cui W, Liu X, Li X, Shi X, Qing S, Ma Y, Zhang W,
Biekemituofu H. Clinical significance of chromosome 1p/19q loss of heterozygosity
and Sox17 expression in oligodendrogliomas. Int J Clin Exp Pathol. 2014 Dec
1;7(12):8609-15. eCollection 2014. PubMed PMID: 25674225; PubMed Central PMCID:
PMC4313992.
)).
----
The diagnosis and classification of diffusely infiltrative gliomas are based on their histopathological appearance; however, histopathological delineation of diffuse gliomas can be difficult because of vague and subjective histopathological criteria. Combined loss of chromosome arms 1p and 19q (denoted as 1p-/19q-) has proven to be a powerful predictor of chemotherapeutic response and survival in [[oligodendroglioma]]s. 

Fluorescence in situ hybridization using probes specific for chromosomes 1 and 19 was performed on 22 paraffin-embedded tissues retrospectively; 15 touch-preparation smear samples were studied prospectively; and loss of heterozygosity (LOH) screening was performed on 11 samples with microsatellite markers specific to chromosome 1 and chromosome 19. Of the 37 cases, 24 had 1p-/19q-, 1 case had 1p- only, 2 cases had 19q- only, and 10 cases had no deletion. The length of the largest deletion was mapped between markers D1S2795 (1p36.31 locus) and D1S2722 (1p34.2 locus) and between markers D19S416 (19q13.11 locus) and D19S397 (19q13.14 locus), using LOH. All of the pure oligodendrogliomas (n=7) harbored 1p-/19q-. In light of previous findings, the 1p-/19q- combination appears to be an objective diagnosis marker of classic oligodendrogliomas, one that can be used, in combination with histological examination, to improve the diagnosis of oligodendroglioma. Fluorescence in situ hybridization on touch preparations is a simple way to obtain information on 1p-/19q- in 24 hours
((Gadji M, Fortin D, Tsanaclis AM, Drouin R. Is the 1p/19q deletion a diagnostic marker of oligodendrogliomas? Cancer Genet Cytogenet. 2009 Oct;194(1):12-22. doi: 10.1016/j.cancergencyto.2009.05.004. PubMed PMID: 19737649.
)).
----
Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed
((van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M,
Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S,
Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting 
RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P,
Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM,
Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM. Interim
results from the CATNON trial (EORTC study 26053-22054) of treatment with
concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma:
a phase 3, randomised, open-label intergroup study. Lancet. 2017 Aug 8. pii:
S0140-6736(17)31442-3. doi: 10.1016/S0140-6736(17)31442-3. [Epub ahead of print] 
PubMed PMID: 28801186.)).

===== Determination =====

Brandner et al. performed a [[Cochrane review]] and simple economic analysis to establish the most sensitive, specific, and [[cost-effective]] techniques for determining [[1p/19q co-deletion]] status. [[Fluorescence in situ hybridization]]s ([[FISH]]) and [[PCR]]-based [[loss of heterozygosity]] (LOH) test methods were considered as the reference standard. Most techniques (FISH, CISH, PCR, Real-time PCR, MLPA, SNP array, [[CGH]], array CGH, next-generation sequencing, mass spectrometry, and NanoString) showed good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma, irrespective of whether FISH or PCR-based LOH was used as the reference standard. Both NGS and SNP arrays had a high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. Findings suggest that [[G-banding]] is not a suitable test for [[1p/19q co-deletion]] analysis. Within these limits considering cost per diagnosis, and using [[FISH]] as a reference, [[Multiplex ligation-dependent probe amplification]] (MLPA) was marginally more [[cost-effective]] than other tests, although these economic analyses were limited by the range of available parameters, time horizon, and data from multiple health care organizations
((Brandner S, McAleenan A, Jones HE, Kernohan A, Robinson T, Schmidt L, Dawson S, Kelly C, Leal ES, Faulkner CL, Palmer A, Wragg C, Jefferies S, Vale L, P T Higgins J, Kurian KM. Diagnostic accuracy of [[1p/19q co-deletion]] tests in [[oligodendroglioma]]: a comprehensive [[meta-analysis]] based on a [[Cochrane]] [[Systematic Review]]. Neuropathol Appl Neurobiol. 2021 Dec 26. doi: 10.1111/nan.12790. Epub ahead of print. PMID: 34958131.)).