Oncotarget

Priority Research Papers:

Genetic landscape of extreme responders with anaplastic oligodendroglioma

Matthias Holdhoff _, Gregory J. Cairncross, Thomas M. Kollmeyer, Ming Zhang, Peixin Zhang, Minesh P. Mehta, Maria Werner-Wasik, Luis Souhami, Jean-Paul Bahary, Young Kwok, Alan C. Hartford, Arnab Chakravarti, Srinivasan Yegnasubramanian, Bert Vogelstein, Nickolas Papadopoulos, Kenneth Kinzler, Robert B. Jenkins, Chetan Bettegowda

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Oncotarget. 2017; 8:35523-35531. https://doi.org/10.18632/oncotarget.16773

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Abstract

Matthias Holdhoff1, Gregory J. Cairncross2, Thomas M. Kollmeyer3, Ming Zhang1, Peixin Zhang4, Minesh P. Mehta5, Maria Werner-Wasik6, Luis Souhami7, Jean-Paul Bahary8, Young Kwok5, Alan C. Hartford9, Arnab Chakravarti10, Srinivasan Yegnasubramanian1, Bert Vogelstein1, Nickolas Papadopoulos1, Kenneth Kinzler1, Robert B. Jenkins3 and Chetan Bettegowda1

1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

2 Charbonneau Cancer Institute at the University of Calgary, Calgary, AB, USA

3 Mayo Clinic, Rochester, MN, USA

4 NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA

5 University of Maryland Medical Center, Baltimore, MD, USA

6 Thomas Jefferson University Hospital, Philadelphia, PA, USA

7 McGill University Health Centre, Montreal, QC, Canada

8 Centre Hospitalier de l’Université de Montréal, Montreal University, Montreal, QC, Canada

9 Darthmouth-Hitchcock Medical Center, Lebanon, NH, USA

10 The Ohio State University, Columbus, OH, USA

Correspondence to:

Matthias Holdhoff, email:

Chetan Bettegowda, email:

Keywords: oligodendroglioma, chemotherapy, survival, genomics, co-deletion 1p/19q

Received: October 01, 2016 Accepted: March 21, 2017 Published: March 31, 2017

Abstract

Background: The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. Methods: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. Results: Six STS (survival of <7.3y) and 7 LTS (survival of ≥7.3y and no progression) had sufficient material for analysis. There was no significant difference between the groups regarding age, performance status and extent of resection. On average, STS had 7 and LTS 4 mutations. Most common mutations in STS vs. LTS were: IDH1 (67 vs. 86%), CIC (50 vs. 71%) and FUBP1 (17 vs. 71%). The hTERT promoter was mutated in 83% STS and 86% LTS. Genotyping of rs55705857 showed a higher prevalence of G allele carriers in LTS than STS (43 vs. 17%).

Conclusions: These findings confirm that IDH, CIC, FUBP1 mutations and rs55705857 genotype are common in AO. No distinct genetic signature was identified to differentiate STS and LTS.


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