Canine osteosarcoma genome sequencing identifies recurrent mutations in  DMD  and the histone methyltransferase gene  SETD2

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Abstract

Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To define the genomic underpinnings of canine OS, we performed multi-platform analysis of OS tumors from 59 dogs, including whole genome sequencing ( n = 24) and whole exome sequencing (WES; n = 13) of primary tumors and matched normal tissue, WES ( n = 10) of matched primary/metastatic/normal samples and RNA sequencing ( n = 54) of primary tumors. We found that canine OS recapitulates features of human OS including low point mutation burden (median 1.98 per Mb) with a trend towards higher burden in metastases, high structural complexity, frequent TP53 (71%), PI3K pathway (37%), and MAPK pathway mutations (17%), and low expression of immune-associated genes. We also identified novel features of canine OS including putatively inactivating somatic SETD2 (42%) and DMD (50%) aberrations. These findings set the stage for understanding OS development in dogs and humans, and establish genomic contexts for future comparative analyses.

Abstract

Heather Gardner et al. report the genomic landscape of canine osteosarcoma, finding recurrent mutations in the histone methyltransferase gene SETD2 and in DMD, the gene encoding dystrophin. The results support the study of naturally-occurring osteosarcoma in dogs for understanding both human disease mechanisms and canine-specific alterations to identify new treatments.

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Most cited references 51

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Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants.

Aziz Belkadi, Alexandre Bolze, Yuval Itan … (2015)

We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) in six unrelated individuals. In the regions targeted by WES capture (81.5% of the consensus coding genome), the mean numbers of single-nucleotide variants (SNVs) and small insertions/deletions (indels) detected per sample were 84,192 and 13,325, respectively, for WES, and 84,968 and 12,702, respectively, for WGS. For both SNVs and indels, the distributions of coverage depth, genotype quality, and minor read ratio were more uniform for WGS than for WES. After filtering, a mean of 74,398 (95.3%) high-quality (HQ) SNVs and 9,033 (70.6%) HQ indels were called by both platforms. A mean of 105 coding HQ SNVs and 32 indels was identified exclusively by WES whereas 692 HQ SNVs and 105 indels were identified exclusively by WGS. We Sanger-sequenced a random selection of these exclusive variants. For SNVs, the proportion of false-positive variants was higher for WES (78%) than for WGS (17%). The estimated mean number of real coding SNVs (656 variants, ∼3% of all coding HQ SNVs) identified by WGS and missed by WES was greater than the number of SNVs identified by WES and missed by WGS (26 variants). For indels, the proportions of false-positive variants were similar for WES (44%) and WGS (46%). Finally, WES was not reliable for the detection of copy-number variations, almost all of which extended beyond the targeted regions. Although currently more expensive, WGS is more powerful than WES for detecting potential disease-causing mutations within WES regions, particularly those due to SNVs.

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To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

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Genome-Informed Targeted Therapy for Osteosarcoma

Leanne Sayles, Marcus Breese, Amanda Koehne … (2018)

Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.This article is highlighted in the In This Issue feature, p. 1.

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Author and article information

Contributors

William P. D. Hendricks:

ORCID: http://orcid.org/0000-0001-7192-8699

whendricks@tgen.org

Journal

Journal ID (nlm-ta): Commun Biol

Journal ID (iso-abbrev): Commun Biol

Title: Communications Biology

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2399-3642

Publication date (Electronic): 19 July 2019

Publication date PMC-release: 19 July 2019

Publication date Collection: 2019

Volume: 2

Electronic Location Identifier: 266

Affiliations

[1 ]ISNI 0000 0004 1936 7531, GRID grid.429997.8, Sackler School of Graduate Biomedical Sciences, , Tufts University, ; Boston, MA 02111 USA

[2 ]ISNI 0000 0004 0507 3225, GRID grid.250942.8, Translational Genomics Research Institute, ; Phoenix, AZ 85004 USA

[3 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, College of Medicine, , The Ohio State University, ; Columbus, OH 43210 USA

[4 ]ISNI 0000 0004 1936 7531, GRID grid.429997.8, Cummings School of Veterinary Medicine, , Tufts University, ; Grafton, MA 01536 USA

[5 ]GRID grid.66859.34, Broad Institute, ; Cambridge, MA 02142 USA

[6 ]ISNI 0000 0004 1936 8083, GRID grid.47894.36, Colorado State University, ; Fort Collins, CO 80525 USA

[7 ]ISNI 0000 0001 0629 5880, GRID grid.267309.9, University of Texas Health Science Center, ; San Antonio, TX 78229 USA

[8 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Veterinary Clinical Sciences, , The Ohio State University, ; Columbus, OH 43210 USA

[9 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Pediatric Oncology, , Dana-Farber Cancer Institute, ; Boston, MA 02215 USA

Author information

Heather L. Gardner http://orcid.org/0000-0001-6007-6144

Gwendolen Lorch http://orcid.org/0000-0001-6443-704X

William P. D. Hendricks http://orcid.org/0000-0001-7192-8699

Article

Publisher ID: 487

DOI: 10.1038/s42003-019-0487-2

PMC ID: 6642146

PubMed ID: 31341965

SO-VID: dac30767-4b4e-4fd4-b568-5f6ee1a6b2a7

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 January 2019

Date accepted : 29 May 2019

Funding

Funded by: Financial support for this research was provided administrative supplements to the Dana-Farber/Harvard Cancer Center Support Grant (P30 CA006516) and the OSU Comprehensive Cancer Center Support Grant (P30 CA016058) from the National Cancer Institute. Additional support was provided by the UL1TR002733 from the National Center for Advancing Translational Sciences and by the Office of The Director and National Institutes of Health under Award Numbers P01CA165995-01A1 and K01OD019923.