Identification of Genomic Alterations in Chemotherapy-Related Genes: A Preliminary Study in Three Thai Adolescents with Fatal Osteosarcoma at Maharaj Nakorn Chiang Mai Hospital
Keywords:
osteosarcoma, genome, single nucleotide polymorphisms, copy number variations, structural variations, chemotherapyAbstract
Objective Osteosarcoma (OS) is the most common primary bone malignancy among adolescents and young adults. It is characterized by a high mortality rate, though it remains a relatively rare disease overall. The treatment protocols can be complex and challenging. We conducted a comparative genomic variation study to identify genes involved in the metabolism of chemotherapy drugs that are affected by various genomic alterations.
Methods This study analyzed the germline and tumor genomes of three OS patients who responded poorly to chemotherapy, developed lung metastases, and ultimately succumbed to the disease. Genes of interest were identified through a systematic review of apoptosis, autophagy, necroptosis, and chemotherapy-related databases. Whole-genome sequencing (WGS) revealed deleterious single nucleotide polymorphisms (SNPs), copy number variations (CNVs), and structural variations (SVs) in genes linked to cancer and chemotherapy. Protein association network analyses were used to highlight both shared and unique biological processes associated with OS in these patients.
Results Pathogenic SNPs were identified exclusively in patients P1 and P3. Patient P1 exhibited a missense mutation in the PIK3CD gene and a splice donor site mutation in the TP53 gene, while patient P3 carried a nonsense mutation in the MLH1 gene. The tumor genome of patient P1 showed extensive CNVs, whereas those of patients P2 and P3 displayed fewer CNV regions. TBX4 and PPM1D were common genes affected in both patients P1 and P2. SVs were detected in all three tumor genomes, impacting different key genes involved in platinum drug resistance and DNA repair. Notably, all three patients shared SVs in the TDG and SPECC1 genes. All identified mutated genes were correlated with clinical features of the patients.
Conclusions This study highlights the potential of genomic analysis to improve the diagnosis, treatment, and management of OS. Insights into therapy resistance mechanisms and key genomic alterations offer opportunities for developing targeted therapies and predictive biomarkers. These findings support the advancement of precision oncology in OS, as a means of paving the way for personalized treatment approaches to improve patient outcomes.
References
Yücetürk G, Sabah D, Keçeci B, Kara AD, Yalçinkaya S. Prevalence of bone and soft tissue tumors. Acta Orthop Traumatol Turc. 2011;45:135-43.
Sadykova LR, Ntekim AI, Muyangwa-Semenova M, Rutland CS, Jeyapalan JN, Blatt N, et al. Epidemiology and Risk Factors of Osteosarcoma. Cancer Investigat. 2020;38:259-69.
Jafari F, Javdansirat S, Sanaie S, Naseri A, Shamekh A, Rostamzadeh D, et al. Osteosarcoma: A comprehensive review of management and treatment strategies. Ann Diagn Pathol. 2020;49:151654. PubMed PMID: 33130384.
Chaiyawat P, Klangjorhor J, Settakorn J, Champattanachai V, Phanphaisarn A, Teeyakasem P, et al. Activation status of receptor tyrosine kinases as an early predictive marker of response to chemotherapy in osteosarcoma. Transl Oncol. 2017;10:846-53.
Rickel K, Fang F, Tao J. Molecular genetics of osteosarcoma. Bone. 2017;102:69-79.
Rode A, Maass KK, Willmund KV, Lichter P, Ernst A. Chromothripsis in cancer cells: An update. Int J Cancer. 2016;138(10):2322-33.
Cortes-Ciriano I, Lee JJ, Xi R, Jain D, Jung YL, Yang L, et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat Genet. 2020;52:331-41.
Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27-40.
Smida J, Xu H, Zhang Y, Baumhoer D, Ribi S, Kovac M, et al. Genome‐wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma. International Journal of Cancer. 2017;141:816-28.
Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu H-Y, et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 2019;9:46-63.
Zhang C, Hansen HM, Semmes EC, Gonzalez-Maya J, Morimoto L, Wei Q, et al. Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population. Bone. 2020;130:115070. PubMed PMID: 31525475.
Wei X, Xu L, Jeddo SF, Li K, Li X, Li J. MARK2 enhances cisplatin resistance via PI3K/AKT/NF-kB signaling pathway in osteosarcoma cells. Am J Transl Res. 2020; 12:1807-23.
Garcia-Ortega DY, Cabrera-Nieto SA, Caro-Sánchez HS, Cruz-Ramos M. An overview of resistance to chemotherapy in osteosarcoma and future perspectives. Cancer Drug Resist. 2022;5:762-93.
Li L, Luo C, Song Z, Reyes-Vargas E, Clayton F, Huang J, et al. Association of anti-HER2 antibody with graphene oxide for curative treatment of osteosarcoma. Nanomedicine. 2018;14:581-93.
Huang D, Savage SR, Calinawan AP, Lin C, Zhang B, Wang P, et al. A highly annotated database of genes associated with platinum resistance in cancer. Oncogene. 2021;40(46):6395-405.
Pires SF, Barros JS, Costa SSD, Carmo GBD, Scliar MO, Lengert AVH, et al. Analysis of the mutational landscape of osteosarcomas identifies genes related to metastasis and prognosis and disrupted biological pathways of immune response and bone development. Int J Mol Sci. 2023;24(13). PubMed PMID: 37445641.
Yarapureddy S, Abril J, Foote J, Kumar S, Asad O, Sharath V, et al. ATF6α activation enhances survival against chemotherapy and serves as a prognostic indicator in osteosarcoma. Neoplasia. 2019;21:516-32.
Tsai H-C, Huang C-Y, Su H-L, Tang C-H. CCN2 enhances resistance to cisplatin-mediating cell apoptosis in human osteosarcoma. PLoS ONE. 2014;9(3): e90159. PubMed PMID: 24637722.
Iwata S, Tatsumi Y, Yonemoto T, Araki A, Itami M, Kamoda H, et al. CDK4 overexpression is a predictive biomarker for resistance to conventional chemotherapy in patients with osteosarcoma. Oncology Reports. 2021;46:135. PubMed PMID: 34036394.
Campbell KJ, Witty JM, Rocha S, Perkins ND. Cisplatin mimics ARF tumor suppressor regulation of relA (p65) nuclear factor-κB transactivation. Cancer Res. 2006;66:929-35.
Davaadelger B, Duan L, Perez RE, Gitelis S, Maki CG. Crosstalk between the IGF-1R/AKT/mTORC1 pathway and the tumor suppressors p53 and p27 determines cisplatin sensitivity and limits the effectiveness of an IGF-1R pathway inhibitor. Oncotarget. 2016;7:27511-26.
He C, Sun J, Liu C, Jiang Y, Hao Y. Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin. Clinical Epigenetics. 2019;11:8. PubMed PMID: 30651137.
Sun X, Wei Q, Cheng J, Bian Y, Tian C, Hu Y, et al. Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells. Human Cell. 2017;30:216-25.
Kim M, Kim D. GFRA1: A novel molecular target for the prevention of osteosarcoma chemoresistance. Int J Mol Sci. 2018;19(4):1078. PubMed PMID: 29617307.
Duan L, Perez RE, Hansen M, Gitelis S, Maki CG. Increasing cisplatin sensitivity by schedule-dependent inhibition of AKT and Chk1. Cancer Biol Ther. 2014; 15:1600-12.
Dai G, Deng S, Guo W, Yu L, Yang J, Zhou S, et al. Notch pathway inhibition using DAPT, a γ‐secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma. Mol Carcinog. 2019;58:3-18.
Xi X, Bao Y, Zhou Y, Chen Y, Zhong X, Liao J, et al. Oncogenic gene TRIM10 confers resistance to cisplatin in osteosarcoma cells and activates the NF‐κB signaling pathway. Cell Biol Int. 2021;45:74-82.
Fellenberg J, Kunz P, Sähr H, Depeweg D. Overexpression of inosine 5′-monophosphate dehydrogenase type ii mediates chemoresistance to human osteosarcoma cells. PLoS ONE. 2010;5(8):e12179. PubMed PMID: 20808934.
Huang Z, Huang Y, He H, Ni J. Podocalyxin promotes cisplatin chemoresistance in osteosarcoma cells through phosphatidylinositide 3-kinase signaling. Mol Med Rep. 2015;12:3916-22.
Woessmann W, Chen X, Borkhardt A. Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. Cancer Chemother Pharmacol. 2002;50: 397-404.
Zou J, Gan M, Mao N, Zhu X, Shi Q, Yang H. Sensitization of osteosarcoma cell line SaOS-2 to chemotherapy by downregulating survivin. Arch Med Res. 2010; 41:162-9.
Zhang Z, Yu L, Dai G, Xia K, Liu G, Song Q, et al. Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells. Scientific Reports. 2017;7: 7070. PubMed PMID: 28765565.
Zhou Y, Zang X, Huang Z, Zhang C. TWIST interacts with endothelin-1/endothelin A receptor signaling in osteosarcoma cell survival against cisplatin. Oncology Lett. 2013;5:857-61.
Vianello C, Cocetta V, Catanzaro D, Dorn GW, De Milito A, Rizzolio F, et al. Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy. Cell Death Dis. 2022;13:398. PubMed PMID: 35459212.
Yang C, Gao R, Wang J, Yuan W, Wang C, Zhou X. High-mobility group nucleosome-binding domain 5 increases drug resistance in osteosarcoma through upregulating autophagy. Tumor Biol. 2014;35:6357-63.
Feng H, Zhang Q, Zhao Y, Zhao L, Shan B. Leptin acts on mesenchymal stem cells to promote chemoresistance in osteosarcoma cells. Aging. 2020;12:6340-51.
Zhan H, Xiao J, Wang P, Mo F, Li K, Guo F, et al. Exosomal CTCF confers cisplatin resistance in osteosarcoma by promoting autophagy via the IGF2-AS/miR-579-3p/MSH6 Axis. J Oncol. 2022;2022:1-18.
Huang J, Ni J, Liu K, Yu Y, Xie M, Kang R, et al. HMGB1 promotes drug resistance in osteosarcoma. Cancer Res. 2012;72:230-8.
Huang J, Liu K, Yu Y, Xie M, Kang R, Vernon PJ, et al. Targeting HMGB1-mediated autophagy as a novel therapeutic strategy for osteosarcoma. Autophagy. 2012;8:275-7.
Jiang K, Zhang C, Yu B, Chen B, Liu Z, Hou C, et al. Autophagic degradation of FOXO3a represses the expression of PUMA to block cell apoptosis in cisplatin-resistant osteosarcoma cells. Am J Cancer Res. 2017;7:1407-22.
Kim M, Jung J-Y, Choi S, Lee H, Morales LD, Koh J-T, et al. GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy. Autophagy. 2017;13:149-68.
Usman RM, Razzaq F, Akbar A, Farooqui AA, Iftikhar A, Latif A, et al. Role and mechanism of autophagy‐regulating factors in tumorigenesis and drug resistance. Asia Pac J Clin Oncol. 2021;17:193-208.
Gao S, Wang K, Wang X. miR-375 targeting autophagy-related 2B (ATG2B) suppresses autophagy and tumorigenesis in cisplatin-resistant osteosarcoma cells. Neoplasma. 2020;67:724-34.
Mukherjee S, Dash S, Lohitesh K, Chowdhury R. The dynamic role of autophagy and MAPK signaling in determining cell fate under cisplatin stress in osteosarcoma cells. PLOS ONE. 2017;12(6):e0179203. PubMed PMID: 28598976.
Xiao X, Wang W, Li Y, Yang D, Li X, Shen C, et al. HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma. J Exp Clin Cancer Res. 2018;37(1):201. PubMed PMID: 30153855
Miao X-D, Cao L, Zhang Q, Hu X-Y, Zhang Y. Effect of PI3K-mediated autophagy in human osteosarcoma MG63 cells on sensitivity to chemotherapy with cisplatin. Asian Pac J Trop Med. 2015;8:731-8.
Zhang Z, Shao Z, Xiong L, Che B, Deng C, Xu W. Expression of Beclin1 in osteosarcoma and the effects of down-regulation of autophagy on the chemotherapeutic sensitivity. J Huazhong Univ Sci Technolog Med Sci. 2009;29:737-40.
Liu B, Feng C, Liu Z, Tu C, Li Z. A novel necroptosis-related lncRNAs signature effectively predicts the prognosis for osteosarcoma and is associated with immunity. Front Pharmacol. 2022;13:944158. PubMed PMID: 36105232.
Passeri G, Northcote-Smith J, Perera R, Gubic N, Suntharalingam K. An osteosarcoma stem cell potent nickel(II)-Polypyridyl Complex Containing Flufenamic Acid. Molecules. 2022;27(10):3277. PubMed PMID: 35630754.
Li J, Yang Z, Li Y, Xia J, Li D, Li H, et al. Cell apoptosis, autophagy and necroptosis in osteosarcoma treatment. Oncotarget. 2016;7:44763-78.
Hua L, Lei P, Hu Y. Construction and validation model of necroptosis-related gene signature associates with immunity for osteosarcoma patients. Sci Rep. 2022; 12(1):15893. PubMed PMID: 36151259.
Xiao H, Jensen PE, Chen X. Elimination of osteosarcoma by necroptosis with graphene oxide-associated Anti-HER2 antibodies. Int J Mol Sci. 2019;20(18):4360. PubMed PMID: 31491952.
Sun M, Zhou C, Zeng H, Puebla‐Osorio N, Damiani E, Chen J, et al. Hiporfin‐mediated photodynamic therapy in preclinical treatment of osteosarcoma. Photochem Photobiol. 2015;91:533-44.
Coupienne I, Fettweis G, Piette J. RIP3 expression induces a death profile change in U2OS osteosarcoma cells after 5-ALA-PDT: Lasers in Surg Med. 2011;43: 557-64.
Qian C, Wu D, Du J. RIPK3 modulates sarcoma through immune checkpoint HAVCR2. Oncol Lett. 2022;24(5):381. PubMed PMID: 36238358.
Li S, Zhang T, Xu W, Ding J, Yin F, Xu J, et al. Sarcoma-targeting peptide-decorated polypeptide nanogel intracellularly delivers shikonin for upregulated osteosarcoma necroptosis and diminished pulmonary metastasis. Theranostics. 2018;8:1361-75.
Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, et al. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol. 2022;15(1):174. PubMed PMID: 36482419.
Fu Z, Deng B, Liao Y, Shan L, Yin F, Wang Z, et al. The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis. BMC Cancer. 2013;13(1):580. PubMed PMID: 24314238.
Eskandari A, Flamme M, Xiao Z, Suntharalingam K. The bulk osteosarcoma and osteosarcoma stem cell activity of a necroptosis‐inducing nickel(II)–phenanthroline complex. chembiochem. 2020;21:2854-60.
Dai W, Cheng J, Leng X, Hu X, Ao Y. The potential role of necroptosis in clinical diseases (Review). Int J Mol Med. 2021;47(5):89. PubMed PMID: 33786617
Marsh S, McLeod H, Dolan E, Shukla SJ, Rabik CA, Gong L, et al. Platinum pathway. Pharmacogenet Genomics. 2009;19:563-4.
Yang J, Bogni A, Schuetz EG, Ratain M, Dolan ME, McLeod H, et al. Etoposide pathway. Pharmacogenet Genomics. 2009;19:552-3.
Lowenberg D, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE. PharmGKB summary: ifosfamide pathways, pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2014;24:133-8.
Mikkelsen TS, Thorn CF, Yang JJ, Ulrich CM, French D, Zaza G, et al. PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics. 2011;21:679-86.
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21:440-6.
Poplin R, Ruano-Rubio V, DePristo MA, Fennell TJ, Carneiro MO, Van Der Auwera GA, et al. Scaling accurate genetic variant discovery to tens of thousands of samples [preprint]. Genomics; 2017. https://doi.org/10.1101/201178
Auwera Gvd, O’Connor BD. Genomics in the cloud: using Docker, GATK, and WDL in Terra. Sebastopol, CA: O’Reilly Media; 2020 2020. p. 467.
Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM [preprint]. Genomics; 2013. https://doi.org/10.48550/arXiv.1303.3997.
Fairley S, Lowy-Gallego E, Perry E, Flicek P. The International Genome Sample Resource (IGSR) collection of open human genomic variation resources. Nucleic Acids Res. 2020;48(D1):D941-D7.
Kutanan W, Liu D, Kampuansai J, Srikummool M, Srithawong S, Shoocongdej R, et al. Reconstructing the human genetic history of Mainland Southeast Asia: insights from genome-wide data from Thailand and Laos. Mol Biol Evol. 2021;38:3459-77.
McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GRS, Thormann A, et al. The ensembl variant effect predictor. Genome Biol. 2016;17(1):122. PubMed PMID: 27268795
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35(11):1978-80.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32:1220-2.
Boeva V, Popova T, Bleakley K, Chiche P, Cappo J, Schleiermacher G, et al. Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data. Bioinformatics. 2012;28:423-5.
Krzywinski M, Schein J, Birol İ, Connors J, Gascoyne R, Horsman D, et al. Circos: An information aesthetic for comparative genomics. Genome Res. 2009;19:1639-45.
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-D46.
Verselis SJ, Rheinwald JG, Fraumeni JF, Jr., Li FP. Novel p53 splice site mutations in three families with Li-Fraumeni syndrome. Oncogene. 2000;19:4230-5.
Shoshani O, Brunner SF, Yaeger R, Ly P, Nechemia-Arbely Y, Kim DH, et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature. 2021;591(7848):137-41.
Shao X, Lv N, Liao J, Long J, Xue R, Ai N, et al. Copy number variation is highly correlated with differential gene expression: a pan-cancer study. BMC Med Genet. 2019;20:175. PubMed PMID: 31706287.
Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, et al. An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther. 2021;1100:563-72.
Garcia-Canaveras JC, Lancho O, Ducker GS, Ghergurovich JM, Xu X, da Silva-Diz V, et al. SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia. Leukemia. 2021;35:377-88.
Bignell GR, Santarius T, Pole JC, Butler AP, Perry J, Pleasance E, et al. Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res. 2007;17:1296-303.
Lee JA, Carvalho CM, Lupski JR. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007; 131:1235-47.
Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109-13.
Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, et al. Chromothripsis from DNA damage in micronuclei. Nature. 2015;522(7555):179-84.
Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T. Chromothripsis and kataegis induced by telomere crisis. Cell. 2015;163:1641-54.
Liu P, Yuan B, Carvalho CMB, Wuster A, Walter K, Zhang L, et al. An organismal CNV mutator phenotype restricted to early human development. Cell. 2017;168:830-42 e7.
Menghi F, Barthel FP, Yadav V, Tang M, Ji B, Tang Z, et al. The tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations. Cancer Cell. 2018;34:197-210 e5.
Li Y, Roberts ND, Wala JA, Shapira O, Schumacher SE, Kumar K, et al. Patterns of somatic structural variation in human cancer genomes. Nature. 2020;578(7793):112-21.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74.
Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: Beyond the migration of single cells. J Biol Chem. 2020;295:2495-505.
Iozzo RV. Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem. 1998;67: 609-52.
Nikitovic D, Berdiaki A, Spyridaki I, Krasanakis T, Tsatsakis A, Tzanakakis GN. Proteoglycans-biomarkers and targets in cancer therapy. Front Endocrinol (Lausanne). 2018;9:69. PubMed PMID: 29559954.
Vitale D, Kumar Katakam S, Greve B, Jang B, Oh ES, Alaniz L, et al. Proteoglycans and glycosaminoglycans as regulators of cancer stem cell function and therapeutic resistance. FEBS J. 2019;286(15):2870-82.
Ahrens TD, Bang-Christensen SR, Jorgensen AM, Loppke C, Spliid CB, Sand NT, et al. The role of proteoglycans in cancer metastasis and circulating tumor cell analysis. Front Cell Dev Biol. 2020;8:749. PubMed PMID: 32984308
Mirabello L, Pfeiffer R, Murphy G, Daw NC, Patino- Garcia A, Troisi RJ, et al. Height at diagnosis and birth-weight as risk factors for osteosarcoma. Cancer Causes Control. 2011;22:899-908.
Pruksakorn D, Phanphaisarn A, Pongnikorn D, Daoprasert K, Teeyakasem P, Chaiyawat P, et al. AgeStandardized incidence rates and survival of osteosarcoma in Northern Thailand. Asian Pac J Cancer Prev. 2016;17:3455-8.
Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20:776-90.
team ACSmae. Osteosarcoma Early Detection, Diagnosis, and Staging: American Cancer Society; 2020 [updated March 1st, 2023]. [cited 2024 Mar 19]. Available from: https://www.cancer.org/cancer/types/osteosarcoma/detection-diagnosis-staging/survival-rates.html
Meazza C, Scanagatta P. Metastatic osteosarcoma: a challenging multidisciplinary treatment. Expert Rev Anticancer Ther. 2016;16:543-56.
Xie L, Xu J, Li X, Zhou Z, Zhuang H, Sun X, et al. Complete remission of metastatic osteosarcoma using combined modality therapy: a retrospective analysis of unselected patients in China. BMC Cancer. 2021;21(1):337. PubMed PMID: 33789614.
Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program. Cancer. 2009;115:1531-43.
Richardson SM, Wurtz LD, Collier CD. Ninety percent or greater tumor necrosis is associated with survival and social determinants of health in patients with osteosarcoma in the national cancer database. Clin Orthop Relat Res. 2023;481:512-22.
Dowty JG, Win AK, Buchanan DD, Lindor NM, Macrae FA, Clendenning M, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat. 2013;34:490-7.
Bonadona V, Bonaiti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304-10.
Ramsoekh D, Wagner A, van Leerdam ME, Dooijes D, Tops CM, Steyerberg EW, et al. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hered Cancer Clin Pract. 2009;7:17. PubMed PMID: 20028567.
Huang KK, Jang KW, Kim S, Kim HS, Kim SM, Kwon HJ, et al. Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck. Sci Rep. 2016;6:19552. PubMed PMID: 26790612
Huang F, Tanaka H, Knudsen BS, Rutgers JK. Mutant POLQ and POLZ/REV3L DNA polymerases may contribute to the favorable survival of patients with tumors with POLE mutations outside the exonuclease domain. BMC Med Genet. 2020;21(1):167. PubMed PMID: 32838755
Escobar-Hoyos LF, Penson A, Kannan R, Cho H, Pan CH, Singh RK, et al. Altered RNA splicing by mutant p53 activates oncogenic RAS signaling in pancreatic cancer. Cancer Cell. 2020;38:198-211 e8.
Smeby J, Sveen A, Eilertsen IA, Danielsen SA, Hoff AM, Eide PW, et al. Transcriptional and functional consequences of TP53 splice mutations in colorectal cancer. Oncogenesis. 2019;8(6):35. PubMed PMID: 31092812
Chen J, Zhang D, Qin X, Owzar K, McCann JJ, Kastan MB. DNA-Damage-Induced Alternative Splicing of p53. Cancers (Basel). 2021;13(2). PubMed PMID: 33445417
Chen Z, Guo J, Zhang K, Guo Y. TP53 mutations and survival in osteosarcoma patients: a meta-analysis of published data. Dis Markers. 2016;2016:4639575. PubMed PMID: 27239089
Ren W, Gu G. Prognostic implications of RB1 tumour suppressor gene alterations in the clinical outcome of human osteosarcoma: a meta-analysis. Eur J Cancer Care (Engl). 2017;26(1). PubMed PMID: 26503016
Zhu H, Tang J, Tang M, Cai H. Upregulation of SOX9 in osteosarcoma and its association with tumor progression and patients’ prognosis. Diagn Pathol. 2013;8:183. PubMed PMID: 24188461
Genda T, Sakamoto M, Ichida T, Asakura H, Hirohashi S. Loss of cell-cell contact is induced by integrin-mediated cell-substratum adhesion in highly-motile and highly-metastatic hepatocellular carcinoma cells. Lab Invest. 2000;80:387-94.
Christofori G. Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. EMBO J. 2003;22:2318-23.
Moh MC, Shen S. The roles of cell adhesion molecules in tumor suppression and cell migration: a new paradox. Cell Adh Migr. 2009;3:334-6.
Laubli H, Borsig L. Altered cell adhesion and glycosylation promote cancer immune suppression and metastasis. Front Immunol. 2019;10:2120. PubMed PMID: 31552050
Voronina N, Wong JKL, Hubschmann D, Hlevnjak M, Uhrig S, Heilig CE, et al. The landscape of chromothripsis across adult cancer types. Nat Commun. 2020;11(1):2320. PubMed PMID: 32385320
Zhang CZ, Leibowitz ML, Pellman D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 2013; 272513-30.
Luijten MNH, Lee JXT, Crasta KC. Mutational game changer: Chromothripsis and its emerging relevance to cancer. Mutat Res Rev Mutat Res. 2018;777:29-51.
Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789-99.
Aplan PD. Causes of oncogenic chromosomal translocation. Trends Genet. 2006;22:46-55.
Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526(7571):75-81.
Group PTC, Calabrese C, Davidson NR, Demircioglu D, Fonseca NA, He Y, et al. Genomic basis for RNA alterations in cancer. Nature. 2020;578(7793):129-36.
Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7:233-45.
Ho SS, Urban AE, Mills RE. Structural variation in the sequencing era. Nat Rev Genet. 2020;21:171-89.
van Belzen I, Schonhuth A, Kemmeren P, Hehir-Kwa JY. Structural variant detection in cancer genomes: computational challenges and perspectives for precision oncology. NPJ Precis Oncol. 2021;5(1):15. PubMed PMID: 33654267
Harbers L, Agostini F, Nicos M, Poddighe D, Bienko M, Crosetto N. Somatic copy number alterations in human cancers: an analysis of publicly available data from the cancer genome atlas. Front Oncol. 2021;11:700568. PubMed PMID: 34395272
Scott AJ, Chiang C, Hall IM. Structural variants are a major source of gene expression differences in humans and often affect multiple nearby genes. Genome Res. 2021;31:2249-57.
Ameur A, Kloosterman WP, Hestand MS. Single-molecule sequencing: towards clinical applications. Trends Biotechnol. 2019;37:72-85.
Amarasinghe SL, Su S, Dong X, Zappia L, Ritchie ME, Gouil Q. Opportunities and challenges in long-read sequencing data analysis. Genome Biol. 2020;21(1):30. PubMed PMID: 32033565
Adewale BA. Will long-read sequencing technologies replace short-read sequencing technologies in the next 10 years? Afr J Lab Med. 2020;9(1):1340. PubMed PMID: 33354530.
Chen Z, He X. Application of third-generation sequencing in cancer research. Med Rev (2021). 2021;1: 150-71.
Tongjai S, Wattanasombat S, Nantasuwan N, Thongkumkoon P, Chaiyawat P, Pruksakorn D. 3OS ChemoGenes Supplementary Data. figshare [Internet]. 2024 [cited 2024 Apr 1]. Available frome: https://doi.org/10.6084/m9.figshare.25514878.v1
