3OS ChemoGenes Supplementary Data

Research article title: Genomic alterations in chemotherapy genes detected in three model Thai adolescent patients with fatal osteosarcoma at Maharaj Nakorn Chiang Mai Hospital, Thailand.

ABSTRACT

OBJECTIVE: Osteosarcoma is the most common primary bone malignancy among adolescents and young adults, 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 investigated the germline and tumor genomes of three primary osteosarcoma patients who responded poorly to chemotherapy, later developed lung metastases, and ultimately succumbed to the disease. Whole Genome Sequencing (WGS) data for both the germline and tumor genomes of these patients were analyzed to identify deleterious single nucleotide polymorphisms (SNPs), copy number variations (CNVs), and structural variations (SVs) in genes associated with chemotherapy and cancer. An analysis of protein association networks was performed on the affected genes of each patient to identify both common and unique biological processes associated with osteosarcoma.

RESULTS: A few pathogenic mutations were identified exclusively in patients P1 and P3. P1 exhibited a missense mutation in the PIK3CD gene and a mutation in a splice donor site of the TP53 gene. P3 was affected by more deleterious mutations, namely, a stop-gain mutation in the MLH1 gene and a frameshift mutation in the REV3L gene. The tumor genome of patient P1 was extensively affected by copy number variations (CNVs), whereas the tumor genomes of patients P2 and P3 demonstrated fewer regions with CNVs. Structural variations were detected in all three tumor genomes and affected different key genes involved in platinum drug resistance and DNA repair. All identified mutated genes were also correlated with the clinical features of the patients.

CONCLUSIONS: The genetic makeup of osteosarcoma is complex and varies from patient to patient, potentially affecting processes related to cell death or resistance to chemotherapy. Our investigations suggest that structural alterations, such as copy number variations (CNVs) and structural variations (SVs), in genes involved in chemotherapy metabolism and DNA repair mechanisms in tumor biopsies, could be useful for clinicians to design chemotherapy regimens suitable for different osteosarcoma (OS) patients.

KEYWORDS: Osteosarcoma, Genome, Single Nucleotide Polymorphisms, Copy Number Variations, Structural variations, Chemotherapy