Deciphering possible mechanisms of action in pathophysiology of osteosarcoma: PI3K-Akt/MAPK pathways contribute to tumorigenesis versus FoxO/mTOR/HIF-1 pathways involved in metastasis.

e23515 Background: Osteosarcoma is a kind of primary bone malignancies with high invasiveness and poor prognosis. However, effective therapy for osteosarcoma is still lacking. In fact, the advancement of clinical practice and innovative therapy was hindered by the limited understanding of the genetic characteristics and the mechanism of metastasis. Exploration of the mutational and evolutionary features of osteosarcoma is warranted. Methods: A total of 24 samples of matched primary and metastatic lesions were collected from 12 osteosarcoma patients. Targeted sequencing including 672 cancer-related genes was conducted in 9 patients while whole exome sequencing was performed in 3 patients. Results: High-frequency mutation genes were TP53 (42%), FLCN (33%), GID4 (33%), ATRX (25%), CCND3 (25%) in primary osteosarcoma, comparing to FLCN (42%), GID4 (42%), CCNE1 (25%), MYO15A (25%), ATRX (25%) in metastatic lesion. The PI3K-Akt and MAPK signaling pathway was significantly enriched in both primary (PI3K, p < 0.001; MAPK, p < 0.001) and metastatic lesions. (PI3K, p < 0.001; MAPK, p < 0.001), Additionally, chromosome region 17p11.2, including the driver genes NCOR1, MAP2K4, ALOX12B, AURKB, CDK12, was significantly amplified in primary (G-score = 1.9, q-value = 0.06) and metastatic lesions (G-score = 3.2, q-value < 0.001). These data suggested that changes of PI3K and MAPK pathways and amplification of region 17p11.2 may contribute to initial osteosarcoma tumorigenesis and possibly early metastasis. In contrast, the FoxO, mTOR and HIF-1 signaling pathway were only enriched in metastatic lesions (FOXO, p < 0.001; mTOR, p < 0.05; HIF-1, p < 0.001), implying that these pathways may be critical for osteosarcoma metastatic occurrence. Finally, clonality analysis showed that cellular clonal prevalence (CCF) of subclones including diver genes of ATRX, MYO15A and MYB, were increased ( ATRX: P, CCF = 0.59, M, CCF = 0.74; MYO15A: P, CCF = 0.43, M, CCF = 0.52; MYB: P, CCF = 0.11, M, CCF = 0.52) in metastatic lesions, which further confirmed that alterations of ATRX and MYO15A were considerably vital for osteosarcoma. Conclusions: The abnormal changes of PI3K-Akt and MAPK signaling pathway as well as the amplification of 17p11.2 chromosome region may contribute to osteosarcoma tumorigenesis and possibly early metastasis; whereas pathways of FoxO, mTOR, HIF-1 and driver genes including ATRX, MYO15A and MYB, may play a key role in the metastasis of osteosarcoma.