TY - JOUR

T1 - SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma

AU - Sakthikumar, Sharadha

AU - Elvers, Ingegerd

AU - Kim, Jaegil

AU - Arendt, Maja L.

AU - Thomas, Rachael

AU - Turner-Maier, Jason

AU - Swofford, Ross

AU - Johnson, Jeremy

AU - Schumacher, Steven E.

AU - Alfoldi, Jessica

AU - Axelsson, Erik

AU - Couto, C. Guillermo

AU - Kisseberth, William C.

AU - Pettersson, Mats E.

AU - Getz, Gad

AU - Meadows, Jennifer R. S.

AU - Modiano, Jaime F.

AU - Breen, Matthew

AU - Kierczak, Marcin

AU - Forsberg-Nilsson, Karin

AU - Marinescu, Voichita D.

AU - Lindblad-Toh, Kerstin

PY - 2018

Y1 - 2018

N2 - Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.

AB - Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.

U2 - 10.1158/0008-5472.CAN-17-3558

DO - 10.1158/0008-5472.CAN-17-3558

M3 - Journal article

C2 - 29724721

VL - 78

SP - 3421

EP - 3431

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 13

ER -