A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma.
Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points. We compared variant calls and variant allele frequencies between different samples. We identified subclonal mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on the functional significance of such clones and strategies to eliminate them.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;; Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USA;
Kenneth S
KS
Chen
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea;
Woo Sun
WS
Kwon
Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Jiwoong
J
Kim
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea;
Su Jin
SJ
Heo
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea;
Hyo Song
HS
Kim
Celemics Inc., Seoul, Republic of Korea;
Hyo Ki
HK
Kim
Department of Pathology, Yonsei University College of Medicine, Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul, Republic of Korea;
Soo Hee
SH
Kim
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea;
Won Suk
WS
Lee
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea;; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea;; Brain Korea 21 Project for Medical Sciences, Seoul, Republic of Korea.
Hyun Cheol
HC
Chung
Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea;; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea;; Brain Korea 21 Project for Medical Sciences, Seoul, Republic of Korea.
Sun Young
SY
Rha
Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
Tae Hyun
TH
Hwang
neoplasm of the skeletal system; osteosarcoma