An 18-year-old man is evaluated due to 3 months of lower extremity pain. The pain is persistent and present both day and night. He has no fever, chills, or history of leg trauma. Imaging shows an expansile lesion of the distal femur. Surgical resection is performed, and the specimen is shown below. Mutations involving which of the following genes are most likely present in this patient?

Question

An 18-year-old man is evaluated due to 3 months of lower extremity pain.  The pain is persistent and present both day and night.  He has no fever, chills, or history of leg trauma.  Imaging shows an expansile lesion of the distal femur.  Surgical resection is performed, and the specimen is shown below.  Mutations involving which of the following genes are most likely present in this patient?

Quizplus · Accepted Answer

11ec160b_39ed_a680_9249_a5e4fa672e45_MD0001_00 This patient's expansile tumor in the distal femur likely indicates osteosarcoma, the most common primary bone tumor affecting children and young adults. Most cases arise at the metaphysis of long bones and present with progressive pain and swelling. Osteosarcomas typically form when a mesenchymal stem cell develops mutations in the following genes: RB1 tumor suppressor gene, which encodes for RB, a protein that regulates cell-cycle progression. Inactivating mutations to RB1 promote unchecked and unregulated cellular replication and are associated with osteosarcoma, retinoblastoma, melanoma, and soft-tissue sarcomas. TP53 tumor suppressor gene, which encodes for P53, a protein that regulates cell-cycle progression and maintains genomic integrity by activating DNA repair following damage. Germ-line mutations to TP53 are associated with Li-Fraumeni syndrome, which increases the risk for multiple tumors (eg, osteosarcoma, other bone and soft-tissue sarcomas, breast cancer, brain tumors, adrenal carcinomas). (Choice A) Activating mutations of BRAF are responsible for most cases of hairy cell leukemia, a B-cell neoplasm that typically presents in older patients with pancytopenia, splenomegaly, and systemic symptoms (eg, fatigue, recurrent infections). It is also present in many cases of malignant melanoma. (Choice B) HER2, an oncogene encoding for an epidermal growth factor receptor, is amplified or overexpressed in many forms of invasive breast cancer. Treatment of the HER2 gene product can improve outcomes in these individuals. (Choice C) Activating mutations in the KRAS proto-oncogene are common in colorectal cancer and non-small cell lung cancer. KRAS encodes for a GTPase that relays cellular growth and proliferation signals from outside the cell. (Choice E) Germ-line mutations of the RET proto-oncogene cause multiple endocrine neoplasia type 2, which is associated with pheochromocytoma, medullary thyroid cancer, parathyroid hyperplasia, and/or mucosal neuromas. Educational objective: Osteosarcoma is the most common primary bone malignancy in children and young adults. It occurs most frequently at the metaphyses of long bones and presents with local pain and swelling. Most cases are associated with sporadic or inherited mutations in RB1 (hereditary retinoblastoma) and TP53 (Li-Fraumeni syndrome). __________ References: Understanding the osteosarcoma pathobiology: a comparative oncology approach. (http://www.ncbi.nlm.nih.gov/pubmed/29056713)

An 18-Year-Old Man Is Evaluated Due to 3 Months of Lower