WBR0277

Author	[[PageAuthor::Ogheneochuko Ajari, MB.BS, MS [1] (Reviewed by Yazan Daaboul, M.D. and Alison Leibowitz [2])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics, MainCategory::Pathology
Sub Category	SubCategory::Oncology
Prompt	[[Prompt::An 17-year-old man presents to the physician's office with complaints of bone pain and swelling over the right leg just above the knee. He has progressively lost weight over the past 2 months. His medical history indicates that he was treated for eye cancer at infancy. Which of the following genes is most likely responsible for this patient's condition?]]
Answer A	AnswerA::''TP16''
Answer A Explanation	AnswerAExp::The ''TP16'' tumor suppressor gene encodes cyclin-dependent kinase inhibitor 2A. ''TP16'' mutations are associated with development of melanoma.
Answer B	AnswerB::''RB'' gene
Answer B Explanation	AnswerBExp::''RB'' gene mutations are implicated in the tumorigenesis of osteosarcoma and retinoblastoma.
Answer C	AnswerC::''L-MYC'' gene
Answer C Explanation	AnswerCExp::The ''L-MYC'' gene is a proto-oncogene that encodes a transcription factor. Mutations of ''L-MYC'' are associated with subsets of small cell lung carcinoma (SCLC) and ovarian cancer.
Answer D	AnswerD::''ABL'' gene
Answer D Explanation	[[AnswerDExp::BCR-ABL gene fusion is associated with chronic myeloid leukemia (CML).]]
Answer E	AnswerE::''RET'' gene
Answer E Explanation	[[AnswerEExp::The RET proto-oncogene is associated with multiple endocrine neoplasia (MEN) syndromes types 2A and 2B.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::Osteosarcoma is a bone tumor that is associated with mutations in the P53 and RB tumor suppressor genes. TP53 gene mutations may be present in up to 50% of cancers in general and approximately 20% of osteosarcomas. Li-Fraumeni syndrome is an autosomal dominant disorder that is characterized by TP53 mutations and predisposition to cancers, classically osteosarcoma. RB is also a tumor suppressor gene that encodes Rb protein. Rb binds to transcription factors and has a role in the regulation of the cell-cycle by binding to the transcription factor E2F, which is only activated when the CDK4/cyclin D complex phosphorylates Rb protein. RB gene mutations are implicated in the tumorigenesis of osteosarcoma and retinoblastoma. In this vignette, the patient's history of eye cancer at infancy and development of a bone tumor during puberty should raise the suspicion of RB gene mutation that accounts for the development of both retinoblastoma and osteosarcoma. Inactivation of the RB suppressor gene may be inherited as an autosomal dominant trait or it may occur sporadically. When osteosarcoma is inherited, one of the alleles on chromosome 13 is inactivated in utero. After birth, only one additional mutation can occur on the remaining allele that results in cancer (called the one-hit theory), increasing the patient's risk of developing a retinoblastoma, the most common malignancy of the eye in children. Osteosarcoma usually affects adolescents and young adults at the time of puberty. Typically, it presents as a heterogeneous bone mass that develops within the medullary cavities of the metaphyseal region of long bones (femur, tibia, and humerus). Although genetic disorders are well-described and account for the majority of cases of osteosarcoma, environmental risk factors, such as high-dose radium, methycholanthrene, chromium, beryllium, and asbestos exposure, have also been associated with the development of osteosarcoma. Educational Objective: Germline and somatic mutations of RB tumor suppressor gene in chromosome 13 are associated with osteosarcoma and retinoblastoma. References: First Aid 2014 page 232]]
Approved	Approved::Yes
Keyword	WBRKeyword::RB, WBRKeyword::Mutation, WBRKeyword::Chromosome 13, WBRKeyword::Osteosarcoma, WBRKeyword::Retinoblastoma, WBRKeyword::Bone tumor, WBRKeyword::Bone mass, WBRKeyword::Eye cancer
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