WBR0277

Author	[[PageAuthor::Ogheneochuko Ajari, MB.BS, MS [1] (Reviewed by Yazan Daaboul, M.D. and Will Gibson)]]
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 as an infant. Which of the following genes is most likely responsible for this patient's condition?]]
Answer A	AnswerA::''CDKN2A''
Answer A Explanation	AnswerAExp::The ''CDKN2A'' tumor suppressor gene encodes cyclin-dependent kinase inhibitor 2A. ''CDKN2A'' mutations are associated with familial 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::''FLCN'' gene
Answer C Explanation	[[AnswerCExp::The FLCN gene encodes the folliculin protein, so named for the benign hair-follicle tumors that arise in Birt-Hogg Dubé patients who harbor a germline mutation of the FLCN gene. Folliculin is thought to negatively regulate mTOR signaling in the absence of amino acids. When folliculin is absent, mTOR activity is upregulated and benign skin lesions are formed. As of 2015, FLCN is not high-yield for USMLE Step 1.]]
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. The Rb protein is the central node that controls cell cycle progression through the G1/S checkpoint. In the presence of DNA damage or insufficient mitogens, Rb protein will forestall cell division. Rb normally enforces its role at the "restriction point" by binding to and sequestering the transcription factor E2F. Upon phosphorylation by the CDK4/cyclin D complex, Rb protein releases its grip on E2F and allows for transcription of a set of genes essential for cell cycle progression. 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 retinoblastoma is inherited, one of the alleles on chromosome 13 is inactivated in utero. After birth, only one additional mutation must occur on the remaining allele to fully ablate the gene's normal activity (called the one-hit theory). 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. It is thought that RB gene inactivation occurs in about 50% of sporadic tumors as well. Educational Objective: Germline and somatic mutations of RB tumor suppressor gene in chromosome 13 are associated with osteosarcoma and retinoblastoma. References: Broadhead ML, Clark JC, Myers DE, et al. The molecular pathogenesis of osteosarcoma: a review. Sarcoma. 2011;Article ID 959248,12 pages. Tsun ZY, Bar-peled L, Chantranupong L, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52(4):495-505. 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, WBRKeyword::RB1
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