WBR0278

Author	[[PageAuthor::Ogheneochuko Ajari, MB.BS, MS [1] (Reviewed by Alison Leibowitz)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics, MainCategory::Pathology
Sub Category	SubCategory::Oncology, SubCategory::Renal
Prompt	[[Prompt::A 2-year-old boy is brought to the ER by his mother for bloody urine and abdominal pain. Upon physical examination, the physician palpates a large abdominal mass on the right flank. An abdominal X-ray reveals a large soft tissue opacity displacing the bowel. CT scan displays heterogeneous soft tissue masses with frequent areas of calcifications and fatty regions. On MRI, the tumor appears heterogeneous on all sequences. Which one of the following genetic alterations is most likely responsible for this patient's presentation?]]
Answer A	AnswerA::Mutation of WT1 gene on chromosome 11p11
Answer A Explanation	AnswerAExp::Nephroblastoma (Wilm's tumor) is often caused by mutation or deletion of WT1, the eponymously named Wilm's Tumor 1 gene.
Answer B	AnswerB::Mutation of TSC2
Answer B Explanation	[[AnswerBExp::TSC2 is a tumor suppressor in the MTOR pathway. Mutations in TSC2 cause tuberous sclerosis, which is characterized by the growth of benign tumors in the brain, skin, kidneys and other organs.]]
Answer C	AnswerC::Mutation of VHL
Answer C Explanation	[[AnswerCExp::The VHL gene encodes a ubiquitin-ligase responsible for increasing the degradation of Hypoxia-Inducible Factor (HIF), a transcription factor that increases the transcription of a variety of gene products including Vascular Endothelial Growth Factor. When the VHL gene is inactivated, HIF activity increases uncontrolled and initiates tumor formation in kidney cells. Germline mutations in the Von-Hippau-Lindau (VHL) tumor suppressor gene cause the Von-Hippau-Lindau cancer predisposition syndrome.]]
Answer D	AnswerD::Deletion of chromosome 11p15.5
Answer D Explanation	[[AnswerDExp::Deletion of chromosome 11p15.5 is associated with Beckwith-Wiedemann syndrome. The causal gene in the regions is unknown but may include CDKN1C, H19 or IGF-2.]]
Answer E	AnswerE::t(2;13) translocation
Answer E Explanation	[[AnswerEExp::A t(2;13) translocation is associated with rhabdomyosarcoma. This translocation fuses he FOXO1 gene from chromosome 13 and the PAX3 gene from chromosome 2 (not high-yield for the USMLE).]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::The patient in this scenario has nephroblastoma (Wilms tumor), a pediatric kidney cancer that arises from pluripotent embryonic renal progenitor cells. Nephroblastoma often manifests as a huge palpable flank mass and/or hematuria. Nephroblastoma is the most common renal malignancy that occurs in early childhood (ages 2-4 years). Both germline and somatic cases of nephroblastoma are associated with inactivation mutations or deletions of the WT1 gene on chromosome 11p. This gene encodes a transcription factor that normally functions in the differentiation of renal and genitourinary tissue. Nephroblastoma may be part of Denys-Drash syndrome or the WAGR complex: Wilms’ tumor, Aniridia, Genitourinary malformation, and mental-motor Retardation. Wilm's tumor is highly responsive to treatment with surgery, radiation and chemotherapy (protocol DD-4A). Educational Objective: Nephroblastoma (Wilms tumor) is associated with the deletion of WT1 genes on chromosome 11p11. References: Lee SB, Haber DA. Wilms tumor and the WT1 gene. Exp Cell Res. 2001;264(1):74-99. Nakamura L, Ritchey M. Current management of wilms' tumor. Curr Urol Rep. 2010;11(1):58-65. First Aid 2014 page 541]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Tumor, WBRKeyword::Wilm's tumor, WBRKeyword::Childhood cancer, WBRKeyword::Pediatric cancer, WBRKeyword::Nephroblastoma, WBRKeyword::Genetics, WBRKeyword::Cancer genetics
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