WBR0121

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Reproductive, SubCategory::General Principles
Prompt	[[Prompt::A 56-year-old woman presents to her primary care physician complaining of abdominal pain, bloating, and early satiety. She explains that these symptoms have been increasing in severity over the past several weeks. The physician notes mild tenderness with palpation on abdominal exam. The patient is then referred to an OB/GYN specialist where a pelvic exam is performed. Pelvic exam reveals a large left adnexal mass. Laboratory studies are significant for elevated CA-125 blood levels. Abdominopelvic CT scan reveals a large left ovarian solid mass that extends to the omentum. The patient undergoes total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO). After resection, the pathologist makes the diagnosis of high-grade serous ovarian adenocarcinoma. Sanger DNA sequencing of the TP53 gene reveals a single mutation pictured in the chromatogram below. Which of the following is the most appropriate term for the molecular effect of this mutation?]]
Answer A	AnswerA::Loss of heterozygosity
Answer A Explanation	AnswerAExp::While loss of heterozygosity is a term commonly used with tumor suppressors, the mutation in this case is heterozygous.
Answer B	AnswerB::Dominant negative mutation
Answer B Explanation	[[AnswerBExp::A dominant negative mutation refers to a mutation whose gene product negates the function of its normal, wild-type counterpart.]]
Answer C	AnswerC::Epistasis
Answer C Explanation	[[AnswerCExp::Epistasis is a phenomenon in which the expression of one gene depends on the presence of other "modifier genes(s)". Both genes interact to control a single phenotype.]]
Answer D	AnswerD::Haploinsufficiency
Answer D Explanation	[[AnswerDExp::While mutation of one allele causes disease, the molecular mechanism of the mutation observed in this vignette is not simply attributed haploinsufficiency, a decreased function of the monomeric gene product. In this case, the mutant protein interferes with the function of another wild-type gene]]
Answer E	AnswerE::Loss-of-function
Answer E Explanation	AnswerEExp::While the observed mutation may cause the protein to lose some of its biological function, it does so in a dominant negative manner. Loss-of-function mutations typically act in a recessive manner at the molecular level.
Right Answer	RightAnswer::B
Explanation	[[Explanation::The TP53 gene encodes the p53 protein, the most commonly disrupted tumor suppressor in human cancer. p53 is a transcriprtional activator that controls cell fate and initiates cell cycle arrest, senescence, and apoptosis. Mutations of p53 usually affect the core domain that binds to DNA and exhibit dominant negative effect of the mutant allele on the wild-type allele. In this vignette, the Sanger sequencing chromatogram demonstrates a heterozygous mutation, meaning that one copy of the TP53 gene is mutated and the other is not. A heterozygous mutation which leads to a phenotype (in this case cancer) is an example of a dominant negative mutation. Unlike mutations of other tumor suppressors, a mutation of a single TP53 allele leads to a significant loss-of-function effect due to the dominant negative effect of the mutant allele that disrupts the effect of the normal wild-type allele. On the molecular level, the p53 protein normally forms a homotetramer, a hollow skewed cube that binds to specific DNA regions at the level of p53 core domains. One hypothesis suggests that when one mutant TP53 allele joins the wild-type homotetramer, the homotetramer is heterotetramerized; and the wild-type p53 loses its conformation and is inactivated. Thus, one mutated allele causes the p53 protein to lose approximately 15/16 of its biological function. On the other hand, a deletion of p53 would cause only a 50% decrease in its biological function. For this reason, p53 is more likely to be mutated than deleted in cancers. Mutations of the TP53 gene are detected in approximately 95% of ovarian cancers and dominant negative mutations compose a majority of these mutations. Educational Objective: A dominant negative mutation refers to a mutation whose gene product negates the function of its normal, wild-type counterpart. Mutant TP53 mutations are found in 95% of ovarian cancers. References: Aramayo R, Sherman MB, Brownless K, et al. Quaternary structure of the specific p53-DNA complex reveals the mechanism of p53 mutant dominance. Nucleic Acids Res. 2011;39(20):8960-71 Willis A, Jung EJ, Wakefield T, et al. Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes Oncogene. 2004;23:2330-2338 First Aid 2014 page 76]]
Approved	Approved::Yes
Keyword	WBRKeyword::Mutation, WBRKeyword::Genetics, WBRKeyword::Dominant, WBRKeyword::Negative, WBRKeyword::Dominant negative, WBRKeyword::Homotetramer, WBRKeyword::Heterotetramer, WBRKeyword::Ovarian, WBRKeyword::Cancer, WBRKeyword::Adenocarcinoma, WBRKeyword::Adnexal, WBRKeyword::Mass, WBRKeyword::Adnexal, WBRKeyword::mass, WBRKeyword::OB/GYN, WBRKeyword::Haploinsufficiency, WBRKeyword::Epistatis, WBRKeyword::Epigenetics, WBRKeyword::Loss of function, WBRKeyword::Loss of heterozygosity, WBRKeyword::Mutation, WBRKeyword::Tumor suppressor gene, WBRKeyword::Tumor suppressor, WBRKeyword::Apoptosis, WBRKeyword::Cell cycle arrest, WBRKeyword::Cell cycle, WBRKeyword::p53, WBRKeyword::TP53
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