Molecular and Genetics: Practice Question

A patient is diagnosed with a gastrointestinal stromal tumor (GIST). Molecular analysis reveals wild-type CKIT and PDGFRA alleles. Which of the following genes is most likely mutated in this patient?
  1. STK11
  2. RET
  3. CDH1
  4. PRKAR1A
  5. SDHB
Show Answer and Explanations

STK11

Incorrect. The product of STK11 is serine/threonine kinase 11. Germline mutations are seen in Peutz-Jeghers syndrome (Peutz-Jeghers polyps, mucocutaneous pigmentation, sex cord tumor with annular tubules, calcifying Sertoli cell tumor, adenoma malignum).

RET

Incorrect. RET is a proto-oncogene encoding a receptor tyrosine kinase involved in cell signaling. It is mutated in MEN2a (medullary thyroid carcinoma, pheochromocytoma, parathyroid adenoma/hyperplasia) and MEN2b (medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas/paragangliomas). It may also be mutated in a variety of other malignancies.

CDH1

Incorrect. CDH1 is the gene that encodes for E-cadherin. Mutations are seen in diffuse gastric carcinoma and lobular breast carcinoma. Germline mutations are seen in hereditary gastric diffuse cancer.

PRKAR1A

Incorrect. PRKAR1A encodes for protein kinase A. PRKAR1A germline mutations are seen in Carney complex, which is associated with myxomas, lentiginous skin pigmentation, and endocrine disorders (asymptomatic growth hormone, primary pigmented nodular adrenocortical disease, large cell calcifying Sertoli cell tumor).

SDHB — Correct answer

Correct. SDHB encodes a subunit of succinate dehydrogenase. It is the most common gene deficiency in CKIT/PDGFRA wild-type GISTs. It is associated with Carney-Stratakis syndrome (SDHB mutation resulting in GISTs and extra-adrenal paragangliomas) and Carney triad (SDHB promoter hypermethylation resulting in GISTs, pulmonary chondromas, and extra-adrenal paragangliomas). SDH-deficient GISTs are often not responsive tyrosine kinase inhibitor therapy.

Summary

Summary: SDHB is the most common gene mutation in CKIT/PDGFRA wild-type GISTs. SDH-deficient GISTs are seen in Carney-Stratakis syndrome (SDHB mutation resulting in GISTs and extra-adrenal paragangliomas) and Carney triad (SDHB promoter hypermethylation resulting in GISTs, pulmonary chondromas, and extra-adrenal paragangliomas). SDH-deficient GISTs are often not responsive tyrosine kinase inhibitor therapy.
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