A 14-year-old boy presents with recurrent episodes of abdominal pain and iron-deficiency anemia. On examination, he has characteristic dark brown to blue-black macules on his lips and buccal mucosa. Genetic testing reveals a heterozygous loss-of-function mutation in the gene located at the locus marked **A** in the diagram. Which of the following best describes the molecular consequence of this mutation in Peutz-Jeghers syndrome?
A. Loss of PTEN phosphatase activity, causing unopposed PI3K/AKT pathway activation
B. Loss of APC tumor suppressor function, resulting in uncontrolled Wnt/β-catenin signaling
C. Loss of STK11/LKB1 serine/threonine kinase function, leading to dysregulated AMPK signaling and mTOR pathway activation
D. Loss of SMAD4 signaling, impairing TGF-β pathway regulation and cell differentiation
Explanation
Why "Loss of STK11/LKB1 serine/threonine kinase function, leading to dysregulated AMPK signaling and mTOR pathway activation" is right
The locus marked A (19p13.3) is the STK11/LKB1 gene, which encodes a serine/threonine kinase that activates AMPK and regulates cell polarity, energy metabolism, and the mTOR pathway. Germline heterozygous loss-of-function mutations in STK11 cause Peutz-Jeghers syndrome in ~70–80% of cases. Loss of STK11 function directly leads to dysregulated AMPK signaling and unopposed mTOR pathway activation, which drives the characteristic hamartomatous polyp formation and tissue overgrowth seen in PJS. This molecular mechanism is the pathogenic basis of the syndrome and directly explains the clinical phenotype of mucocutaneous pigmentation and gastrointestinal hamartomas (ACG Guidelines on Hereditary Cancer Syndromes 2022).
Why each distractor is wrong
Loss of APC tumor suppressor function, resulting in uncontrolled Wnt/β-catenin signaling: APC mutations cause familial adenomatous polyposis (FAP), not Peutz-Jeghers syndrome. APC is located at 5q22.2 (marked B), not 19p13.3. While both are polyposis syndromes, their molecular mechanisms and clinical features differ fundamentally.
Loss of SMAD4 signaling, impairing TGF-β pathway regulation and cell differentiation: SMAD4 mutations are associated with juvenile polyposis syndrome (JPS), located at 18q21.2 (marked C). Although JPS also presents with hamartomatous polyps, the molecular mechanism and cancer risk profile differ from PJS, and SMAD4 is not the gene at locus A.
Loss of PTEN phosphatase activity, causing unopposed PI3K/AKT pathway activation: PTEN mutations cause Cowden syndrome and other PTEN-related disorders, located at 10q23.31 (marked D). While PTEN loss does dysregulate PI3K/AKT signaling, this is not the pathogenic mechanism in Peutz-Jeghers syndrome, which is caused by STK11 mutations.
High-YieldNEET PG
STK11/LKB1 loss → AMPK dysregulation + mTOR activation → hamartoma formation + mucocutaneous lentigines + 85–93% lifetime cancer risk (especially GI, breast, and gynecologic malignancies in PJS).
ACG Guidelines on Hereditary Cancer Syndromes 2022
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