A 58-year-old man with squamous cell carcinoma of the lung develops hypercalcemia, not explained by bone metastasis. Serum PTH-related protein (PTHrP) is markedly elevated. Which molecular mechanism best explains why squamous carcinomas — but not adenocarcinomas — characteristically produce PTHrP?
- A Amplification of the PTHrP gene located on chromosome 12p
- B Activation of the SOX2 transcription factor in squamous differentiation programs that upregulate PTHrP transcription ✓
- C Loss of PTEN leading to PI3K/Akt signalling that directly induces PTHrP secretion
- D EGFR exon 19 deletions present selectively in squamous carcinoma driving PTHrP expression
Correct answer: B. Activation of the SOX2 transcription factor in squamous differentiation programs that upregulate PTHrP transcription
Explanation
SOX2 is a key transcription factor amplified and activated in squamous cell carcinomas that drives the squamous differentiation program; part of this program includes transcriptional upregulation of PTHrP, explaining the characteristic association of humoral hypercalcemia of malignancy with squamous histology. PTHrP gene amplification is not a recognized driver. EGFR exon 19 deletions are characteristic of adenocarcinoma, not squamous. PTEN loss is a broad event not specific to squamous-PTHrP linkage.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.