A 35-year-old woman presents with a history of multiple facial papules, oral cobblestone lesions, and acral keratoses. Genetic testing reveals a germline loss-of-function mutation in the gene located at the locus marked **A** in the diagram. Which of the following best explains the molecular mechanism underlying the increased cancer predisposition in this patient?

Question

Accepted Answer

C. Loss of PTEN phosphatase activity leads to constitutive PI3K-AKT-mTOR pathway activation, promoting uncontrolled cell growth and survival. ## Why option 1 is correct

The structure marked **A** (Chromosome 10q23.3) encodes PTEN, a lipid and protein phosphatase that normally dephosphorylates PIP3 to PIP2, thereby antagonizing the PI3K/AKT/mTOR signaling axis. Germline loss-of-function mutations in PTEN cause Cowden syndrome, the prototypical PTEN hamartoma tumor syndrome (PHTS). Loss of PTEN function permits constitutive PI3K-AKT-mTOR activation, driving cell growth, survival, and proliferation—the molecular basis for the markedly elevated lifetime risks of breast cancer (≈85%), thyroid carcinoma (≈35%), endometrial carcinoma (≈28%), and other malignancies in Cowden syndrome. This mechanism is the defining pathophysiology of PHTS spectrum disorders (Harrison 21e Ch 84; NCCN PHTS Guidelines).

## Why each distractor is wrong

- **Option 2**: While p53 loss is a critical mechanism in Li-Fraumeni syndrome (TP53 mutations on chromosome 17p), it is not the primary defect in Cowden syndrome. PTEN, not p53, is mutated at chromosome 10q23.3.
- **Option 3**: Mismatch repair deficiency (MLH1, MSH2, MSH6, PMS2) causes Lynch syndrome and is associated with microsatellite instability, not Cowden syndrome. PTEN is not a mismatch repair gene.
- **Option 4**: BRCA1 mutations (chromosome 17q21) cause hereditary breast and ovarian cancer syndrome through impaired homologous recombination repair. This is a different hereditary cancer syndrome and not the genetic basis of Cowden syndrome. The locus marked **A** is chromosome 10q23.3 (PTEN), not chromosome 17q21 (BRCA1).

**High-Yield:** Cowden syndrome = PTEN loss → unopposed PI3K-AKT-mTOR activation → hamartomas + 85% breast cancer risk + thyroid/endometrial/renal cancers.

[cite: Harrison 21e Ch 84; NCCN PHTS Guidelines]

Answer

A. Mutation of the tumor suppressor gene results in loss of p53-mediated apoptosis, allowing accumulation of DNA damage

Answer

B. Defective BRCA1 function impairs homologous recombination repair, leading to chromosomal instability and cancer development

Answer

D. Inactivation of the DNA mismatch repair pathway causes microsatellite instability and increased mutation burden

Explanation

Why option 1 is correct

Why each distractor is wrong

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