A 16-year-old boy presents with hundreds of colorectal adenomatous polyps discovered on screening sigmoidoscopy. Genetic testing confirms a germline mutation in the gene marked **A** on the diagram. His father had undergone prophylactic colectomy at age 18 and has characteristic osteomas of the mandible and skull, along with multiple epidermoid cysts. Which of the following best explains the molecular consequence of loss of function of the gene at **A**?
A. Inactivation of the menin protein, disrupting MEN1-associated tumor suppression and causing neuroendocrine proliferation
B. Impaired BRCA1-mediated homologous recombination repair, causing genomic instability and early-onset breast/ovarian malignancy
C. Failure to phosphorylate and degrade β-catenin, leading to its nuclear accumulation and transcriptional activation of proliferation genes
D. Loss of mismatch repair capacity, resulting in microsatellite instability and hypermethylation of CpG islands
Explanation
Why option 1 is correct
The gene at A (chromosome 5q21-q22) is APC, a key negative regulator of the WNT/β-catenin signaling pathway. APC normally functions as part of a "destruction complex" with AXIN, GSK3β, and CK1 that phosphorylates β-catenin and targets it for ubiquitin-mediated proteasomal degradation. Loss of APC function eliminates this degradation pathway, allowing β-catenin to accumulate in the cytoplasm, translocate to the nucleus, and activate transcription of TCF/LEF target genes (MYC, CYCLIN D1), driving unchecked proliferation of intestinal crypt epithelium. This explains the development of hundreds to thousands of adenomatous polyps in Gardner syndrome/FAP. (Bailey & Love 28e; Robbins 10e Ch 17)
Why each distractor is wrong
Option 2: This describes the mechanism of MLH1 (chromosome 3p21, marked B), a mismatch repair gene whose loss causes Lynch syndrome (hereditary nonpolyposis colorectal cancer) with microsatellite instability. MLH1 mutations do not cause the characteristic extra-intestinal manifestations (osteomas, desmoids, CHRPE) seen in Gardner syndrome.
Option 3: This describes BRCA1 (chromosome 17q21, marked C), which mediates homologous recombination repair. BRCA1 mutations cause hereditary breast and ovarian cancer syndrome, not familial adenomatous polyposis or Gardner syndrome.
Option 4: This describes MEN1 (chromosome 11q13, marked D), which encodes the menin protein and causes multiple endocrine neoplasia type 1 (parathyroid, pancreatic, pituitary tumors). MEN1 mutations do not cause adenomatous polyposis or the Gardner phenotype.
