A 35-year-old woman presents to dermatology with a history of multiple atypical moles and a family history of melanoma in her mother and maternal grandmother. Genetic testing reveals a germline mutation in the gene marked **A** (CDKN2A 9p21). Which of the following best explains the mechanism by which loss of function of this gene increases melanoma susceptibility?
A. Loss of PTEN phosphatase activity results in unopposed PI3K/AKT signaling and enhanced cell survival
B. Loss of MLH1 mismatch repair function leads to microsatellite instability and increased mutation burden
C. Loss of BRCA2 function impairs homologous recombination repair, allowing accumulation of genomic instability
D. Loss of p16INK4a and p14ARF leads to unchecked CDK4/6 activity and impaired p53-mediated apoptosis in response to DNA damage
Explanation
Why option 1 is correct
The structure marked A is CDKN2A on chromosome 9p21, which encodes two critical tumor suppressors: p16INK4a and p14ARF. p16INK4a inhibits CDK4/6 complexes, preventing phosphorylation of Rb and blocking G1-S cell cycle progression. p14ARF stabilizes p53 by inhibiting MDM2-mediated p53 degradation. Loss of both proteins in FAMMM syndrome uncouples these two key checkpoints—the G1-S checkpoint and the apoptotic response to DNA damage—allowing melanoma precursor cells to proliferate uncontrollably and escape death signals. This dual loss of function is the hallmark mechanism driving FAMMM pathogenesis (Bolognia Dermatology 5e, Ch 113).
Why each distractor is wrong
Option 2 (BRCA2): BRCA2 mutations are labeled B in the diagram and cause hereditary breast-ovarian cancer syndrome, not FAMMM. While BRCA2 does impair homologous recombination repair, it is not the gene mutated in this patient's CDKN2A-driven syndrome.
Option 3 (PTEN): PTEN mutations are labeled C and are associated with Cowden syndrome (hamartomas, breast/thyroid cancer), not FAMMM. PTEN loss does increase PI3K/AKT signaling but is not responsible for the atypical mole phenotype or FAMMM-associated melanoma risk.
Option 4 (MLH1): MLH1 mutations are labeled D and cause Lynch syndrome (colorectal and other cancers), not FAMMM. MLH1 deficiency causes microsatellite instability but does not explain the characteristic dysplastic nevi or FAMMM melanoma predisposition.
High-YieldNEET PG
CDKN2A mutations in FAMMM cause loss of both p16INK4a (G1-S checkpoint) and p14ARF (p53 stabilization), creating a "double hit" to cell cycle control and apoptosis—this dual mechanism distinguishes FAMMM from single-gene tumor suppressors like PTEN or MLH1.
Bolognia Dermatology 5e, Ch 113 Melanoma
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