Which of the following genetic alterations is MOST frequently associated with small cell lung cancer?

Question

Accepted Answer

D. Loss of TP53 and RB1 (inactivation of both tumor suppressors). ## Molecular Genetics of SCLC **Key Point:** SCLC is characterized by near-universal inactivation of **two critical tumor suppressors: TP53 and RB1**. This dual loss is the defining molecular signature of SCLC. ### Genetic Landscape of SCLC | Alteration | Frequency | Significance | |------------|-----------|---------------| | TP53 inactivation | >90% | Loss of p53-mediated apoptosis and cell cycle control | | RB1 inactivation | >90% | Loss of G1/S checkpoint control | | PTEN loss | ~40% | PI3K/AKT pathway activation | | NOTCH inactivation | ~25% | Loss of differentiation signals | | EGFR mutation | <5% | Rare in SCLC (common in adenocarcinoma) | | ALK translocation | <5% | Rare in SCLC (characteristic of NSCLC) | | KRAS mutation | ~5% | Uncommon; more typical of NSCLC adenocarcinoma | **High-Yield:** The **TP53 + RB1 dual inactivation** is present in >90% of SCLC cases and is considered the molecular hallmark. This combination drives the aggressive phenotype and rapid cell cycle progression characteristic of SCLC. ### Pathogenic Mechanism 1. **TP53 loss** → Impaired apoptosis, genomic instability, loss of p21-mediated cell cycle arrest 2. **RB1 loss** → Uncontrolled G1/S transition, loss of E2F repression, increased proliferation 3. **Combined effect** → Highly aggressive tumor with rapid doubling time and early metastasis **Clinical Pearl:** SCLC is exquisitely sensitive to initial chemotherapy (platinum + etoposide) due to high apoptotic potential when TP53 is lost. However, resistance develops rapidly, explaining the poor long-term survival despite initial response. **Mnemonic:** **SCLC = TP53 + RB1 KNOCKOUT** — Remember that SCLC is defined by loss of BOTH checkpoint guardians (p53 and Rb), not just one. ![Lung Cancer — Small Cell diagram](https://mmcphlazjonnzmdysowq.supabase.co/storage/v1/object/public/blog-images/explanation/3511.webp)

Answer

A. ALK translocation t(2;5)

Answer

B. EGFR exon 19 deletion

Answer

C. KRAS G12C mutation

Which of the following genetic alterations is MOST frequently associated with small cell lung cancer?

Explanation

Molecular Genetics of SCLC

Genetic Landscape of SCLC

Pathogenic Mechanism

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Alteration	Frequency	Significance
TP53 inactivation	>90%	Loss of p53-mediated apoptosis and cell cycle control
RB1 inactivation	>90%	Loss of G1/S checkpoint control
PTEN loss	~40%	PI3K/AKT pathway activation
NOTCH inactivation	~25%	Loss of differentiation signals
EGFR mutation	<5%	Rare in SCLC (common in adenocarcinoma)
ALK translocation	<5%	Rare in SCLC (characteristic of NSCLC)
KRAS mutation	~5%	Uncommon; more typical of NSCLC adenocarcinoma