While performing a Western blot, a graduate student spilled a small amount of the radiolabeled antibody on her left forearm. Although very little harm was done to the skin, the radiation did cause minor damage to the DNA of the exposed skin by severing covalent bonds between the nitrogenous bases and the deoxyribose sugar, leaving several apurinic/apyrimidinic sites. Damaged cells would most likely repair these sites by which of the following mechanisms?

Nonhomologous end joining repair

A 35-year-old woman, gravida 2, para 2, comes to the physician with intermenstrual bleeding and heavy menses for the past 4 months. She does not take any medications. Her father died of colon cancer at the age of 42 years. A curettage sample shows dysplastic tall, columnar, cells in the endometrium without intervening stroma. Germline sequencing shows a mutation in the MLH1 gene. Which of the following is the most likely underlying cause of neoplasia in this patient?

Instability of short tandem DNA repeats

Inability to excise bulky DNA adducts

Defective checkpoint control transitions

Impaired repair of deaminated DNA bases

Accumulation of double-stranded DNA breaks

An investigator is studying DNA repair processes in an experimental animal. The investigator inactivates a gene encoding a protein that physiologically excises nucleotides from damaged, bulky, helix-distorting DNA strands. A patient with a similar defect in this gene is most likely to present with which of the following findings?

Dry skin and increased photosensitivity

Ataxic gait and facial telangiectasias

Malignant breast and ovarian growths

Leukocoria and a painful bone mass

Colorectal and endometrial cancers

A 74-year-old retired female teacher is referred to the endocrinology clinic. She is very concerned about a large mass in her neck that has progressively enlarged over the past 2 weeks. She also reports a 15 pound weight loss over the last 3 months. She now has hoarseness and difficulty swallowing her food, giving her a sensation that food gets stuck in her windpipe when she swallows. There is no pain associated with swallowing. Her speech is monotonous. No other gait or language articulation problems are noted. Testing for cranial nerve lesions is unremarkable. On palpation, a large, fixed and non-tender mass in the thyroid is noted. Cervical lymph nodes are palpable bilaterally. The patient is urgently scheduled for an ultrasound-guided fine needle aspiration to guide management. Which of the following is the most likely gene mutation to be found in this mass?

Inactivating mutation of the p53 tumor suppressor gene

Activating mutation of the Ras protooncogene

DNA repair genes and cancer for USMLE Step 2 CK: High-Yield Pathology Lessons

DNA Repair Mechanisms - The Cell's Mechanics

Mismatch Repair (MMR): Corrects replication errors (microsatellites).
- Defect → Lynch Syndrome (HNPCC).
Nucleotide Excision Repair (NER): Repairs bulky lesions (UV-induced pyrimidine dimers).
- Defect → Xeroderma Pigmentosum (XP).
Base Excision Repair (BER): Fixes single base defects (e.g., deamination).
Double-Strand Break (DSB) Repair:
- Homologous Recombination: Error-free. Defect in BRCA1/2 → Hereditary Breast/Ovarian Cancer.
- Non-Homologous End Joining: Error-prone.

⭐ Xeroderma Pigmentosum results from defective nucleotide excision repair of pyrimidine dimers formed by UV light, leading to a >1000-fold increased risk of skin cancer.

Defective Repair Syndromes - When Mechanics Go on Strike

Core Concept: Inherited defects in DNA repair genes lead to genomic instability and a significantly increased predisposition to cancer.
Key Syndromes & Associated Cancers:
- Xeroderma Pigmentosum (XP):
  - Defect: Nucleotide Excision Repair (NER).
  - Cancers: ↑ Skin cancers (melanoma, basal & squamous cell).
- Ataxia-Telangiectasia:
  - Defect: ATM gene (Non-Homologous End Joining).
  - Cancers: ↑ Leukemia, lymphoma.
- Lynch Syndrome (HNPCC):
  - Defect: Mismatch Repair (MMR).
  - Cancers: ↑ Colorectal, endometrial, ovarian.

⭐ Lynch syndrome is the most common cause of hereditary colorectal cancer.

Tumor Suppressor Genes - The Guardian Angels

Function as cellular brakes, halting proliferation. Require a "two-hit" loss of function to promote cancer (Knudson's hypothesis).
- Germline mutation (1st hit): Inherited cancer syndromes, earlier onset.
- Somatic mutations (both hits): Sporadic cancers, later onset.
Key Examples:
- TP53 (Guardian of the Genome):
  - On chromosome 17p. Halts cell cycle (G1/S) for DNA repair; triggers apoptosis.
  - Most frequently mutated gene in human cancers (>50%).
- RB1 (Retinoblastoma):
  - On chromosome 13q. Regulates G1/S checkpoint by inhibiting E2F transcription factor.
  - Associated with retinoblastoma, osteosarcoma.
- BRCA1/2:
  - Essential for repairing double-stranded DNA breaks.
  - Mutations confer high risk for breast, ovarian, and prostate cancer.

⭐ Li-Fraumeni syndrome results from a germline TP53 mutation, leading to multiple types of cancer at a young age.

High‑Yield Points - ⚡ Biggest Takeaways

Defects in DNA repair genes are a cornerstone of carcinogenesis, leading to genomic instability.

Mismatch repair defects (e.g., MSH2, MLH1) cause Lynch syndrome (HNPCC), identified by microsatellite instability.

Nucleotide excision repair defects cause Xeroderma Pigmentosum, leading to UV-induced skin cancers.

Homologous recombination defects (BRCA1, BRCA2) are linked to hereditary breast and ovarian cancer.

Non-homologous end joining defects are seen in ataxia-telangiectasia (ATM gene).

Continue reading on Oncourse

CONTINUE READING — FREE

or get the app

App Store|Google Play