Neoplasia: synthetic lethality and DNA repair: practice question

A Pathology question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Pathology · Neoplasia: synthetic lethality and DNA repair

Sample item

A 55-year-old woman has high-grade serous ovarian carcinoma with a germline BRCA1 mutation. After a response to platinum chemotherapy, maintenance olaparib is advised. What explains the selective killing of her tumour cells by this drug?

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

D. Unrepaired single-strand breaks become double-strand breaks that BRCA-deficient cells cannot repair

BRCA1 and BRCA2 are needed for homologous recombination repair of double-strand breaks. PARP inhibitors block base excision repair of single-strand breaks, which then collapse into double-strand breaks at replication forks. Normal cells repair these by homologous recombination, but BRCA-deficient tumour cells cannot, an example of synthetic lethality.

Option by option

  • A. Inhibition of thymidylate synthase, which starves dividing cells of thymidine

    Thymidylate synthase inhibition describes 5-fluorouracil and similar antimetabolites and is not the action of olaparib.

  • B. Inhibition of topoisomerase I, which traps cleavage complexes during replication

    Topoisomerase I inhibition describes irinotecan and topotecan.

  • C. Stabilisation of microtubules, which arrests dividing cells in metaphase

    Microtubule stabilisation describes taxanes such as paclitaxel.

  • D. Unrepaired single-strand breaks become double-strand breaks that BRCA-deficient cells cannot repair (correct)

    Combining PARP inhibition with homologous recombination deficiency is lethal to the tumour cells while sparing BRCA-proficient normal cells.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

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Questions about this Pathology question

What is the answer to this Pathology question?

The best answer is D, Unrepaired single-strand breaks become double-strand breaks that BRCA-deficient cells cannot repair. BRCA1 and BRCA2 are needed for homologous recombination repair of double-strand breaks.

Why is "Inhibition of thymidylate synthase, which starves dividing cells of t…" not the answer?

Thymidylate synthase inhibition describes 5-fluorouracil and similar antimetabolites and is not the action of olaparib.

Why is "Inhibition of topoisomerase I, which traps cleavage complexes during…" not the answer?

Topoisomerase I inhibition describes irinotecan and topotecan.

Why is "Stabilisation of microtubules, which arrests dividing cells in metaph…" not the answer?

Microtubule stabilisation describes taxanes such as paclitaxel.

What concept does this question test?

It tests Neoplasia: synthetic lethality and DNA repair in Pathology. PARP inhibitors block base excision repair of single-strand breaks, which then collapse into double-strand breaks at replication forks. Normal cells repair these by homologous recombination, but BRCA-deficient tumour cells cannot, an example of synthetic lethality.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Neoplasia: synthetic lethality and DNA repair?

Learn each disease as a bundle: cause, key histology, markers, and the clinical hallmark. Then use the flashcards and the other Pathology questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.