Neoplasia: DNA mismatch repair defects: 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: DNA mismatch repair defects

Sample item

A 38-year-old man has adenocarcinoma of the caecum. His mother had endometrial carcinoma at 45 and a maternal uncle had colon cancer at 50. Tumour immunohistochemistry shows loss of MSH2 and MSH6 with retained MLH1 and PMS2. What is the most likely underlying defect?

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

The answer and the reasoning

A. Germline mismatch repair gene mutation causing microsatellite instability

Lynch syndrome is caused by germline mutation in a mismatch repair gene, most often MLH1 or MSH2, and leads to microsatellite instability. Loss of MSH2 with its partner MSH6 on immunohistochemistry points to an MSH2 defect. Sporadic MLH1-deficient tumours usually show BRAF V600E and MLH1 promoter methylation.

Option by option

  • A. Germline mismatch repair gene mutation causing microsatellite instability (correct)

    A germline mismatch repair defect fits the family pattern and the MSH2 and MSH6 loss.

  • B. Defective nucleotide excision repair of pyrimidine dimers

    Defective nucleotide excision repair is the basis of xeroderma pigmentosum, with UV-related skin cancers.

  • C. Germline APC mutation with hundreds of adenomatous polyps

    Familial adenomatous polyposis from APC mutation presents with hundreds of polyps and is not characterised by mismatch repair loss.

  • D. Somatic BRAF V600E with MLH1 promoter hypermethylation

    BRAF V600E with MLH1 methylation causes sporadic tumours with loss of MLH1 and PMS2, not MSH2 and MSH6.

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 A, Germline mismatch repair gene mutation causing microsatellite instability. Lynch syndrome is caused by germline mutation in a mismatch repair gene, most often MLH1 or MSH2, and leads to microsatellite instability.

Why is "Defective nucleotide excision repair of pyrimidine dimers" not the answer?

Defective nucleotide excision repair is the basis of xeroderma pigmentosum, with UV-related skin cancers.

Why is "Germline APC mutation with hundreds of adenomatous polyps" not the answer?

Familial adenomatous polyposis from APC mutation presents with hundreds of polyps and is not characterised by mismatch repair loss.

Why is "Somatic BRAF V600E with MLH1 promoter hypermethylation" not the answer?

BRAF V600E with MLH1 methylation causes sporadic tumours with loss of MLH1 and PMS2, not MSH2 and MSH6.

What concept does this question test?

It tests Neoplasia: DNA mismatch repair defects in Pathology. Loss of MSH2 with its partner MSH6 on immunohistochemistry points to an MSH2 defect. Sporadic MLH1-deficient tumours usually show BRAF V600E and MLH1 promoter methylation.

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: DNA mismatch repair defects?

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.