Gastrointestinal: Lynch syndrome: 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 · Gastrointestinal: Lynch syndrome

Sample item

A 38-year-old man has a caecal adenocarcinoma. His father and paternal uncle had colon cancer in their forties. Immunohistochemistry on the tumour shows loss of MSH2 and MSH6 with retained MLH1 and PMS2. What is the best interpretation?

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

The answer and the reasoning

C. Likely Lynch syndrome from a germline MSH2 mutation, so germline testing is indicated

Lynch syndrome is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2, leading to microsatellite instability. MSH2 pairs with MSH6 and MLH1 with PMS2, so loss of MSH2 and MSH6 together points to MSH2 as the primary defect. Sporadic mismatch repair loss usually involves MLH1 and PMS2 through promoter methylation, so this pattern with family history calls for germline testing.

Option by option

  • A. Chromosomal instability pathway driven by biallelic APC loss

    APC loss causes microsatellite-stable adenomas in familial adenomatous polyposis, and the stains do not test for it.

  • B. Tumour with intact mismatch repair, so no genetic referral is needed

    Loss of two mismatch repair proteins means repair is deficient, not intact.

  • C. Likely Lynch syndrome from a germline MSH2 mutation, so germline testing is indicated (correct)

    Correct. Paired MSH2 and MSH6 loss with this family history indicates Lynch syndrome.

  • D. Sporadic cancer from MLH1 promoter hypermethylation

    Methylation of the MLH1 promoter gives 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 C, Likely Lynch syndrome from a germline MSH2 mutation, so germline testing is indicated. Lynch syndrome is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2, leading to microsatellite instability.

Why is "Chromosomal instability pathway driven by biallelic APC loss" not the answer?

APC loss causes microsatellite-stable adenomas in familial adenomatous polyposis, and the stains do not test for it.

Why is "Tumour with intact mismatch repair, so no genetic referral is needed" not the answer?

Loss of two mismatch repair proteins means repair is deficient, not intact.

Why is "Sporadic cancer from MLH1 promoter hypermethylation" not the answer?

Methylation of the MLH1 promoter gives loss of MLH1 and PMS2, not MSH2 and MSH6.

What concept does this question test?

It tests Gastrointestinal: Lynch syndrome in Pathology. MSH2 pairs with MSH6 and MLH1 with PMS2, so loss of MSH2 and MSH6 together points to MSH2 as the primary defect. Sporadic mismatch repair loss usually involves MLH1 and PMS2 through promoter methylation, so this pattern with family history calls for germline testing.

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 Gastrointestinal: Lynch syndrome?

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.