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Difficulty: MediumGenetic and Molecular Mechanisms

A 45-year-old woman undergoes a hemicolectomy for a newly diagnosed right-sided colon adenocarcinoma. Her family history is significant for a mother who had endometrial cancer at age 49. The physician suspects Lynch syndrome (hereditary nonpolyposis colorectal cancer) and initiates a stepwise molecular and genetic diagnostic workup. Assuming each diagnostic test yields findings that require proceeding to the next sequential step, arrange the following management actions in the correct chronological order.

  1. 1Perform immunohistochemical (IHC) staining for mismatch repair (MMR) proteins on the resected colon tumor tissue.
  2. 2Perform testing for BRAF V600E mutation and MLH1 promoter hypermethylation on the tumor tissue.
  3. 3Obtain a peripheral blood sample from the patient for germline sequencing of mismatch repair genes.
  4. 4Offer targeted, site-specific germline genetic testing to the patient's asymptomatic first-degree relatives.

Answer

The correct sequence is: tumor IHC for MMR proteins, followed by tumor BRAF/methylation testing, then patient germline sequencing, and finally cascade testing of relatives.
The correct sequence reflects the established, cost-effective diagnostic algorithm for Lynch syndrome. It begins with evaluating the tumor phenotype (IHC), progresses to ruling out common somatic causes of MMR deficiency (BRAF V600E/methylation), moves to definitively diagnosing the index patient via germline sequencing, and concludes by utilizing that confirmed diagnosis to guide cascade testing for at-risk family members.

Step-by-Step Solution

1
Determine the optimal initial screening test for a patient with suspected Lynch syndrome.
Immunohistochemical (IHC) staining of the tumor tissue for mismatch repair proteins.
Universal screening of colorectal tumors using IHC (or microsatellite instability testing) is the standard first step to identify tumors with mismatch repair deficiency.
2
Determine the next step if the screening test suggests mismatch repair deficiency (e.g., loss of MLH1).
Testing the tumor for a BRAF V600E mutation and MLH1 promoter hypermethylation.
Approximately 15% of sporadic colorectal cancers show MLH1 loss due to somatic promoter hypermethylation, often alongside a BRAF V600E mutation. This step rules out sporadic disease before proceeding to expensive germline testing.
3
Identify the confirmatory test for the patient if tumor testing is consistent with an inherited etiology.
Germline sequencing of the mismatch repair genes from a peripheral blood sample.
Lynch syndrome is defined by a hereditary, germline mutation. A definitive diagnosis requires confirming this mutation in the index patient's DNA.
4
Determine the management of the patient's family members once a diagnosis is confirmed.
Offer targeted (site-specific) genetic testing to first-degree relatives.
Cascade testing of relatives is only indicated after the specific pathogenic variant responsible for the syndrome is identified in the affected index patient.

Key Concept

The diagnostic algorithm for Lynch syndrome follows a stepwise progression: phenotypic tumor screening, somatic mutation testing to rule out sporadic disease, definitive germline sequencing in the index patient, and subsequent cascade testing for relatives.
Estimated Time:1m 30s
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Topics

Genetic and Molecular Mechanisms

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