AMP case report: Diagnostic pitfalls of testing rare molecular aberrations in lung adenocarcinomas

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This case highlights some of the important consensus recommendations when evaluating lung adenocarcinomas for therapeutically relevant changes in the EGFR, ALK, and ROS1 genes. Importantly, the joint guideline recommends that “test results that are unexpected, discordant, equivocal, or otherwise of low confidence are confirmed or resolved using an alternative method or sample.” Multiple testing modalities leverage strengths in terms of cost, turnaround time, and performance characteristics such as sensitivity and specificity. Although molecular algorithms for new lung adenocarcinomas are important tools to standardize testing and improve outcomes for patients with actionable genetic aberrations, a healthy appreciation of the characteristics of the patient population, specimen type, biology of the disease, and limitations of even highly sensitive and specific tests must be maintained to avoid diagnostic pitfalls.

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Dr. Priore is a molecular genetic pathology fellow, Department of Pathology and Laboratory Medicine, and Dr. Rosenbaum and Dr. Roth are assistant professors, Center for Personalized Diagnostics—all at the Hospital of the University of Pennsylvania, Philadelphia.

Test yourself: Here are three questions taken from the case report.

Answers are online now at www.amp.org/casereports and will be published next month in CAP TODAY.

1. What is the most common molecular aberration of the ALK gene in lung adenocarcinomas?

a. Single nucleotide variant
b. Inversion
c. Amplification
d. Balanced translocation

2. A test with a sensitivity and specificity of 99 percent is used to detect a disease with a prevalence of 40 percent in one population and two percent in another population. What percentage of positive cases will represent true positives in each population, respectively?

a. 40 percent and two percent
b. 99 percent and 99 percent
c. 99 percent and 67 percent
d. 100 percent and 100 percent

3. Which statement is true about EGFR and ALK genetic aberrations in lung adeno­­carcinomas?

a. They are more common in never smokers.
b. They are more common in patients of Asian ethnicity.
c. The most common change observed is a single nucleotide variant.
d. They often occur together in the same tumor.

Test yourself answers for January 2019 case report

In the January 2019 issue was a case report, “Identification by NGS of a diagnostic and theranostic mutation in a high-grade sarcoma of the humerus,” written by members of the Association for Molecular Pathology. Here are answers to the three “test yourself ” questions that followed that case report.

1. Mutations in which of the following genes can help distinguish between dedifferentiated chondrosarcoma and undifferentiated pleomorphic sarcoma of bone?

a. MDM2
b. TP53
c. IDH2
d. PIK3CA

2. What molecule is isocitrate converted to by IDH1/2 enzymes?

a. D-2-hydroxyglutarate
b. 2-oxyglutarate, also known as α-ketoglutarate
c. Isocitrate
d. Citrate
e. Succinyl Co-A

3. What is the key oncometabolite produced as a result of gain of function of IDH2 due to mutations in the Arg140 or Arg172 residues?
a. D-2-hydroxyglutarate
b. 2-oxyglutarate, also known as α-ketoglutarate
c. Isocitrate
d. Citrate
e. Succinyl Co-A