A pulmonary nodule with an unexpected mutation profile

Summary

https://doi.org/10.1093/clinchem/hvae148

A 70-year-old man presented with 3 weeks of confusion and ataxia.

Student discussion

Lulu Sun, Hannah R. Krigman, Anjali Rohatgi, George Ansstas, and Andrew E.O. Hughes

Case description

A 70-year-old man presented with 3 weeks of confusion and ataxia. He had a 20 pack/year history of smoking (he quit over 10 years ago) and melanoma in situ excised 2 years ago. Upon admission, a computed tomography scan demonstrated 3 hemorrhagic brain masses and 2 right upper lobe lung nodules.

The patient underwent core biopsy and fine-needle aspiration (FNA) of a right upper lobe nodule. The core biopsy showed normal tissue, and the cytology specimen showed cuboidal cells with marked nuclear variability. The cell block contained fragments of atypical cells with intranuclear inclusions and hobnailing. The cytology specimen was signed out as non-small cell carcinoma, consistent with adenocarcinoma.

Molecular profiling was performed using an in-house targeted DNA sequencing panel (GatewaySeq), which is routine for new diagnoses of lung adenocarcinoma at our institution. GatewaySeq is a tumor-only hybridization capture-based next-generation sequencing (NGS) assay that targets single nucleotide variants and small insertions and deletions in 133 genes, copy number alterations in 11 genes, and rearrangements involving 8 genes in addition to microsatellite status and tumor mutational burden (TMB). Testing identified 6 oncogenic/likely oncogenic variants: BRAF p.Glu501Lys, BRCA1 p.Val1838Gly, KIT p.Val559Asp, TERT c.-126_-124delinsTTT, TERT c.-126_-124delinsTCT, and TP53 p.Gln331Ter. In addition, 54 variants of uncertain significance were detected in 31 genes. TMB was 94 mutations per megabase (mut/Mb). Fifty of the 60 total variants identified were C > T transitions, and mutational signature analysis revealed a type SBS7a signature, a mutation profile associated with ultraviolet (UV) radiation.