Coexistence of two missense mutations in the KRAS gene in adenocarcinoma of the lung: a possible indicator of poor prognosis.

Background: KRAS mutations are present in up to 30% of patients with lung adenocarcinoma. The two most common KRAS mutations in non-small cell lung cancer (NSCLC) are G12C (~40%) and G12V (~22%). We describe the case of a 63-year-old Asian male patient with a very aggressive lung adenocarcinoma harbouring two coexisting missense mutations in the same exon.

Methods: The patient presented with a 6 cm spiculated lung mass and bilateral mediastinal lymphadenopathy on imaging. A cytology sample was obtained from EBUS-TBNA of mediastinal lymph nodes, and mutation screening was performed by next-generation sequencing using the Ion Torrent Cancer Hotspot panel.

Results: Cytological examination and immunocytochemistry confirmed the presence of metastatic lung adenocarcinoma. The molecular analysis revealed the coexistence of two missense mutations: c.34G > T; p.(Gly12Cys) and c.38G > T; A; p.(Gly13Asp) in exon 2 of the KRAS gene. The two independent variants were confirmed on Integrative Genomic Viewer (IGV), suggesting molecularly independent clones. The patient was treated with palliative care and died within two months of the diagnosis.

Conclusions: The present case showed aggressive clinical behaviour. It is questionable whether this aggressive course was due to the coexistence of multiple mutations or to a specific single mutation. Data in the literature regarding the outcome of polyclonal KRAS polyclonal lung adenocarcinomas are scarce, but some evidence seems to indicate that specific mutations may have prognostic value, possibly depending on the disease setting.