Prevention and early detection of distant metastasis are critical for improving the outcome of patients with lung cancer. Previously, we showed that the presence of isolated basal cell hyperplasia (BCH) in the small bronchi distant from the tumor is associated with a high risk of distant metastasis in patients with lung squamous cell carcinoma (LUSC) and adenocarcinoma. However, mechanisms underlying this phenomenon are unknown. Here we aimed to assess the mutational landscape of metastatic LUSC associated with isolated BCH.
The study included 10 (48 to 77 years old) patients with LUSC (T1-4N0-2M0) divided into three groups: 1) patients with isolated BCH and metastases; 2) patients with isolated BCH but without metastases; and 3) patients without premalignant bronchial lesions and metastases. Premalignant lesions were analyzed in hematoxylin and eosin-stained sections of formalin-fixed paraffin-embedded samples of small bronchi distant (3-5 cm) from the tumor. Tumor samples were sequenced on a NextSeq 500 (Illumina) using SureSelect XT Human All Exon v7 kit (Agilent).
LUSC patients with BCH and metastases showed 1.6-times more mutations than cases without premalignant bronchial lesions and metastases. Interestingly, among patients with BCH, mutations were 1.8-times more in metastatic tumors than in non-metastatic tumors confirming that the presence of hyperplasia is not absolute for distant metastasis. Metastatic LUSC more often also harbored mutations in genes involved in cell-cell adhesion (CDH8, CDH9, ITGAL, SDK1, SDK2, et al.) and signal pathways of carcinogenesis (TP53, RB1, MMP1, MMP2, EGFR, et al.). Importantly, the most frequently mutated genes in metastatic tumors were TP53 (100% of cases) and PTPRT (75% of cases).
Taken together, our findings indicate that metastatic LUSC associated with isolated BCH shows a highly mutable phenotype.
Cancer Research Institute, Tomsk National Research Medical Center.
Russian Science Foundation, #20-75-10060.
All authors have declared no conflicts of interest.