FGFR1–4 RNA-Based Gene Alteration and Expression Analysis in Squamous Non-Small Cell Lung Cancer

Abstract

While fibroblast growth factor receptors (FGFRs) are involved in several biological pathways and FGFR inhibitors may be useful in the treatment of squamous non-small cell lung cancer (Sq-NSCLC), FGFR aberrations are not well characterized in Sq-NSCLC. We comprehensively evaluated FGFR expression, fusions, and variants in 40 fresh-frozen primary Sq-NSCLC (stage IA3–IV) samples and tumor-adjacent normal tissues using real-time PCR and next-generation sequencing (NGS). Protein expression of FGFR1–3 and amplification of FGFR1 were also analyzed. FGFR1 and FGFR4 median gene expression was significantly (p < 0.001) decreased in tumors compared with normal tissue. Increased FGFR3 expression enhanced the recurrence risk (hazard ratio 4.72, p = 0.029), while high FGFR4 expression was associated with lymph node metastasis (p = 0.036). Enhanced FGFR1 gene expression was correlated with FGFR1 protein overexpression (r = 0.75, p = 0.0003), but not with FGFR1 amplification. NGS revealed known pathogenic FGFR2,3 variants, an FGFR3::TACC3 fusion, and a novel TACC1::FGFR1 fusion together with FGFR1,2 variants of uncertain significance not previously reported in Sq-NSCLC. These findings expand our knowledge of the Sq-NSCLC molecular background and show that combining different methods increases the rate of FGFR aberrations detection, which may improve patient selection for FGFRi treatment.

FGFR families: biological functions and therapeutic interventions in tumors

“…Although occurring infrequently, the gene mutations, fusions, or rearrangements of FGFR1 also lead to the development of some tumors. For example, FGFR gene fusions or rearrangements have been reported in squamous NSCLC, 187 acute myeloid leukemia, 188 8p11 myeloproliferative syndrome, 189 , 190 and stem cell leukemia/lymphoma syndrome. 191 The common fusion partners of NSCLC, acute myeloid leukemia, and 8p11 myeloproliferative syndrome are transforming acidic coiled‐coil‐containing protein 1 (TACC1), FGFR1 oncogene partner 2, and breakpoint cluster region, respectively.…”

Advances in Genomic Data and Biomarkers: Revolutionizing NSCLC Diagnosis and Treatment

“…Biomarkers for Targeted Therapy. Mutations affecting the KRAS gene, particularly G12C, are implicated in the proliferation of cells and the inhibition of apoptosis in NSCLC, primarily in adenocarcinoma [ 59 ]. Another biomarker of interest is Fibroblast Growth Factor Receptor 1 (FGFR1), a tyrosine kinase that regulates various cellular processes such as proliferation, differentiation, migration, and survival.…”

Molecular diagnostics of aberrations in the FGFR family genes

“…Точечные мутации (преимущественно замены S249C, R248C и K650E в гене FGFR3) выявляются при раке лёгкого значительно реже: в опухолях плоскоклеточного типа они обнаруживаются приблизительно в 1,5 % случаев [4,38]. Частота перестроек генов FGFR1-4 в плоскоклеточных карциномах, по данным различных исследований, составляет от 0,5 до 5 % [19,[38][39][40], а в аденокарциномах лёгкого -от < 0,1 % до 0,6 % [19,38,39,41]. В подавляющем большинстве опухолей лёгкого с FGFR-транслокациями был выявлен один из вариантов перестройки FGFR3-TACC3.…”

“…В этих случаях транслокация FGFR3-TACC3 служит вероятным механизмом развития вторичной резистентности. Обращает на себя внимание, что в тех работах, где перестройки выявлялись на основе NGS-анализа ДНК [4,19,38], их частота оказалась почти на порядок ниже, чем в исследованиях, где материалом для анализа служила РНК [39][40][41].…”