Biology subjects

Montesion, M.

Publications and source records attributed to Montesion, M..

4 recordsLinked to original sources

bioRxiv2026

LINE-1 retrotransposition is a recurrent cause of MET exon 14 skipping in cancer

MET exon 14 skipping is a pathogenic event that results in decreased ubiquitin-mediated degradation of the MET receptor, sustained oncogenic signaling, and conferred sensitivity to MET tyrosine kinase inhibitors. While exon 14 skipping is most commonly caused by somatically acquired base substitutions and small indels near the exon 14 splice sites, here we report nine cases in which long interspersed element-1 (LINE-1, L1)-mediated insertions within or adjacent to MET exon 14, including one case of a LINE-1-mediated pseudogene insertion, appear to cause exon 14 skipping. These describe the first recurrent and clinically actionable mutations caused by LINE-1 retrotransposition in cancer.

cancer biology↗

bioRxiv2024

A diverse landscape of FGFR alterations and co-mutations defines novel therapeutic strategies in pediatric low-grade gliomas

Alterations in Fibroblast growth factor receptor (FGFR)-family proteins frequently occur as oncogenes in many cancers, including a subset of pediatric gliomas. Here, we performed a genomic analysis of 11,635 gliomas across ages and found that 4.5% of all gliomas harbor FGFR alterations including structural variants (SV) and single nucleotide variants (SNV), with an incidence of almost 10% in pediatric gliomas. FGFR family members are differentially enriched by age, tumor grade, and histological subtype, with FGFR1-alterations associated with glioneuronal histologies and pediatric low-grade gliomas. Across development, we find FGFR1 expression in both neuronal and glial precursors, while FGFR3 expression is largely restricted to astrocytic lineages. Leveraging novel isogenic model systems, we confirm FGFR1 alterations to be sufficient to activate MAPK and mTOR signaling, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway inhibitors, including pan-FGFR inhibitors. Models driven by FGFR1 SVs exhibited different patterns of sensitivity compared to those driven by SNVs. Finally, we performed a retrospective analysis of clinical responses in children diagnosed with FGFR-driven gliomas and found that targeted MAPK or FGFR-inhibition with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome.

cancer biology↗

bioRxiv2022

Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation

Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 "real-world" SCLC cases. This large cohort allowed us to identify new recurrent alterations and new genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), of which 12.7% were human papillomavirus-positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival while CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer. STATEMENT OF SIGNIFICANCEMinimal changes in therapy and survival outcomes have occurred in SCLC for the past four decades. The identification of new genetic subtypes, novel recurrent mutations, and an improved understanding of the mechanisms of transformation to SCLC from NSCLC may guide the development of personalized therapies for subsets of patients with SCLC.

cancer biology↗

bioRxiv2020

CDKN2C homozygous loss identifies a distinct subtype of TP53/RB1-wildtype leiomyosarcoma with frequent CIC genomic alterations and 1p/19q-codeletion

PurposeLeiomyosarcomas (LMS) harbor frequent inactivation of TP53 and RB1, and extensive DNA copy number alterations. Here, we describe a distinct recurrent genomic signature in TP53/RB1-wildtype uterine LMS. MethodsTissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS were sequenced by hybrid-capture-based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant cases. ResultsWe identified 77 LMS with homozygous copy loss of CDKN2C at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in TP53, RB1, and ATRX were rare in comparison with the remainder of the LMS cohort (11.7% vs 73.4%, 0% vs 54.5%, 2.6% vs 24.5%, all p<0.0001). CDKN2C-null LMS cases were significantly enriched for GAs in CIC (40.3% vs 1.4%) at 19q13.2, CDKN2A (46.8% vs 7.0%), and RAD51B (16.9% vs 1.7%; all p<0.0001). Chromosome arm-level aneuploidy analysis of available LMS cases (n=1,251) found that 85% (n=33/39) of CDKN2C-null LMS cases exhibited 1p/19q-codeletion, with significant enrichment in comparison to the remainder of the evaluated LMS cohort (85% vs. 5.1%, p<0.0001). 99% of CDKN2C-null cases were in females; median age was 61 years at surgery (range, 36-81 years). 55 cases were of uterine primary, 4 cases non-uterine, and the remaining 18 of uncertain primary site. 6 patients had a prior history of leiomyomatosis or uterine smooth muscle tumor of uncertain malignant potential. 60% of cases showed at least focal epithelioid variant histology. Most cases were of known advanced stage, with 62% of confirmed uterine primary cases at FIGO stage IVB. ConclusionThe identification of this novel genomic subset may have prognostic and/or therapeutic clinical relevance, including use of specific cyclin-dependent kinase inhibitors.

cancer biology↗