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Results for “somatic driver alteration”

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22 records · Page 2Linked to original sources
PubMed2026

EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis.

UNLABELLED: Diverse fusions of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) are oncogenic drivers in lung adenocarcinoma. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. In this study, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that variant 3 (V3) is more oncogenic than variant 1 (V1). By using multiplexed genome editing and quantifying the effects of 29 putative tumor-suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor-suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor-suppressor gene alterations on the biology of oncogenic fusion-driven cancers. SIGNIFICANCE: EML4-ALK-driven lung cancer is treated as a uniform disease despite the presence of distinct fusion variants in patients. Our findings show that EML4-ALK variants are functionally distinct, which may have implications for the treatment of this cancer type and highlights the need to consider differences among variants of other oncogenic fusions.

Animals↗
PubMed2025

In Vivo CRISPR Activation Screening Reveals Chromosome 1q Genes VPS72, GBA1, and MRPL9 Drive Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) frequently undergoes regional chromosomal amplification, resulting in elevated gene expression levels. We aimed to elucidate the role of these poorly understood genetic changes by using CRISPR activation (CRISPRa) screening in mouse livers to identify which genes within these amplified loci are cancer driver genes. METHODS: We used data from The Cancer Genome Atlas to identify that frequently copy number-amplified and up-regulated genes all reside on human chromosomes 1q and 8q. We generated CRISPRa screening transposons that contain oncogenic Myc to drive tumor formation. We conducted CRISPRa screens in vivo in the liver to identify tumor driver genes. We extensively validated the findings in separate mice and performed RNA sequencing analysis to explore mechanisms driving tumorigenesis. RESULTS: We targeted genes that frequently undergo amplification in human HCC using an in vivo CRISPRa screening system in mice, which induced extensive liver tumorigenesis. Human chromosome 1q genes Zbtb7b, Vps72, Gba1, and Mrpl9 emerged as drivers of liver tumorigenesis. In human HCC there is a trend in correlation between levels of MRPL9, VPS72, or GBA1 and poor survival. In validation assays, activation of Vps72, Gba1, or Mrpl9 resulted in extensive liver tumorigenesis and decreased survival in mice. RNA sequencing revealed different mechanisms driving HCC, with Mrpl9 activation altering genes functionally related to mitochondrial function, Vps72 levels altering phospholipid metabolism, and Gba1 activation enhancing endosomal-lysosomal activity, all leading to promotion of cellular proliferation. Analysis of human tumor tissues with high levels of MRPL9, VPS72, or GBA1 revealed congruent results, indicating conserved mechanisms driving HCC. CONCLUSIONS: This study reveals chromosome 1q genes Vps72, Gba1, and Mrpl9 as drivers of HCC. Future efforts to prevent or treat HCC can focus on these new driver genes.

Animals↗
PubMed2026

The Landscape of Genomic and Socioeconomic Variables in Patients with Colorectal Cancer Based on Genetic Ancestry.

BACKGROUND: Despite differences in tumor alterations across genetic ancestries, investigations of the colorectal cancer molecular landscape have used self-reported ethnicity instead of genetic ancestry. METHODS: We used tumor and matched normal whole-exome sequencing data from 16,388 patients with stage I to IV colorectal cancer to investigate colorectal cancer's germline and somatic molecular landscape and the potential influence of socioeconomic factors (Distressed Communities Index, DCI) across diverse genetic ancestries. Genetic ancestry determined via supervised local ancestry inference included African (AFR, N = 1,697), Native American (AMR, N = 1,291), East Asian (EAS, N = 2,247), European (EUR, N = 9,726), Levantine Middle Eastern (LME, N = 1,192), and South Asian (SAS, N = 184). RESULTS: Microsatellite instability (MSI) was the most common form of hypermutation (80.8%), higher in the EUR genetic ancestry than in the AFR, AMR, and EAS genetic ancestry. Among germline findings, positive results were most common in high-penetrance genes associated with Lynch syndrome. Enrichment patterns included MLH1 (SAS) and PMS2 (AFR). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between the EUR and other ancestry groups in both MSI and microsatellite stable tumors. Mutational signatures suggested enrichment of reactive oxygen species and POLE in AFR, colibactin in EAS, and aflatoxin and NTHL1 in SAS. DCI scores differed by ancestry (higher distress in AFR/AMR than in EUR), but driver mutation frequencies did not vary across DCI quintiles. CONCLUSIONS: Genetic ancestry shapes hereditary risk, tumor biology, and environmental exposures. IMPACT: These findings suggest that incorporating ancestry into screening, trials, and precision oncology may improve equity, though outcome-linked prospective studies and implementation research are warranted.

Aged↗
PubMed2026

Somatic-only SDHD variant with tumor-specific loss of heterozygosity in metastatic carotid body tumor: a case report with review of literature.

Carotid body tumors (CBTs) are rare paragangliomas in which genetic predisposition, particularly pathogenic variants in succinate dehydrogenase (SDHx) genes, plays an important role in tumorigenesis. Previous genetic studies of CBTs have primarily focused on germline SDHx variants, whereas somatic alterations remain poorly characterized. Among SDHx genes, SDHB variants are known to be associated with a higher metastatic risk, while SDHD variants are generally linked to a lower metastatic rate. We report the case of a 41-year-old man who presented with a painless right-sided neck mass. Imaging studies demonstrated a hypervascular tumor located at the carotid bifurcation with circumferential encasement of the carotid artery. During surgery, the tumor was classified as a Shamblin type III CBT, and complete surgical resection with vascular reconstruction was performed. Histopathological examination confirmed paraganglioma with metastasis to a single cervical lymph node. Germline genetic testing did not reveal any pathogenic variants. However, comprehensive tumor genomic profiling identified a somatic SDHD c.304C>G (p.His102Asp) variant accompanied by tumor-specific loss of heterozygosity (LOH) and copy-number loss at the SDHD locus, findings compatible with biallelic SDHD inactivation. The patient remained free of recurrence during follow-up. To our knowledge, this represents the first reported case of metastatic CBT harboring a somatic-only SDHD variant with tumor-specific LOH. This case suggests that reliance on germline testing alone may underestimate the molecular drivers of CBT and highlights the potential clinical value of tumor-based genomic profiling for risk stratification and prognostic assessment.

Carotid body tumor↗