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Results for “Human HRAS gene”

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PubMed2026

Construction and evaluation of an independently generated transgenic mouse model carrying mutated human HRAS genes for short-term carcinogenicity assessment.

The study aimed to construct and evaluate an independently generated transgenic mouse model applied to the short-term carcinogenicity assessment. Mutated human HRAS fragment containing an intron point-mutation was inserted into C57BL/6JGpt mice via bacterial artificial chromosome transgenic technology, eventually generating BALB/c;B6J-Tg(hHRAS)16/Gpt mice, abbreviated as HRAS mice. The inserted human HRAS fragment in HRAS mice was characterized, revealing five tandem copies at chromosome 19. Baseline profiles, including biochemical, hematological, immunophenotypic, survival, and carcinogenic data of HRAS mice, were collected. To evaluate the tumor susceptibility in HRAS mice, we applied N-Nitroso-N-methylurea (MNU) to HRAS mice in a short-term carcinogenicity assessment conducted according to Good Laboratory Practice. The genetic characteristics of HRAS mice include five tandem arrays of mutated human HRAS fragments located in genomic coordinate 7,755,606 on chromosome 19 and the duplication of a 9-kilobase genome sequence (genomic coordinate 7,755,606-7,746,509) located on chromosome 19. HRAS mice showed a relatively lower incidence and range of spontaneous tumor formation during long-term observation compared to CByB6F1-Tg(HRAS)2Jic (Tg.rasH2) transgenic mice. The short-term carcinogenicity assessment showed a strong tumor response to MNU, with high incidences of lymphoma (≥ 90%) and stomach squamous cell papilloma (≥ 90%) in both male and female HRAS mice. The HRAS mice showed susceptibility to MNU and exhibited baseline characteristics distinct from those of Tg.rasH2 mice. The co-expression of HRAS and MKI67 at the cellular localization level was found in neoplasms of HRAS mice. These findings preliminarily evaluated the feasibility of HRAS mice applied to the short-term carcinogenicity assessment.

Animals↗

PubMed2025

Genomic subtypes of non-muscle-invasive bladder cancer: guiding immunotherapy decision-making for patients exposed to aristolochic acid.

BACKGROUND: The limited genomic data on non-muscle-invasive bladder cancer (NMIBC) hampers our understanding of its carcinogenesis and development. Specifically, Aristolochic acid (AA), a potent human carcinogenic compound from aristolochia plants and commonly found in Chinese herbal medicine, has been extensively documented as being closely associated with the onset and progression of bladder cancer. However, the field of AA-induced NMIBC remains largely unexplored in terms of its genomic and molecular characteristics, as well as clinical therapeutic strategies. METHODS: To bridge this knowledge gap, we conducted a comprehensive study using a cohort of 81 NMIBC samples. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to obtain detailed genomic and transcriptomic data. We subjected these datasets to genomic analysis and subtype analysis to gain valuable insights into NMIBC. RESULTS: By temporally dissecting mutations in NMIBC specimens, we identified a comprehensive mutational landscape of NMIBC and the associations of these mutations with recurrence-free survival. Additionally, we discerned four genomic subtypes of NMIBC: AA-like, FGFR3/HRAS, FGFR3 & chr9Del, and genome instability (GI). The AA-like subtype presented a high frequency of gene mutations along with a pronounced AA mutagenesis signature of SBS22 (Fisher test: P-value 3.5e-4, OR 25.25) even after temporal dissection. The FGFR3/HRAS subtype exhibited FGFR3 or HRAS mutations with few copy number alterations (CNAs). The FGFR3 & chr9Del subtype was characterized by the co-occurrence of chr9p and chr9q deletions as well as FGFR3 mutations, while the GI subtype showed a high frequency of CNAs. Notably, the AA-like and GI subtypes demonstrated better outcomes after immunotherapy, whereas the FGFR3/HRAS subtype showed poorer outcomes. CONCLUSIONS: Our findings provide novel perspectives on the genomics of NMIBC, unveiling four prominent genomic subtypes, each showing different outcomes following immunotherapy. TRIAL REGISTRATION: No. 2019PHB268-01 (retrospectively registered on February 14, 2020).

Humans↗

PubMed2026

Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.

BACKGROUND: Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. METHODS: We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations. RESULTS: In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying PTPN11 variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in HRAS, PTPN11 and SOS1 genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers. CONCLUSION: Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.

Human Genetics↗

PubMed2026

Costello Syndrome Associated With Somatic Mosaicism of Rare p.Gly13Asp HRAS Variant: Expanding the Phenotypic Spectrum.

BACKGROUND: Costello syndrome (CS) is a rare RASopathy, mostly caused by de novo heterozygous pathogenic variants in the HRAS gene. Over 80% of cases involve the germline p.Gly12Ser variant, resulting in a fairly uniform phenotype of neuro-cardio-facio-cutaneous involvement with an increased risk of malignancy. Consequences of other rare HRAS variants are less well understood due to the limited number of reported cases. METHODS: An adult, young woman was referred due to sparse, slow-growing scalp hair, Blaschko-linear hyperpigmentation, acanthosis nigricans, palmoplantar hyperkeratosis, and joint hyperlaxity. Molecular, imaging, and detailed laboratory studies were performed. RESULTS: Although initial clinical exome- and whole-exome sequencing (WES) were inconclusive, indicating possible mosaicism, subsequent WES from hair-derived DNA samples revealed somatic mosaicism for the rare HRAS p.Gly13Asp variant. Brain MRIs showed a cerebral cavernoma, while cardiological evaluation, urinalysis, abdominal, and pelvic ultrasound were unremarkable. Nevertheless, she remains under close follow-up. CONCLUSION: Among the ten reported individuals carrying the p.Gly13Asp variant, our patient is only the second with confirmed mosaicism and the fifth mosaic CS case described to date. This case expands the phenotypic spectrum of CS and highlights the need for multi-tissue analysis in attenuated or atypical presentations to ensure a correct diagnosis, oncological risk assessment, and informed genetic and reproductive counseling.

Humans↗