Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS

Lou, Emil; Xiu, Joanne; Baca, Yasmine; Nelson, Andrew C.; Weinberg, Benjamin A.; Beg, Muhammad Shaalan; Salem, Mohamed E.; Lenz, Heinz Josef; Philip, Philip; El‐Deiry, Wafik S.; Korn, W. Michael

doi:10.3390/cells10061275

Cited by 7 publications

(6 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Specifically, the different pathways were found to be related mainly to cellular signal transduction, DNA replication and damage repair, as well as metabolism. Many of them have been proven to be inextricably linked to tumorigenesis, cell proliferation, immune cell differentiation, and survival outcomes ( Zou et al, 2020 ; Colardo et al, 2021 ; Lou et al, 2021 ). Pathway enrichment (GO and KEGG) analysis for survival-related genes returned several pathways already found by GSVA, further confirming their vital role in controlling the biology of gliomas.…”

Section: Discussionmentioning

confidence: 99%

A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

Tian

Chen

Yan

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Background: Gliomas are the most malignant tumors of the nervous system. Even though their survival outcome is closely affected by immune-related genes (IRGs) in the tumor microenvironment (TME), the corresponding regulatory mechanism remains poorly characterized.Methods: Specific enhancer RNAs (eRNAs) can be found in tumors, where they control downstream genes. The present study aimed to identify eRNA-regulated IRGs, evaluate their influence on the TME, and use them to construct a novel prognostic model for gliomas.Results: Thirteen target genes (ADCYAP1R1, BMP2, BMPR1A, CD4, DDX17, ELN, FGF13, MAPT, PDIA2, PSMB8, PTPN6, SEMA6C, and SSTR5) were identified and integrated into a comprehensive risk signature, which distinguished two risk subclasses. Discrepancies between these subclasses were compared to explore potential mechanisms attributed to eRNA-regulated genes, including immune cell infiltration, clinicopathological features, survival outcomes, and chemotherapeutic drug sensitivity. Furthermore, the risk signature was used to construct a prognostic tool that was evaluated by calibration curve, clinical utility, Harrell’s concordance index (0.87; 95% CI: 0.84–0.90), and time-dependent receiver operator characteristic curves (AUCs: 0.93 and 0.89 at 3 and 5 years, respectively). The strong reliability and robustness of the established prognostic tool were validated in another independent cohort. Finally, potential subtypes were explored in patients with grade III tumors.Conclusion: Overall, eRNAs were associated with immune-related dysfunctions in the TME. Targeting of IRGs regulated by eRNAs could improve immunotherapeutic/therapeutic outcomes.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

Tian

Chen

Yan

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…As A59 is just N-terminal to G60, perhaps it is the reason why the M67L mutation, which is two amino acids C-terminal to S65, can induce changes in A59 dynamics. The side chain of A59 has an important role in regulating K-RAS dynamics, especially as related to switch I [52], with A59T mutations being present in the Harvey (H-RAS) and Kirsten (K-RAS) sarcoma viruses and possessing a gain-of-function phenotype [51,60], and K-RAS A59T being cancer-associated [61]. These features suggest that almost any disturbance on A59 may have an effect on K-RAS behavior.…”

Section: Discussionmentioning

confidence: 99%

A cancer-associated K-RAS mutant that preferentially binds GDP displays gain-of-function and atypical signaling

Qian

Tripathi

Sánchez-Solana

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: The RAS genes, which are the prototype for the RAS superfamily of small GTPases, encode guanine nucleotide binding proteins that are frequently mutated in cancer. The superfamily has five major branches: RAS, RHO, RAB, RAN, and ARF. Its wild type members function as molecular switches that are active when GTP-bound and inactive when GDP-bound. Previously analyzed cancer-associated point mutants of RAS, such as those affecting codons 12, 13, and 61, and mutants of other superfamily members have followed this paradigm, as their steady-state level of bound GTP is higher than that of the wild type protein. However, it is possible that a less common cancer-associated mutant might be active when bound to GDP. Methods: We searched the Catalog of Somatic Mutations in Cancer (COSMIC) database and the TCGA database in the NCI Genomic Data Commons cancer-associated mutations in the RAS superfamily beyond the commonly mutated RAS codons, conducted biological and biochemical tissue culture studies and in vitro biochemical guanine nucleotide binding studies of a K-RAS mutant identified by this search, and complemented these findings with all-atom molecular dynamics simulations. Results: The database search identified a recurrent cancer-associated K-RAS mutant, M67L, as well as another cancer-associated mutant that affect the same codon in K-RAS and N-RAS and additional point mutants in the analogous codon in 10 other members of the RAS superfamily of GTPases. Detailed analysis of the K-RAS M67L mutant indicated that it has a gain-of-function biologically, but its low GTP level is similar to that of wild type K-RAS. Unlike the GDP-bound wild type, the GDP-bound M67L mutant interacts with and activates at least three RAS effectors: RALGDS, PI3K-p110a, and RAPGEF6. However, it interacts weakly with the prototypic RAS effector, RAF. All-atom molecular dynamics simulations of the mutant, conducted with and without RALGDS, provide structural insight into these characteristics of the GDP-bound mutant. Conclusion: Cancer-associated mutations that are active when GDP-bound occur in K-RAS and probably in other members of the RAS superfamily.

show abstract

“…К ним относится крайне редкая миссенс-мутация KRAS А59Т с точечной заменой аланина на треонин. Частота ее встречаемости составляет 0,08% [5,35]. E. Lou и соавт.…”

Section: Original Articleunclassified

“…Среди них ген KRAS принимает участие в сигнальных путях, обеспечивающих регуляцию клеточной пролиферации, дифференцировку и выживание. Соматические мутации KRAS при колоректальном раке встречаются в 35-50% случаев, достигая максимума при метастатическом опухолевом процессе [4][5][6][7].…”

unclassified

See 1 more Smart Citation

Somatic mutations in colorectal cancer: regional experience

Огнерубов

Ezhova

2022

Consilium Medicum

View full text Add to dashboard Cite

Introduction. Colorectal cancer is one of the most common malignant neoplasms in economically developed countries, ranking 3rd and 2nd in the structure of morbidity and mortality, respectively. Current knowledge about the molecular features of colorectal cancer is necessary to implement the principle of personalized therapy. Aim. To study regional features of tumor genomic landscape in colorectal cancer. Materials and methods. The retrospective study from 2019 to 2022 included 153 patients with stage IIV colorectal cancer aged 32 to 80 years, with a median of 63.8 years. DNA samples extracted from paraffin blocks of tumor tissue were analyzed using a real-time polymerase chain reaction. The study patients included 43.8% of males and 56.2% of females. Results. Somatic mutations were detected in 48.4% of patients. The maximum number of mutations was detected in the KRAS gene 60 (81%). The mutation rate was significantly higher in females versus males. KRAS mutations predominate in the colon compared to the rectum, accounting for 66.7 and 33.3%, respectively. In tumors of the right colon, these mutations were detected in 18.3% of cases, and in the left colon, 48.4%. NRAS mutations were found in 9.5% of cases, mainly in tumors of the left colon. BRAF mutations were diagnosed in 6 patients, 5 of them were women, and the tumors were localized in the right colon. The highest rate of KRAS mutations was observed in codons 12 and 13, accounting for 86.7% of cases. The G12V mutation occurred in the majority of patients (25%), followed by G12D (20%) and G12A (16.6%). Conclusion. Somatic mutations in RAS and BRAF genes in colorectal cancer were detected in 48.4% of patients in the Tambov region. Among them, there is a predominance of KRAS mutations 81% in females. KRAS oncogenic mutations are predictors of treatment response and prognosis.

show abstract

Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS

Cited by 7 publications

References 37 publications

A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

A cancer-associated K-RAS mutant that preferentially binds GDP displays gain-of-function and atypical signaling

Somatic mutations in colorectal cancer: regional experience

Contact Info

Product

Resources

About