Dataset Information

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.

ABSTRACT: Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies. Co-alteration landscapes were largely similar across KRAS mutations but distinct from KRAS wild-type, though differences were observed in some tumor types for tumor mutational burden, PD-L1 expression, microsatellite instability, and other mutational signatures. Prognosis of KRAS-mutant versus other genomic cohorts of lung, pancreatic, and colorectal cancer were assessed using a real-world clinicogenomic database. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.

SUBMITTER: Lee JK

PROVIDER: S-EPMC9734185 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.

Lee Jessica K JK Sivakumar Smruthy S Schrock Alexa B AB Madison Russell R Fabrizio David D Gjoerup Ole O Ross Jeffrey S JS Frampton Garrett M GM Napalkov Pavel P Montesion Meagan M Schutzman Jennifer L JL Ye Xin X Hegde Priti S PS Nagasaka Misako M Oxnard Geoffrey R GR Sokol Ethan S ES Ou Sai-Hong Ignatius SI Shi Zhen Z

NPJ precision oncology 20221209 1

Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was sim ...[more]

PMID: 36494601

Similar Datasets

Project description:BackgroundKinase-impaired class III BRAF mutations have recently received attention as a possible prognostic factor and therapeutic target. Class III BRAF variants differ from class I and class II mutations in terms of mechanism of pathway activation and therapeutic vulnerabilities. Genomic landscape analyses of tumors in large real-world cohorts represent a great opportunity to further characterize tumor-related molecular events and treatment vulnerabilities, however, such data is not yet available for tumors with BRAF class III mutations.MethodsWe investigated the pan-cancer genomic landscape of BRAF class III mutations in 376,302 patients. Patients had comprehensive genomic profiling either by FoundationOne® or FoundationOne®CDx from formalin-fixed, paraffin embedded tissue biopsies. 2 patient cases that harbored BRAF class III mutations who demonstrated dramatic response to anti-EGFR treatment were presented.ResultsBRAF class III mutations are likely to co-occur with RAF1, NRAS and HRAS alterations, while concomitant KRAS alterations were rare. Moreover, we found that alterations that predict resistance to anti-EGFR agents were significantly less common in tumors harboring BRAF class III mutations, which is of great importance as anti-EGFR therapies are a potential targeted treatment option in these tumors.DiscussionOur findings suggest a heterogenous interplay of oncogenic alterations in BRAF class III mutated tumors and have important implications for the molecular mechanisms of carcinogenesis while revealing potential therapeutic vulnerabilities.HighlightsTumors harboring BRAF class III (BRAF vIII) mutations comprise a novel subset with distinct genomic heterogeneity. BRAF vIII mutations may sensitize tumors to anti-EGFR treatments. BRAF vIII alterations show significantly less co-occurrence with alterations that predict resistance to anti-EGFR agents. Rare tumors with limited therapy options should be screened for BRAF vIII mutations as they may benefit from anti-EGFR agents.

Project description:Background & Aims: Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment, and ICI-related toxicities (i.e., immune-related adverse events (irAEs) have been reported in many clinical studies. However, the toxicity data of real-world have not been fully assessed. Methods: Patients with histologically confirmed solid tumors who had been treated with PD-1 inhibitors were included in the study. Patient data were collected from electronic medical records, including basic characteristics, data of irAEs, management and outcome. Incidences of irAEs were pooled and compared, and the risk of irAEs was also analyzed. Results: A total of 362 solid tumor patients treated with sintilimab (n = 171), camrelizumab (n = 60), toripalimab (n = 72), and pembrolizumab (n = 59) were included. In total, any grade irAEs, grade 1–2 irAEs, and grade ≥3 irAEs accounted for 47.24%, 38.67% and 8.56% of cases, reapectively. Further, 29.24% of patients discontinued immunotherapy due to irAEs, with pneumonitis being the main reason for discontinuation. By comparing the toxicity profiles between different ICIs, we found that reactive capillary haemangiomas were camrelizumab-specific. Additionally, the frequency of irAEs was association with ICIs type, the pooled incidence (standardized rate) of irAEs related to sintilimab, camrelizumab, toripalimab and pembrolizumab were 55.56% (52.81%), 48.33% (55.55%), 33.33% (29.23%) and 38.98% (38.29%), respectively. Sintilimab and camrelizumab had higher incidences of any grade and grade 1–2 than toripalimab (55.56% vs. 33.33%, p = 0.002; 48.54% vs. 25.00%, p = 0.0001) and pembrolizumab (55.56% vs. 38.98%, p = 0.0028; 48.54% vs. 25.42%, p = 0.002), while the grade ≥3 irAEs of pembrolizumab (13.56%) were approximately 1.63- to 1.93-fold higher than other ICIs, and the standardized grade ≥3 of pembrolizumab was significantly higher than that of sintilimab (13.21% vs. 7.12%, p = 0.026), especially for grade ≥3 pneumonitis. Multivariate analysis found that cumulative cycles of ICI (OR = 1.081; 95% CI: 1.023–1.142; p = 0.006), and lung cancer (OR = 1.765; 95% CI: 1.105–2.820; p = 0.017) were independent risk factors for irAEs. Conclusion: The frequency of irAEs is associated with ICI type. The pooled incidence of irAEs related to sintilimab and pneumonitis caused by pembrolizumab were higher. These data indicate the importance of having different monitoring priorities for different PD-1 inhibitors.

Project description:ObjectiveDisulfidptosis is a newly discovered disulfide stress-induced cell death form. Clinical significance and biological mechanisms of disulfidptosis in human cancers need to be further elucidated. Thus, this study was designed to characterize pan-cancer landscape of disulfidptosis across human tumors.MethodsMulti-omics features (transcriptomics, genomics, and DNA methylation) of disulfidptosis genes were investigated in TCGA pan-cancer cohorts. A disulfidptosis score system was defined across human tumors via ssGSEA. The activity of classical oncogenic pathways and hallmarks of cancer as well as the infiltration of immunocyte subpopulations were estimated, respectively. Drug sensitivity was inferred, and immune checkpoint blockade (ICB) response was evaluated in an independent cohort IMvigor210. ACHN, CAL-27, and NCI-H23 cells were transiently transfected with GYS1 siRNAs, and cell apoptosis and proliferation were measured through TUNEL and EdU assays, respectively.ResultsAberrant mRNA expression and DNA methylation of disulfidptosis genes as well as their genomic alterations were found in human tumors. The disulfidptosis score was utilized for quantifying the activity of disulfidptosis, which enabled to estimate patient prognosis. The disulfidptosis score presented positive correlations to angiogenesis and EMT, indicating the role of disulfidptosis in mediating tumor malignant features. Moreover, the score was negatively linked with infiltrating immune and stromal cells in the immune microenvironment. In the ICB cohort, shorter survival time was observed in patients with high disulfidptosis score, indicating the potential of disulfidptosis score in influencing clinical benefits from ICB. Additionally, tumors with low disulfidptosis score exhibited higher sensitivity to a few small molecular compounds, e.g., Sabutoclax, PRIMA-1MET, BIBR-1532, and Elephantin. Knockdown of disulfidptosis gene GYS1 effectively hindered tumor progression.ConclusionCollectively, our findings depict a pan-cancer map of disulfidptosis to inform functional and therapeutic research.

Dataset Information

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.

Publications

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets