Impact of T-cell Receptor Status on Mutational Landscape and Outcome in T-ALL.
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ABSTRACT:
SUBMITTER: Dourthe ME
PROVIDER: S-EPMC10027033 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
Publications
Impact of T-cell Receptor Status on Mutational Landscape and Outcome in T-ALL.
Dourthe Marie Emilie ME Courtois Lucien L Andrieu Guillaume P GP Simonin Mathieu M Touzart Aurore A Lhermitte Ludovic L Petit Arnaud A Boissel Nicolas N Baruchel André A Asnafi Vahid V Macintyre Elizabeth E
HemaSphere 20230317 4
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Project description:ObjectiveTo explore the correlation of mutation landscape with clinical outcomes in patients with peripheral T-cell lymphoma (PTCL).MethodsWe retrospectively analyzed the clinicopathological and prognosis data of 53 patients with PTCL from November 2011 to December 2017. Targeted next-generation sequencing of a 659-gene panel was performed for tissues from 53 patients with PTCLs. The correlation of mutation landscape with clinical outcomes was analyzed.ResultsTET2 was the most frequently mutated gene (64%), followed by RHOA (43%), PCLO (23%), DNMT3A (19%), IDH2 (17%), PIEZO1 (17%) and TP53 (15%). When mutated genes were categorized into functional groups, the most common mutations were those involved in epigenetic/chromatin modification (75%), T-cell activation (74%), and the DNA repair/TP53 pathway (64%). TET2/TP53 mutations were significantly associated with positive B symptoms (P = 0.045), and elevated lactate dehydrogenase (LDH) level (P = 0.011). Moreover, TET2/TP53 mutation was a risk factor for PTCL patient survival (HR 3.574, 95% CI 1.069 - 11.941, P = 0.039). The occurrence of JAK/STAT pathway mutations in angioimmunoblastic T-cell lymphoma (AITL) patients conferred a worse progression-free survival (HR 2.366, 95% CI 0.9130-6.129, P = 0.0334).ConclusionsHeterogeneous gene mutations occur in PTCL, some of which have a negative impact on the survival outcome.
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Project description:PurposeAlthough it has been suggested that pulmonary tuberculosis (TB) is associated with increased risk of lung cancer, the exact mechanism is not clearly identified. We investigated the effect of pulmonary TB on the epidermal growth factor receptor (EGFR) mutational status and clinical outcome in patients with pulmonary adenocarcinoma.Materials and methodsWe reviewed data of patients diagnosed with pulmonary adenocarcinoma harboring EGFR mutations and treated at our institution from 2008 to 2015. We divided our population into two groups: patients with pre-existing TB lesions on chest computed tomography scan (TB group) and those without the lesions (non-TB group). We compared the differences in EGFR mutational status, response to tyrosine kinase inhibitors (TKIs) and survival between the two groups.ResultsA total of 477 patients with pulmonary adenocarcinoma were analyzed. One hundred eighty-three patients (39%) had EGFR-mutated tumors and 100 (21%) patients had pre-existing TB lesions. The frequency of EGFR mutation was significantly higher in the TB group compared with the non-TB group (56% vs. 34%, p=0.038). Pre-existing TB lesions were independently associated with more frequent EGFR mutations in multivariate analysis (odds ratio, 1.43). In addition, both the progression-free survival (9.1 months vs. 11.6 months, p=0.020) and the overall survival (19.4 months vs. 24.5 months, p=0.014) after first-line EGFR-TKIs were significantly shorter in the TB group than in the non-TB group.ConclusionPrevious pulmonary TB may be associated with more frequent EGFR mutations and poorer treatment response to EGFR-TKIs in patients with pulmonary adenocarcinoma.
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Project description:BackgroundCurrently developed molecular markers can predict the effectiveness of cancer immunotherapy and screen beneficiaries to some extent, but they are not stable enough. Therefore, there is an urgent need for discovering novel biomarkers. At the same time, sex factor plays a vital role in the response to immunotherapy, so it is particularly important to identify sex-related molecular indicators.MethodsWe integrated a pan-cancer cohort consisting of 2348 cancer patients who received immune checkpoint inhibitors and targeted sequencing. Using somatic mutation profiles, we identified mutational signatures, molecular subtypes, and frequently mutated genes, and analyzed their relationships with immunotherapeutic outcomes. We also explored sex disparities of determined biomarkers in response to treatments.ResultsWe found that male patients exhibited better immunotherapy outcomes and higher tumor mutational burden. A total of seven mutational signatures were identified, among which signatures 1 and 3 were associated with worse immunotherapy outcomes, while signatures 2 and 6 correlated with better outcomes. Gender-based analysis revealed that mutational signature 1 continued to show a worse immunotherapy outcome in female patients, whereas signature 6 demonstrated a better outcome in male patients. Based on mutational activities, we identified four potential molecular subtypes with gender differences and relevance to treatment outcomes. PI3K-AKT, RAS signaling pathways, and 68 significantly mutated genes were identified to be associated with immunotherapy outcomes, with nine genes (i.e., ATM, ATRX, DOT1L, EP300, EPHB1, NOTCH1, PBRM1, RBM10, and SETD2) exhibiting gender differences. Finally, we discovered co-mutated gene pairs and TP53 p.R282W mutations related to treatment outcomes, highlighting their gender-specific differences.ConclusionThis study identified several molecular biomarkers related to cancer immunotherapy outcomes in terms of mutational signatures, molecular subtypes, and mutated genes, and explored their gender-relatedness in order to provide clues and basis for clinical treatment efficacy evaluation and patient selection.
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Project description:Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.
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Project description:BackgroundThe ryanodine receptors (RYRs) have been implicated in many muscular, cardiac and neurological diseases. However, there are almost no studies so far focusing on RYR genetic alterations and its roles in cancer, especially in non-small cell lung cancer (NSCLC).MethodsThe whole-exome sequencing (WES) data, demographic and clinical data of 1,052 NSCLC patients was downloaded from The Cancer Genome Atlas (TCGA) database and analyzed using the corresponding packages of the R software. Mutational profile was established and its correlation with tumor mutational burden (TMB), prognosis, age and smoking status was analyzed and compared.ResultsRYR mutations were found in 502 NSCLC patients, in which mutations of RYR1, RYR2 and RYR3 were found in 17.3% (182/1,052), 40.0% (421/1,052) and 21.3% (224/1,052) of patients, respectively. Random distribution of mutations without hotspot mutations were observed with all three RYR isoforms. Significant co-mutations were found between RYR1 and RYR3, while mutual exclusive mutations were found between RYR1 and RYR2, and between RYR2 and RYR3. Significant correlation was found between cumulative number of mutations and cumulative TMB for all three RYR isoforms, and patients with RYR mutations exhibited significantly higher TMB than those without RYR mutations. Significant correlation was also found between mutational status and age in RYR2 and RYR3, and between mutational status and smoking history grading in all three isoforms, and between mutational status and number of pack years in RYR3. More interestingly, significant stratification of patient survival was revealed by RYR2 mutational status, which was found to be one of the independent risk factors for patient prognosis in multivariate Cox analysis.ConclusionsThe mutational profile of RYR in NSCLC has been characterized for the first time. Strong correlation was found between RYR mutational status and TMB, age and smoking status. RYR2 mutational status was an independent risk factor for NSCLC patient prognosis.
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Project description:PurposeAggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.Experimental designWhole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.ResultsDespite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.ConclusionsThe mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.
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