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Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Prognosis for Colorectal Cancer

ABSTRACT: Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Prognosis for Colorectal Cancer

PROVIDER: PRJNA919183 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22998014_1.fastq.gz	Fastqsanger.gz
	SRR22998014_2.fastq.gz	Fastqsanger.gz
	SRR22998015_1.fastq.gz	Fastqsanger.gz
	SRR22998015_2.fastq.gz	Fastqsanger.gz
	SRR22998016_1.fastq.gz	Fastqsanger.gz

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Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Prognosis for Colorectal Cancer

Project description:Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Prognosis for Colorectal Cancer

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Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Prognosis for Colorectal Cancer

Project description:Background and aims Tumor genetic testing is indispensable in the management of primary and advanced colorectal cancer, with one-third of patients progressing despite standard care. We aimed to refine the indications for genomics-guided precision therapy. Methods We prospectively sequenced 869 tumors from Chinese patients with colorectal cancer and performed a comprehensive analysis of clinical and genomic profiles. The clinical significance of single mutation and co-occurring events was assessed in metastatic colorectal cancer (mCRC). The tumor immune microenvironment was evaluated by Immunoscore assay and single-cell sequencing. Results Single gene somatic mutations in BRAF and RBM10 were associated with shorter progression-free survival (PFS) in treatment-naive mCRC patients (BRAF: hazard ratio [HR] = 2.2 [95% CI, 1.1-4.4]; RBM10: HR= 6.8 [95% CI, 2.6-17.3]), and RBM10 remained a risk factor irrespective of the addition of bevacizumab to the chemotherapy regimens. KRAS mutations coexisting with those in AMER1 or APC were enriched in the metastatic cohort (26.23%), which had poor PFS and did not benefit from bevacizumab. 40 patients (4.6%) carried pathogenic or likely pathogenic germline alterations in the DNA damage repair pathway and 30% of them had double-hit events in the tumor with higher MSI scores. High tumor indel burden with MSI-high suggested a large number of tumor-infiltrating lymphocytes, whereas POLE-mutant with TMB-ultrahigh indicated a relatively quiescent immunophenotype. The heterogeneous genomic-immunological ecosystem was reflected in the divergent antigen presentation, immune checkpoint protein expression and responses of T cells to pembrolizumab treatment. Conclusion Integrated analysis of the clinical, genomic, and immunological profiles of colorectal cancer provides insights into prognostic stratification, drug response and potential clinical trials.

2023-01-10 | GSE222202 | GEO

Molecular Profiling Provides Clinical Insights into Targeted and Immunotherapies as well as Prognosis for Colorectal Cancer

Project description:We performed single cell sequencing to validate the genomic-guided predictive efficacy of immunotherapy and comprehend the interactions between tumor cells and immune-system cells in cases of wtih complete response and progressive disease.

2023-01-09 | GSE222300 | GEO

Whole transcriptome targeted gene quantification provides new insights on pulmonary sarcomatoid carcinomas

Project description:Whole transcriptome targeted gene quantification provides new insights on pulmonary sarcomatoid carcinomas

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FinnGen provides genetic insights from a well-phenotyped isolated population.

Project description:Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

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