Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features.
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ABSTRACT:
SUBMITTER: Mendelaar PAJ
PROVIDER: S-EPMC7835235 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy is poor, with median survival of less than one year. The purpose of this study was to identify candidate therapeutically targetable somatic events in mCRC patient samples by whole genome sequencing (WGS), so as to obtain targeted treatment strategies for individual patients.Four patients were recruited, all of whom had received?>?2 prior therapy regimens. Percutaneous needle biopsies of metastases were performed with whole blood collection for the extraction of constitutional DNA. One tumor was not included in this study as the quality of tumor tissue was not sufficient for further analysis. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing systems, which yielded coverage of greater than 30X for all samples. NGS data were processed and analyzed to detect somatic genomic alterations including point mutations, indels, copy number alterations, translocations and rearrangements.All 3 tumor samples had KRAS mutations, while 2 tumors contained mutations in the APC gene and the PIK3CA gene. Although we did not identify a TCF7L2-VTI1A translocation, we did detect a TCF7L2 mutation in one tumor. Among the other interesting mutated genes was INPPL1, an important gene involved in PI3 kinase signaling. Functional studies demonstrated that inhibition of INPPL1 reduced growth of CRC cells, suggesting that INPPL1 may promote growth in CRC.Our study further supports potential molecularly defined therapeutic contexts that might provide insights into treatment strategies for refractory mCRC. New insights into the role of INPPL1 in colon tumor cell growth have also been identified. Continued development of appropriate targeted agents towards specific events may be warranted to help improve outcomes in CRC.
| S-EPMC4074842 | biostudies-other
Project description:The incidences of colorectal cancer (CRC) are continuously increasing in some areas of the world, including Malaysia. In this study, we aimed to characterize the landscape of somatic mutations using the whole-genome sequencing approach and identify druggable somatic mutations specific to Malaysian patients. Whole-genome sequencing was performed on the genomic DNA obtained from 50 Malaysian CRC patients' tissues. We discovered the top significantly mutated genes were APC, TP53, KRAS, TCF7L2 and ACVR2A. Four novel, non-synonymous variants were identified in three genes, which were KDM4E, MUC16 and POTED. At least one druggable somatic alteration was identified in 88% of our patients. Among them were two frameshift mutations in RNF43 (G156fs and P192fs) predicted to have responsive effects against the Wnt pathway inhibitor. We found that the exogenous expression of this RNF43 mutation in CRC cells resulted in increased cell proliferation and sensitivity against LGK974 drug treatment and G1 cell cycle arrest. In conclusion, this study uncovered our local CRC patients' genomic landscape and druggable alterations. It also highlighted the role of specific RNF43 frameshift mutations, which unveil the potential of an alternative treatment targeting the Wnt/β-Catenin signalling pathway and could be beneficial, especially to Malaysian CRC patients.
| S-EPMC9972984 | biostudies-literature
Project description:The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC.
| S-EPMC5564304 | biostudies-literature
Project description:Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3' UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3' UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy.
| S-EPMC6235880 | biostudies-literature
Project description:Liver is the most common site where metastatic lesions of colorectal cancer (CRC) arise. Although researches have shown mutations in driver genes, copy number variations (CNV) and alterations in relevant signaling pathways promoted the tumor evolution and immune escape during colorectal liver metastasis (CLM), the underlying mechanism remains largely elusive. Tumor and matched metastatic tissues were collected from 16 patients diagnosed with colorectal cancer and subjected to whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for studying colorectal cancer clonal evolution and immune escape during CLM. Shared somatic mutations between primary and metastatic tissues with a commonly observed subclonal-clonal (S-C) changing pattern indicated a common clonal origin between two lesions. The recurrent mutations with S-C changing pattern included those in KRAS, SYNE1, CACNA1H, PCLO, FBXL2, and DNAH11. The main CNV events underwent clonal-clonal evolution (20q amplification (amp), 17p deletion (del), 18q del and 8p del), subclonal-clonal evolution (8q amp, 13q amp, 8p del) and metastasis-specific evolution (8q amp) during the process of CLM. In addition, we revealed a potential mechanism of tumor cell immune escape by analyzing human leukocytes antigens (HLA) related clonal neoantigens and immune cell components in CLM. Our study proposed a novel liver metastasis-related evolutionary process in colorectal cancer and emphasized the theory of neo-immune escape in colorectal liver metastasis.
| S-EPMC8397721 | biostudies-literature
Project description:Based on several reports that indicate the presence of blood microbiota in patients with diseases, we became interested in identifying the presence of bacteria in the blood of healthy individuals. Using 37 samples from 5 families, we extracted sequences that were not mapped to the human reference genome and mapped them to the bacterial reference genome for characterization. Proteobacteria account for more than 95% of the blood microbiota. The results of clustering by means of principal component analysis showed similar patterns for each age group. We observed that the class Gammaproteobacteria was significantly higher in the elderly group (over 60 years old), whereas the arcsine square root-transformed relative abundance of the classes Alphaproteobacteria, Deltaproteobacteria, and Clostridia was significantly lower (p < 0.05). In addition, the diversity among the groups showed a significant difference (p < 0.05) in the elderly group. This result provides meaningful evidence of a consistent phenomenon that chronic diseases associated with aging are accompanied by metabolic endotoxemia and chronic inflammation.
| S-EPMC9225573 | biostudies-literature
Project description:Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyse 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP and SHQ1) and driver amplifications (AR and MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5-52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumour genome, most consistent with subclonal diversification of the tumour. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression.
| S-EPMC4917969 | biostudies-literature
Project description:Tumors rich in stroma are associated with advanced stage and poor prognosis in colorectal adenocarcinoma (CRC). Abundance of stromal cells also has implications for genomic analysis of patient tumors as it may prevent detection of somatic mutations. As part of our efforts to interrogate stroma-cancer cell interactions and to identify actionable therapeutic targets in metastatic CRC, we aimed to determine the proportion of stroma embedded in hepatic CRC metastases by performing computational tumor purity analysis based on whole exome sequencing data (WES). Unlike previous studies focusing on histopathologically prescreened samples, we used an unbiased in-house collection of tumor specimens. WES from CRC liver metastasis samples were utilized to evaluate stromal content and to assess the performance of three in silico tumor purity tools, ABSOLUTE, Sequenza and PureCN. Matching tumor derived organoids were analyzed as a high purity control as they are enriched in cancer cells. Computational purity estimates were compared to those from a histopathological assessment conducted by a board-certified pathologist. According to all computational methods, metastatic specimens had a median tumor purity of 30% whereas the organoids were enriched for cancer cells with a median purity estimate of 94%. In line with this, variant allele frequencies (VAFs) of oncogenes and tumor suppressor genes were undetectable or low in most patient tumors, but higher in matching organoid cultures. Positive correlation was observed between VAFs and in silico tumor purity estimates. Sequenza and PureCN produced concordant results whereas ABSOLUTE yielded lower purity estimates for all samples. Our data shows that unbiased sample selection combined with molecular, computational, and histopathological tumor purity assessment is critical to determine the level of stroma embedded in metastatic colorectal adenocarcinoma.
| S-EPMC10079084 | biostudies-literature
Project description:HIV infection continues to be a major global public health issue. The population heterogeneity in susceptibility or resistance to HIV-1 and progression upon infection is attributable to, among other factors, host genetic variation. Therefore, identifying population-specific variation and genetic modifiers of HIV infectivity can catapult the invention of effective strategies against HIV-1 in African populations. Here, we investigated whole genome sequences of 390 unrelated HIV-positive and -negative individuals from Botswana. We report 27.7 million single nucleotide variations (SNVs) in the complete genomes of Botswana nationals, of which 2.8 million were missing in public databases. Our population structure analysis revealed a largely homogenous structure in the Botswana population. Admixture analysis showed elevated components shared between the Botswana population and the Niger-Congo (65.9%), Khoe-San (32.9%), and Europeans (1.1%) ancestries in the population of Botswana. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated. The most deleterious variants were enriched in five genes: ACTRT2 (the Actin Related Protein T2), HOXD12 (homeobox D12), ABCB5 (ATP binding cassette subfamily B member 5), ATP8B4 (ATPase phospholipid transporting 8B4) and ABCC12 (ATP Binding Cassette Subfamily C Member 12). These genes are enriched in the glycolysis and gluconeogenesis (p < 2.84e-6) pathways and therefore, may contribute to the emerging field of immunometabolism in which therapy against HIV-1 infection is being evaluated. Published transcriptomic evidence supports the role of the glycolysis/gluconeogenesis pathways in the regulation of susceptibility to HIV, and that cumulative effects of genetic modifiers in glycolysis/gluconeogenesis pathways may potentially have effects on the expression and clinical variability of HIV-1. Identified genes and pathways provide novel avenues for other interventions, with the potential for informing the design of new therapeutics.
| S-EPMC10765519 | biostudies-literature
Project description:BackgroundDistant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution.Patients and methodsWe conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors.ResultsCRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes.ConclusionsIn CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.
| S-EPMC5834069 | biostudies-literature