Ontology highlight
ABSTRACT:
PROVIDER: PRJNA714799 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR13973800.fastq.gz | Fastqsanger.gz | |||
| SRR13973800_1.fastq.gz | Fastqsanger.gz | |||
| SRR13973800_2.fastq.gz | Fastqsanger.gz | |||
| SRR13973900.fastq.gz | Fastqsanger.gz |
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Project description:WES files (fastQ) from 19 germline DNA, 22 tumor DNA, 5 patient-derived xenograft (PDX) DNA, and 9 plasma cfDNA) samples from 28 CRC-BRAF-mutated patients collected at baseline to anti-BRAF/EGFR therapies.
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Project description:In this study we performed ultra deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR in 17 plasma-DNA samples from a total of 10 patients treated with anti-EGFR therapy.
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Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
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Project description:Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we performed whole genome sequencing of plasma DNA (plasma-Seq) from patients treated with anti-EGFR therapy. We demonstrate that development of resistance to anti-EGFR therapies is frequently associated with focal amplifications of KRAS, MET, and ERBB2. However, we also show that focal KRAS amplifications can be acquired in tumor genomes of patients under cytotoxic chemotherapy. Furthermore, we provide evidence that specific chromosomal polysomies, such as overrepresentations of 12p and 7p, harboring KRAS and EGFR, respectively, determine responsiveness to anti-EGFR therapy. In contrast, employing ultra-sensitive deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR, we did not observe the occurrence of novel, acquired mutations. Overall, whole-genome plasma DNA sequencing represents a non-invasive blood-based surrogate measure of changes in tumors. As such, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.
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Project description:Interventions: This is a prospective multi-centre biomarker study involving the collection of plasma from patients with a Ras wild-type (according to the local standard of care) tumour planned for treatment with first-line cetuximab in combination with Irinotecan with fluorouracil (5FU) and folinic acid (FOLFIRI) or Oxaliplatin with fluorouracil (5FU) and folinic acid (FOLFOX) will be periodically assessed with the following minimum study procedures. Additional non-study assessments may occur at the discretion of the treating clinician.
Blood sampling at the following time points:
a) Baseline (within 7 days of starting anti-EGFR treatment)
b) Week 3 of anti-EGFR treatment (after 2 weeks of treatment)
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d) Every 4 weeks thereafter until disease progression
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Images from the following staging CT chest/abdomen/pelvis performed as part of routine care will be centrally reviewed by a radiologist:
a. Screening – within 4 weeks of starting anti-EGFR therapy
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Follow-up as per standard practice until disease progression, death or a maximum of 3 years, which ever occurs first.
Primary outcome(s): To explore the emergence of Ras mutations in cfDNA as an escape mechanism for first-line cetuximab anti-EGFR therapy.
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Patients recruited will be followed to documented disease progression; a mean time of follow up is estimated to be 11.4 months (estimated time from initiation of first-line cetuximab therapy to mean time progression free survival).
Please note that cfDNA and ctDNA are used interchangeably. ]
Study Design: Purpose: Screening;Duration: Longitudinal;Selection: Defined population;Timing: Prospective
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