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  • Cold Spring Harbor Laboratory  (5)
  • English  (5)
  • 1
    Online Resource
    Online Resource
    Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance
    Cold Spring Harbor Laboratory ; 2019
    In:  Molecular Case Studies Vol. 5, No. 2 ( 2019-04), p. a003657-
    Details
    In: Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 5, No. 2 ( 2019-04), p. a003657-
    Abstract: Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline PALB2 variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of RB1. We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    URL: Article
    DOI: 10.1101/mcs.a003657
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2019
    detail.hit.zdb_id: 2835759-0
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  • 2
    Online Resource
    Online Resource
    Successful BRAF/MEK inhibition in a patient with BRAF V600E -mutated extrapancreatic acinar cell carcinoma
    Cold Spring Harbor Laboratory ; 2020
    In:  Molecular Case Studies Vol. 6, No. 4 ( 2020-08), p. a005553-
    Details
    In: Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 6, No. 4 ( 2020-08), p. a005553-
    Abstract: Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAF V600E -mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic BRAF V600E mutation and a germline PALB2 stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that BRAF alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    URL: Article
    DOI: 10.1101/mcs.a005553
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2020
    detail.hit.zdb_id: 2835759-0
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  • 3
    Online Resource
    Online Resource
    Accurate and efficient detection of gene fusions from RNA sequencing data
    Cold Spring Harbor Laboratory ; 2021
    In:  Genome Research Vol. 31, No. 3 ( 2021-03), p. 448-460
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 31, No. 3 ( 2021-03), p. 448-460
    Abstract: The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples ( n = 803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS . In addition, we confirmed the transforming potential of two novel fusions, RRBP1 - RAF1 and RASGRP1 - ATP1A1 , in cellular assays. These results show Arriba's utility in both basic cancer research and clinical translation.
    Type of Medium: Online Resource
    ISSN: 1088-9051 , 1549-5469
    URL: Article
    DOI: 10.1101/gr.257246.119
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2021
    detail.hit.zdb_id: 1483456-X
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification
    Cold Spring Harbor Laboratory ; 2016
    In:  Molecular Case Studies Vol. 2, No. 6 ( 2016-11), p. a001180-
    Details
    In: Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 2, No. 6 ( 2016-11), p. a001180-
    Abstract: Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (including PDL1 [ CD274 ] and JAK2 ) and 10p (including GATA3 ). Integrated analysis of molecular data and histopathology provided a rationale for immune checkpoint inhibitor (ICI) therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Histopathological analyses ruled out sarcoma and established the diagnosis of a poorly differentiated adenocarcinoma. Although neither histopathology nor molecular data were able to pinpoint the tissue of origin, our analyses established several differential diagnoses including triple-negative breast cancer (TNBC). We analyzed 157 TNBC samples from The Cancer Genome Atlas, revealing PDL1 copy number gains coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs) , and suggest a targeted therapeutic strategy in Chromosome 9p24.1/ PDL1 -amplified cancers.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    URL: Article
    DOI: 10.1101/mcs.a001180
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2016
    detail.hit.zdb_id: 2835759-0
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  • 5
    Online Resource
    Online Resource
    Successful immune checkpoint blockade in a patient with advanced stage microsatellite-unstable biliary tract cancer
    Cold Spring Harbor Laboratory ; 2017
    In:  Molecular Case Studies Vol. 3, No. 5 ( 2017-09), p. a001974-
    Details
    In: Molecular Case Studies, Cold Spring Harbor Laboratory, Vol. 3, No. 5 ( 2017-09), p. a001974-
    Abstract: Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and reactivate antitumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/programmed death receptor ligand (PD-L1) pathway have shown clinical efficacy. The effects were particularly pronounced in tumors with DNA mismatch repair (MMR) deficiency and a high mutational load, which typically occur in the colon and endometrium. Here, we report on a 24-yr-old woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and durable response to the immune checkpoint inhibitor pembrolizumab, although treatment was initiated at an advanced stage of disease. The patient's tumor displayed DNA MMR deficiency and microsatellite instability (MSI) but lacked other features commonly discussed as predictors of response toward checkpoint blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells. Notably, high levels of HLA class I and II antigen expression were detected in the tumor, suggesting a potential causal relation between functionality of the tumor's antigen presentation machinery and the success of immune checkpoint blockade. We suggest determining MSI status in combination with HLA class I and II antigen expression in tumors potentially eligible for immune checkpoint blockade even in the absence of conventional markers predictive for anti-PD-1/PD-L1 therapy and in entities not commonly linked to the MSI phenotype. Further studies are required to determine the value of these markers for predicting the success of immune checkpoint blockade.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    URL: Article
    DOI: 10.1101/mcs.a001974
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2017
    detail.hit.zdb_id: 2835759-0
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