Evaluation of High-Throughput Genomic Assays for the Fc Gamma Receptor Locus

Hargreaves, Chantal E.; Iriyama, Chisako; Rose-Zerilli, Matthew; Nagelkerke, Sietse Q.; Hussain, Khiyam; Ganderton, Rosalind H.; Lee, Charlotte; Machado, Lee; Hollox, Edward J.; Parker, Helen; Latham, Kate V.; Kuijpers, Taco W.; Potter, Kathleen; Coupland, Sarah E.; Davies, Andrew; Stackpole, Michael; Oates, Melanie; Pettitt, Andrew R.; Glennie, Martin J.; Cragg, Mark S.; Strefford, Jonathan C.

doi:10.1371/journal.pone.0142379

Cited by 13 publications

(19 citation statements)

References 28 publications

(47 reference statements)

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“…Genotyping of FCGR2A H131R, FCGR3A F158 V and FCGR2B I232T single nucleotide polymorphisms (SNPs) was performed in triplicate on genomic DNA samples alongside sequence‐confirmed positive (Coriell Cell Repository, Camden, NJ, USA) and non‐template controls as previously reported . FCGR2A rs1801274 and FCGR3A rs396991 SNPs were genotyping using the commercially available TaqMan assays (Life Technologies, Paisley, UK), C_9077561_20 and C_25815666_10, respectively, according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first‐line immunochemotherapy

Jamois

Gibiansky²,

Gibiansky³

et al. 2019

Brit J Clinical Pharma

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Aims Obinutuzumab (G) is a humanized type II, Fc‐glycoengineered anti‐CD20 monoclonal antibody used in various indications, including patients with previously untreated front‐line follicular lymphoma. We investigated sources of variability in G exposure and association of progression‐free survival (PFS) with average concentration over induction (CmeanIND) in front‐line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Methods Individual exposures (CmeanIND) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan–Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. Results Overall, G exposure was lower in high body‐weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G‐bendamustine‐treated patients; PFS was inferior in males and patients with FCGR2a/2b T232 T low‐affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G‐CHOP/CVP arms, PFS improved with increasing CmeanIND (hazard ratio = 1.74 and 0.394 at 5th and 95th percentile compared to median CmeanIND) and was inferior in patients with high baseline tumour size and B symptoms. Conclusions It remains unclear whether for G‐CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with >1 dose level of G could help resolve this uncertainty.

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Section: Methodsmentioning

confidence: 99%

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first‐line immunochemotherapy

Jamois

Gibiansky²,

Gibiansky³

et al. 2019

Brit J Clinical Pharma

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“…In this context, genetic association studies at this locus that involve genotyping copy number, sequence variants, or both, can often be unreliable due to a combination of technical variation due to noisy assays measuring copy-number variation and biological variation because of the underlying complexity of the locus [Haridan et al, 2015;Hargreaves et al, 2015a]. Improved assays based on the paralog ratio test (PRT) [Armour et al, 2007] and multiplex ligation probe amplification (MLPA) [Schouten et al, 2002] have allowed some studies to suggest an association of the FCGR3B deletion with SLE [Morris et al, 2010;Niederer et al, 2010b] and RA [Robinson et al, 2012].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Genomic Structure of Copy-Number Variation of the Low-Affinity Fcγ Receptor Region Allows Confirmation of the Association ofFCGR3BDeletion with Rheumatoid Arthritis

et al. 2017

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Fcγ receptors are a family of cell–surface receptors that are expressed by a host of different innate and adaptive immune cells, and mediate inflammatory responses by binding the Fc portion of immunoglobulin G. In humans, five low‐affinity receptors are encoded by the genes FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B, which are located in an 82.5‐kb segmental tandem duplication on chromosome 1q23.3, which shows extensive copy‐number variation (CNV). Deletions of FCGR3B have been suggested to increase the risk of inflammatory diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA). In this study, we identify the deletion breakpoints of FCGR3B deletion alleles in the UK population and endogamous native American population, and show that some but not all alleles are likely to be identical‐by‐descent. We also localize a duplication breakpoint, confirming that the mechanism of CNV generation is nonallelic homologous recombination, and identify several alleles with gene conversion events using fosmid sequencing data. We use information on the structure of the deletion alleles to distinguish FCGR3B deletions from FCGR3A deletions in whole‐genome array comparative genomic hybridization (aCGH) data. Reanalysis of published aCGH data using this approach supports association of FCGR3B deletion with increased risk of RA in a large cohort of 1,982 cases and 3,271 controls (odds ratio 1.61, P = 2.9×10−3).

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“…Given that CRS can range from mild to life-threatening, there have been substantial efforts to predict those patients that may develop CRS following treatment with CAR T or immune checkpoint therapies through the use of scalable multiplex assays that focus on the Fc gamma receptors (FcγRs) [196], since therapeutic IgG monoclonal antibodies elicit downstream responses through interactions with FcγRs [197]. These multiplex cytokine assays have been used in vitro to identify Fc gamma receptor polymorphisms that predict IFNγ release following treatment with Campath-1H human IgG1, which can induce CRS.…”

Section: Discussionmentioning

confidence: 99%

“…The utility of using these polymorphisms to predict the response rate to drugs has been demonstrated with the FCGR2B polymorphism, which corresponded to a reduced response rate to rituximab, which targets CD20 in B cell malignancies [200]. Importantly, multiplex assays that target the FcγR locus are scalable for use in clinical trials [196], and may be instrumental in predicting and ultimately mitigating CRS in cancer patients receiving immune targeted therapies. Other efforts to mitigate CRS and potential immune therapy-related toxicities include an engineering approach to reduce glycosylation and increase sialylation of the Fc domain of the antibodies [201], including trastuzumab, which targets HER2 and is FDA-approved for the treatment of HER2+ breast cancer [202,203].…”

Section: Discussionmentioning

confidence: 99%

GP130 Cytokines in Breast Cancer and Bone

Omokehinde

Johnson

2020

Cancers

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Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.

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Evaluation of High-Throughput Genomic Assays for the Fc Gamma Receptor Locus

Cited by 13 publications

References 28 publications

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first‐line immunochemotherapy

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first‐line immunochemotherapy

Understanding the Genomic Structure of Copy-Number Variation of the Low-Affinity Fcγ Receptor Region Allows Confirmation of the Association ofFCGR3BDeletion with Rheumatoid Arthritis

GP130 Cytokines in Breast Cancer and Bone

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