Evidence map›Paper›PMID 37301715›Full record

ArticleEuropean journal of cancer (Oxford, England : 1990)2023

Germline immunomodulatory expression quantitative trait loci (ieQTLs) associated with immune-related toxicity from checkpoint inhibition.

Robert Ferguson, Vylyny Chat, Leah Morales, Danny Simpson, Kelsey R Monson, Elisheva Cohen, Sarah Zusin, Gabriele Madonna, Mariaelena Capone, Ester Simeone and 7 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of cancer (Oxford, England : 1990), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
1.6field-weighted citation impact, top 15% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 7 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 5 institutions in 2 countries.

Robert FergusonLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.
Vylyny ChatLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.
Leah MoralesLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.
Danny SimpsonLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.
Kelsey R MonsonLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.
Elisheva CohenLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.
Sarah ZusinLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.
Gabriele MadonnaMelanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.
Mariaelena CaponeMelanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.
Ester SimeoneMelanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.
Anna PavlickDivision of Hematology & Medical Oncology, the Cutaneous Oncology Program, Weill Cornell Medicine and New York-Presbyterian, New York, USA.
Jason J LukeDepartment of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
Thomas F GajewskiDepartment of Pathology, University of Chicago, Chicago, IL, USA; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA; Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
Iman OsmanLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA; Department of Medicine, New York University-Grossman School of Medicine, New York, NY, USA; Ronald O. Perelman Department of Dermatology, New York University-Grossman School of Medicine, New York, NY, USA.
Paolo AsciertoMelanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.
Jeffrey WeberLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA; Department of Medicine, New York University-Grossman School of Medicine, New York, NY, USA.
Tomas KirchhoffLaura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA. Electronic address: Tomas.Kirchhoff@nyulangone.org.
Eastern Cooperative Oncology Group · USIstituto Nazionale Tumori IRCCS "Fondazione G. Pascale" · ITCornell University · USUniversity of Chicago · USUniversity of Pittsburgh · US

Funding

Project 4P50CA225450 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI KIRCHHOFF, TOMAS · 2019 to 2025
$12.5M
(8) Genomic determinants of the T-cell regulome in immune checkpoint blockadeR01CA227505 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI KIRCHHOFF, TOMAS, WEBER, JEFFREY S · 2018 to 2022
$3.0M
NCI NIH HHS P50 CA225450NCI NIH HHS R01 CA227505
6 · The paper itself

Abstract

backgroundImmune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI).

methodsWe identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi-institutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients, followed by validation in an additional 97 patients.

resultsWe found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82).

conclusionWe report that rs7036417 is associated with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs.

Indexed as

Autoimmune DiseasesMelanomaHumansIpilimumabQuantitative Trait LociRetrospective StudiesIpilimumabGermline variantsImmune checkpoint inhibitionIrAEsMelanoma

Identifiers

PMID37301715
PMCPMC11000635
OpenAlexW4376866175

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.