A loss-of-function polymorphism in <i>ATG16L1</i> compromises therapeutic outcome in head and neck carcinoma patients

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ABSTRACT

The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 (ATG16L1) is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn’s disease, and epidemiological associations between Crohn’s disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association.

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Comprehensive molecular portraits of human breast tumors

Nikolaus Schultz (2013)

Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer.

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Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck

Robert Ferris, George Blumenschein, Jérôme Fayette … (2016)

Background Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. Methods In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. Results The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. Conclusions Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

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Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

Barbara Burtness, Kevin Harrington, Richard Greil … (2019)

Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.

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Author and article information

Journal

Journal ID (nlm-ta): Oncoimmunology

Journal ID (iso-abbrev): Oncoimmunology

Title: Oncoimmunology

Publisher: Taylor & Francis

ISSN (Print): 2162-4011

ISSN (Electronic): 2162-402X

Publication date (Electronic, pub): 17 April 2022

Publication date (Electronic, collection): 2022

Publication date PMC-release: 17 April 2022

Volume: 11

Issue: 1

Electronic Location Identifier: 2059878

Affiliations

[a ]Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France; , Paris, France

[b ]Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus; , Villejuif, France

[c ]Université Paris Sud, Paris Saclay; , Faculty of Medicine Kremlin Bicêtre, France

[d ]Computational Health Informatics Program (CHIP), Boston Children’s Hospital; , Boston, MA, USA

[e ]Harvard Medical School; , Boston, MA, USA

[f ]Danish Cancer Society Research Center; , Copenhagen, Denmark

[g ]Department of Head and Neck Surgical and Medical Oncology, Gustave Roussy Cancer Campus, Paris-Saclay University; , Villejuif, France

[h ]Experimental and Translational Pathology Platform (PETRA), AMMICa Inserm US23/UMS CNRS3655, Gustave Roussy Cancer Campus; , Villejuif, France

[i ]Department of Radiation Oncology, Weill Cornell Medical College; , New York, NY, USA

[j ]Sandra and Edward Meyer Cancer Center; , New York, NY, USA

[k ]Caryl and Israel Englander Institute for Precision Medicine; , New York, NY, USA

[l ]Institut du Cancer Paris CARPEMAP-HP, Hôpital Européen Georges Pompidou, Pôle de Biologie; , Paris, France

[m ]Department of Cancer Medicine, Gustave Roussy Cancer Campus; , Villejuif, France

Author notes

CONTACT Erika Vacchelli kroemer@ 123456orange.fr Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France; , Paris, France

[*]

G.K. and E.V. are senior coauthors of this paper.

Author information

Julie Le Naour https://orcid.org/0000-0002-3749-2171

Zsofia Sztupinszki https://orcid.org/0000-0002-8691-4086

Guido Kroemer https://orcid.org/0000-0002-9334-4405

Erika Vacchelli https://orcid.org/0000-0001-8010-0594

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Publisher ID: 2059878

DOI: 10.1080/2162402X.2022.2059878

PMC ID: 9037530

PubMed ID: 35481288

SO-VID: ffbe7844-257a-49f1-a6ce-eee88d134643

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients

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Most cited references 155

Comprehensive molecular portraits of human breast tumors

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

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