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Expression & Epigenetic Silencing of MicroRNA for Predicting Therapeutic Response and Prognosis of HPV-negative HNSCC

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03953443
Recruitment Status : Enrolling by invitation
First Posted : May 16, 2019
Last Update Posted : December 20, 2019
Lovelace Respiratory Research Institute
Information provided by (Responsible Party):
New Mexico Cancer Care Alliance

Brief Summary:
A two-part molecular epidemiological study will be conducted to comprehensively assess the association between miR expression and miR promoter methylation and the response to therapy and prognosis in primary, HPV-negative HNSCC patients. Part 1 will be a prospective collection of 25 pairs of fresh tumor-distant normal mucosal tissue in patients with HNSCC. Ultimately, 15 HPV-negative tumor-mucosal pairs will be utilized for discovery work in identifying miRs whose expression is up- or down-regulated in tumors. Part 2 will test the association between miR expression and miR promoter methylation, and therapeutic response and survival in all archived surgical cases of HPV-negative HNSCC at University of New Mexico Hospital (UNMH) collected after 1990.

Condition or disease Intervention/treatment
Head and Neck Squamous Cell Carcinoma Other: Not interventional

Detailed Description:

* Part 1, Prospective Collection of Fresh Tumor-Distant Normal Pairs

The investigators will prospectively collect 25 pairs of fresh HNSCC tumor-distant normal mucosal tissue.

* Part 2, Retrospective Molecular Epidemiology Study of the Association of miRs with Therapeutic Response and Prognosis in HNSCC.

The investigators will comprehensively test the association between miR expression and miR promoter methylation, and the response to therapy and survival in all cases of surgical HPV-negative HNSCC at UNMH collected after 1990. Lip and nonkeratinizing nasopharyngeal cases will be excluded as these are etiologically distinct and related to cutaneous SCC or to EB virus infection, respectively. No cases will be excluded due to gender, age, race or ethnicity.

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Study Type : Observational
Estimated Enrollment : 25 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: INST 1008: Expression and Epigenetic Silencing of MicroRNA for Predicting the Therapeutic Response and Prognosis of HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC)
Actual Study Start Date : December 17, 2010
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : December 31, 2026

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. Identify tumor specific microRNAs (miRs) whose expression increases or decreases by over 2 fold in fresh tumor vs. distant normal mucosa from patients with head and neck squamous cell carcinoma (HNSCC) negative for human papillomavirus (HPV) [ Time Frame: As long as needed to collect 15 HPV-negative tumor-mucosal sample pairs and complete sequencing, up to 10 years ]
    SOLiD sequencing of fresh tumor-distant normal pairs will discover miRs whose expression is altered in HNSCC tumors. SOLiD sequencing will provide fully quantitative data for the expression of known and novel miRs. Because HPV-related tumors comprise approximately 20% of all HNSCC and are biologically distinct from HPV negative tumors classically associated with tobacco and alcohol, only HNSCC without p16 overexpression will be used in this discovery experiment. This restriction will increase homogeneity of the samples and the power to detect miRs associated with the etiology of HPV-negative HNSCC. The miRs identified will be validated using qPCR assay in the tumor-normal pairs and in p16-negative HNSCC cell lines (n>15). In addition, miRs previously reported to be dysregulated in HNSCC will be subjected to similar validation, even if not identified during the SOLiD sequencing discovery phase.

  2. Identify miRs whose reduced expression in HPV-negative HNSCC is due to promoter methylation [ Time Frame: As long as needed to complete sequencing and analyze results, up to 5 years ]
    miRs with reduced expression in tumor tissue identified under Outcome 1 will be scrutinized for CpG rich promoters by checking the UCSC database. The methylation status of CpG rich promoters of miRs will be examined by COBRA assay in tumor vs. normal pairs (n=15) and in p16-negative HNSCC cell lines (n>15). The heterogeneity of methylation status across the CpG rich promoter will be characterized by bisulfate sequencing using the COBRA PCR product. The silencing of miRs by promoter methylation will be examined by comparing mean miR expression levels between the methylation categories for the tumor-normal pairs and for the HNSCC cell lines. This is primarily a descriptive study.

  3. Define the statistical association between the expression of tumor specific miRs, miR methylation, and the therapeutic response and prognosis of HPV-negative HNSCC using patient medical records [ Time Frame: As long as needed to collect and analyze information from medical records, up to 5 years ]
    The therapeutic response and prognosis of HPV-negative HNSCC will be collected from two sources: the patient's case file from the New Mexico Tumor Registry (NMTR) and from the patient's UNMH medical record. qRT PCR will be designed to quantify the miR expression in RNA extracted from the formalin-fixed, paraffin embedded (FFPE) tissues. A methylation-specific PCR (MSP) will be designed to facilitate the large-scale methyl-typing in all retrospective clinical samples. The primary analysis will be performed in HPV-negative HNSCC. A secondary analysis will be conducted to include all HNSCC, with and without p16 overexpression. p16 overexpression status will be adjusted in the secondary analysis. The association between miR expression status (high or low) and miR methylation status (yes or no), and patient's PFS and OS will be examined using Kaplan-Meier survival plots and the log-rank test.

Biospecimen Retention:   Samples With DNA
Fresh HNSCC tumor-distant normal mucosal tissue

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with known or suspected HNSCC

Inclusion Criteria:

  • Patients with a known or suspected diagnosis of HNSCC

    • Any primary site may be included, except nonkeratinizing nasopharyngeal SCC or lip SCC.
    • Patients are planned for diagnostic biopsies for suspected HNSCC, or for therapeutic surgery for HNSCC.
    • Patients are naïve to radiation to the head and neck, prior to research biopsies.
    • Patients have not received chemotherapy for the diagnosis of HNSCC, prior to research biopsies.
  • Age > 18 years.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  • Patients sign an informed consent, agreeing to fresh tumor biopsy as well as distant normal mucosal biopsy for purposes of described research. Research biopsies will be in addition to planned surgery. In cases where tumor resection is planned, a representative part of the tumor will be submitted for research purposes.

Exclusion Criteria:

  • Nonkeratinizing nasopharyngeal carcinoma
  • Lip squamous cell carcinoma

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03953443

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United States, New Mexico
University of New Mexico - Cancer Center
Albuquerque, New Mexico, United States, 87106
Sponsors and Collaborators
New Mexico Cancer Care Alliance
Lovelace Respiratory Research Institute
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Principal Investigator: Garth Olson, MD University of New Mexico Comprehensive Cancer Center
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Responsible Party: New Mexico Cancer Care Alliance Identifier: NCT03953443    
Other Study ID Numbers: INST 1008
First Posted: May 16, 2019    Key Record Dates
Last Update Posted: December 20, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site