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Alterations in Head and Neck Cancer That Could Lead to Targeted Therapy Identified by Comprehensive Genomic Analysis

by Kathy Jones on  April 7, 2013 at 7:44 PM Genetics & Stem Cells News   - G J E 4
Head and neck cancers with certain distinctive patterns could be amenable to specific targeted therapies, according to a researcher. This data was presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.
 Alterations in Head and Neck Cancer That Could Lead to Targeted Therapy Identified by Comprehensive Genomic Analysis
Alterations in Head and Neck Cancer That Could Lead to Targeted Therapy Identified by Comprehensive Genomic Analysis
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The study was part of The Cancer Genome Atlas (TCGA), a National Institutes of Health project to catalogue the genetic alterations responsible for several types of cancer, in particular those with a poor prognosis.

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"It is likely our study will become a landmark research tool for HNSCC for many years as the secrets included in this massive data set are gradually unlocked," said David N. Hayes, M.D., M.P.H., an associate professor at the University of North Carolina (UNC), who practices otolaryngology at the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Hayes and colleagues conducted comprehensive genomic analysis of tumor tissue and healthy tissue from 279 patients with previously untreated HNSCC. Eighty percent of the patients reported a history of smoking.

The researchers identified more than 30 sites of significant somatic copy number alteration, or sites of significant change in the number of copies of a certain gene or genetic region. Most of the sites were identical to those recently identified in lung squamous cell carcinoma.

"HNSCC is a tobacco-related cancer," Hayes said. "We frequently see very altered genomes in other tobacco-related tumors. One of the striking things we observed was a high degree of similarity to other squamous tumors, including lung squamous cell carcinoma. Lessons learned from studying the similarities and differences between tumors, such as these copy number alterations, will be one of the angles researchers will follow to better understand the pathways altered in cancer."

The researchers also identified differences in alterations between tumors infected with the human papillomavirus (HPV) and those that were negative for the virus. "The current report greatly clarifies an observation that has been made in smaller cohorts of patients with HNSCC that EGFR gene amplification is infrequent in tumors that are infected with HPV but that these same tumors have a high rate of PIK3CA gene mutations," Hayes said.

This finding raises questions about the efficacy of the EGFR inhibitor approved by the U.S. Food and Drug Administration for the treatment of metastatic HNSCC in patients with HPV-positive tumors, according to Hayes. "It also suggests that these patients may benefit from treatment with the inhibitors of PIK3CA that are in development," he added. "However, any treatment conclusions should be based on treatment data, which were not part of the TCGA study."

About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world''s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit AACR.org.

Abstract Number: 1117

Presenter: David N. Hayes, M.D., M.P.H.

Title: Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in the Cancer Genome Atlas

Authors: David N. Hayes1, Jennifer Grandis2, Adel K. El-Naggar3. 1UNC Lineberger Comp. Cancer Ctr., Chapel Hill, NC; 2University of Pittsburgh, Pittsburgh, PA; 3The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer death in the United States and Worldwide. Most cancers are tobacco-related, although an increasing number of tumors are found in nonsmokers in association with the human papilloma virus (HPV).

Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, RNA and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression, promoter methylation, and reverse-phase protein arrays on surgically resected samples from previously untreated patients with HNSCC. We report for the first time the results for 279 HNSCC samples for whom complete data are available.

Results: The demographics of 279 patients enrolled in the study documented a median age of 61 years (range: 19-90); 27% female, and history of tobacco smoking in 80%. Over 30 sites of significant somatic copy number alteration (SCNA) were identified, most of which were shared with recently reported alterations in lung squamous cell carcinoma. However, some notable SCNA were absent in HNSCC: PDGFRA amplification and deletion of FOXP. Similarly, SCNA were compared between HPV + and HPV - tumors identifying numerous differences, including a paucity of receptor tyrosine kinase alterations in HPV + tumors and novel deletions in chromosome 11q and 14q. Exome sequencing revealed at least 15 significantly mutated genes at the False Discovery Rate (FDR) of <0.01, including: CDKN2A, TP53, PIK3CA, FAT1, MLL2, TGFBR2, HLA-A, NOTCH1, HRAS, NFE2L2, and CASP8. Consideration of differences between HPV + and HPV - tumors suggested differences which included nearly universal alteration of TP53 and frequent p16 mutations in HPV - tumors. By contrast, few TP53 or CDKN2A mutations were observed in HPV + samples. Strikingly, a large number of co-occurring genomic alterations were observed. For example, mutations of HRAS were observed nearly universally in combination with either CASP8 or FAT1. All three of these mutations were absent in HPV + patients. mRNA expression profiling revealed four distinct expression subtypes, each one enriched with distinct SCNA and mutational profiles: classical, basal, mesenchymal, and atypical. Deep sequencing by multiple platforms allowed for a detailed accounting of the role of HPV in alterations of the cancer genomes of HNSCC patients, including integration sites, disruption of tumor suppressor genes, and more complex rearrangements. Potential therapeutic targets for clinical trials with currently available drugs will be discussed.

Conclusions: HNSCC is a heterogeneous tumor which displays distinctive patterns of somatic alteration potentially amenable to molecularly targeted therapies. We document for the first time using TCGA data, the role of an oncogenic virus in the human cancer genome. Results presented on behalf of TCGA.




Source: Newswise
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