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Results from next-generation sequencing efforts, as well as gene expression analysis has made it obvious that this information will be critical for estimating prognosis and determining appropriate therapy for head and neck cancers. The Cancer Genome Atlas (TCGA), supported by the National Cancer Institute (NCI), has provided detailed information about common gene defects and expression patterns, as well as protein expression profiles found in head and neck squamous cell carcinoma (HNSCC). Although similar data are emerging for some salivary cancer types and molecular analyses of thyroid cancers are rapidly evolving, we will limit discussion here to HNSCC.

HPV-associated HNSCC should be considered a different disease from tobacco-associated or sporadic HNSCC that arises in nonsmokers. Clinically, HPV-positive (HPV[+]) HNSCC have much better survival than HPV-negative (HPV[−]), occur in a younger cohort with different risk factors, and have a distinct set of molecular defects driving the tumor. Because of these differences, HPV(−) and HPV(+) HNSCC will be presented separately.

HPV-Negative HNSCC

The etiology of HNSCC not associated with HPV is primarily driven by tobacco use. Tobacco carcinogens are thought to drive genetic changes that result in cancer. Common or distinct genetic events observed in HPV(−) HNSCC are categorized below. Percentages listed are among HPV(−) HNSCC.

  1. Tumor suppressors (inactivating events)

    1. P53: proliferation, apoptosis, genome maintenance

      1. Mutation: 79%

      2. Deletions: 1%

    2. CDKN2A (p16INK4a): proliferation

      1. Mutation: 25%

      2. Deletion: 36%

      3. Methylation: 32%

    3. FAT1: migration, proliferation

      1. Mutation: 25%

      2. Deletions: 8%

    4. NOTCH1: differentiation

      1. Mutation: 19%

      2. Deletions: 2%

    5. CASP8: apoptosis

      1. Mutation: 12% (linked with HRAS activation)

      2. Deletions: 1%

    6. Let-7c miRNA: differentiation

      1. Copy number loss: 35%

      2. Deletions: 1%

    7. NSD1 (chromatin modifier)

      1. Mutations: 12%

      2. Deletions: 1%

  2. Oncogenes (activating events)

    1. PIK3CA: proliferation, survival

      1. Mutation: 16%

      2. Amplification: 20% (large amplicon 3q26-ter, not clear if PIK3CA is the target)

    2. 11q13: amplification of multiple genes: 32%

      1. CCND1(cyclin D1): proliferation

      2. EMS1 (cortactin): migration, invasion, proliferation

      3. FADD: apoptosis (role as oncogene questionable)

    3. EGFR: proliferation, survival

      1. Amplification: 12%

    4. FGFR1: proliferation, survival

      1. Amplification: 12%

    5. HRAS: proliferation, migration, survival

      1. Mutation: 6% (linked with CASP8 mutations)

    6. MYC: proliferation, survival.

      1. Amplifications: 13%

The most commonly amplified and deleted chromosomal regions and involved genes are

  1. Commonly amplified regions

    1. 11q13: 32%

      1. Genes in amplicon: cyclin D1, EMS1 (cortactin), FADD

    2. 3q26-ter: 20%

      1. Genes in amplicon: PIK3CA, p63, h-TERC, SOX2, others

    3. 8q24: 14%

      1. Genes in amplicon: POU5F1B (functional isoform OCT4)

    4. 7p11: 12%

      1. Genes in amplicon: EGFR

    5. 8p11: 12%

      1. Genes in amplicon: FGFR1

  2. Commonly deleted regions

    1. 9p21: 32%

      1. Genes in deleted region: CDKN2A (encoding p16INK4a and ARF)

Major Biological Pathways Altered in HPV(−) HNSCC and Genetic Alterations Driving These Pathways

Common names of genes are given m=mutation, a=amplification, d=deletion.

For amplification/deletions, chromosomal region is listed (eg, d:9p21 = deletion of chromosomal region 9p21)

  1. Proliferation/cell cycle: p53 (m), CDKN2A (p16INK4a, m, d:9p21), CCND1 (cyclin D1, a:11q13), EMS1 (cortactin, a:11q13), EGFR (a:7p21), FGFR (a:8p11), FAT1 ...

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