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High risk HPV-positive lung carcinomas: molecular evidence for a pattern of pulmonary metastasis

ABSTRACT: BACKGROUND: Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital and oropharyngeal cancers. A role for hrHPV in lung cancer has been proposed, although previous reports on the contribution of hrHPV infection to lung cancer have provided contradictory results. The current study evaluated hrHPV prevalence in lung tumor specimens of different histological subtypes in a Western study population using a validated test algorithm for hrHPV detection in formalin-fixed paraffin-embedded (FFPE) tumor specimen (i.e., GP5+6+-PCR and p16INK4A immunohistochemistry). MATERIALS AND METHODS: Tumor tissue specimens from 228 lung cancer patients were subjected to GP5+6+-PCR and p16INK4A immunohistochemistry. hrHPV-positive tumors were further characterized using genotyping of GP5+/6+-PCR products, HPV E7 transcript analysis, loss of heterozygosity (LOH) analysis and array comparative genomic hybridization (arrayCGH), and the clinical history of patients was retrieved. RESULTS: Three patients (3/228, 1.3%) with hrHPV-positive lung tumors were identified, revealing hrHPV types 16, 18 and 33, respectively. All three patients (1 male, 2 females) had a history of hrHPV-associated disease; two cervical carcinoma, and one oropharyngeal carcinoma. Further characterization revealed identical hrHPV genotype, pattern of p16INK4A expression, HPV E7 mRNA expression, and genomic aberrations in the individual pairings of lung tumor and foregoing hrHPV-associated cancer. CONCLUSION: The present study found molecular evidence that supports association of hrHPV in lung cancer with the presence of pulmonary metastasis of a hrHPV-positive cancer that originated elsewhere, and not with primary lung cancer in a Western population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE40777 | GEO | 2013/07/01

SECONDARY ACCESSION(S): PRJNA174868

REPOSITORIES: GEO

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Project description:Approximately 25% of all head and neck cancers (HNC), and up to 60% of oropharyngeal cancers (OPC) are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. According to some reports, the rate of HPV-associated tumors is much lower in AA patients as compared to EA patients in United States. This study aimed to compare the gene expression profiles of HPV-active, -inactive and -negative OPCs from european american patients, and determine their biological differences. ANALYSIS 3: Three-condition, one-color experiment: HPV-active, HPV-inactive and HPV-negative oropharyngeal tumor samples from european american patients. Biological replicates: 8 HPV Negative Tumors. 4 HPV Inactive Tumors. 11 HPV Active Tumors.

Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25 are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-active OPCs and normal benign uvula/tonsil tissues and determine what biological processes and pathways are affected in HPV-active tumors. ANALYSIS 5: Two-condition, one-color experiment: HPV-active oropharyngeal tumor samples and normal benign uvula/tonsil tissues. Biological replicates: 12 HPV active samples and 4 Normal samples.

Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25 are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-negative and HPV-inactive OPCs from both African American and European American patients, and determine their biological and racial differences. ANALYSIS 4: Four-condition, one-color experiment: African American (AA) HPV-inactive, African American (AA) HPV-negative, European American (EA) HPV-inactive, European American (EA) HPV-negative oropharyngeal tumor samples. Biological replicates: 4 AA HPV Inactive samples, 8 AA HPV Negative samples, 4 EA HPV Inactive samples and 8 EA HPV Negative samples,

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High risk HPV-positive lung carcinomas: molecular evidence for a pattern of pulmonary metastasis

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