Comparative genomic hybridization analysis of tonsillar cancer reveals a different pattern of genomic imbalances in human papillomavirus‐positive and ‐negative tumors

Abstract

Our aim was to map and compare genomic imbalances in human papillomavirus (HPV)-positive and -negative squamous cell carcinomas of the tonsil. Twenty-five primary carcinomas were analyzed by comparative genomic hybridization. Fifteen (60%) were found to be HPV-positive by PCR, and the majority were HPV-16. There were statistically significant differences in the distribution of DNA gains and losses between the HPV-positive and -negative samples. Eleven of 15 HPV-positive samples (73%) showed gain on chromosome 3q24-qter, while only 4/10 (40%) HPV-negative samples had the same gain (p ‫؍‬ 0.049). Furthermore, 4/10 (40%) HPV-negative samples but no HPV-positive samples had gain on chromosome 7q11.2-q22 (p ‫؍‬ 0.017). As expected, and similar to previous studies, patients with an HPV-positive tumor had a statistically significantly better disease-specific survival than patients with an HPV-negative tumor (p ‫؍‬ 0.002). Head-and-neck cancer constitutes 3.4% of all cancer cases each year in Europe 1 and is the fifth most common cancer type in the United States. 2 In approximately 50 -60% of patients, the tumor has spread to regional lymph nodes by the time of diagnosis, and it is known that formation of metastases reduces the chance of survival by about 50%. 2 Treatment of head-and-neck cancer has not improved greatly over the last years, and the 5-year survival rate remains low. 3 The main reasons for the low survival rate are advanced tumor stage at detection, high prevalence of recurrence and multiple primary tumors. 3 The major risk factors of head-and-neck squamous cell carcinoma (HNSCC) in the Western world are smoking and alcohol consumption. However, during the past 2 decades the role of high-risk human papillomavirus (HPV) has been studied, and data supporting HPV as a causative agent in the development and progression of a subset of these cancers have accumulated. 4 -6 The overall frequency of HPV in HNSCC is around 25-30%, with considerable variability depending on the tumor location. 7 The highest frequency is reported from studies on tonsillar cancer, 7-9 where 35-70% of tumors are HPV-positive, most commonly with HPV-16 and/or HPV-33. Furthermore, we and others have shown that patients with HPV-positive tonsillar cancer have a statistically significant reduction in risk of death from cancer compared to patients with HPV-negative tumors and that this is independent of tumor stage. 4,8 In addition, in a relatively limited study, patients with high viral load tumors had a significantly better prognosis compared to patients with low viral load tumors. 10 The fact that HPV is a favorable predictive/prognostic factor in tonsillar cancer prompted us to analyze whether differences in the pattern of chromosomal gains and losses were correlated with the presence of HPV. We hypothesized that such differences could explain the variable clinical course of HPV-positive cancer.In high-risk HPV-positive cancer of the tonsil, the early proteins E6 and E7 are generally expressed, 11 and it is known that the presence of t...

Discrimination of ‘Driver’ and ‘Passenger’ HPV in Tonsillar Carcinomas by the Polymerase Chain Reaction, Chromogenic In Situ Hybridization, and p16INK4a Immunohistochemistry

“…INK4a IHC allows a rapid review of possible HPV status and is associated with a favorable prognosis [1][2][3][4][5][6][7][8][9][10]32]; and, (2) the visualization of HPV in TSCC cells by CISH supports the classification of a specimen as driver HPV positive. PCR allows identification of the HPV type present in a TSCC as well as the detection of HPV below the CISH sensitivity threshold.…”

“…Moreover, HPV status is important in TSCC patient management since HPV positive tumors may have a favorable prognosis [1][2][3][4][5][6][7][8][9][10]. The prevalence of HPV (mostly HPV16) in TSCC varies from 29 to 93% [1][2][3][4][5][11][12][13][14]; the highest values have been reported using PCR methods; lower ones have generally been found following in situ hybridization or immunohistochemical (IHC) assays [15]. Episomal and integrated HPV DNA have been reported in TSCC [6,7].…”

High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia

“…Furthermore, frequent recurrent gain of 3q has been reported in cervical neoplasia before the acquisition of the invasive phenotype: Kirchhoff et al (1999) and Umayahara et al (2002) identified 3q gain in 35% (6 out of 17) and 61% (11 out of 18), respectively, of CIN3 samples compared with 14% (3 out of 21) high-grade VIN in this study. These combined data suggest that chromosomal aberrations characteristic of advanced SCC at several sites, including hrHPV-associated cancers such as tonsillar SCC (Oga et al, 2001;Yen et al, 2001;Dahlgren et al, 2003;Noguchi et al, 2003;Klussmann et al, 2009), commonly appear at an early stage of cervical transformation.…”

“…Previous studies have reported significant genetic differences between hrHPV-associated and hrHPV-independent SCC at a range of anatomical sites, including the oral cavity, oropharynx and cervix (Dahlgren et al, 2003;Braakhuis et al, 2004;Smeets et al, 2006;Klussmann et al, 2009;Wilting et al, 2009). The alterations identified as specific for hrHPV-independent tumours, namely recurrent losses at 5q and 9p and gains at 7q and 11q, were not observed in our VSCC series.…”

Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus

“…Recently, the role of the human papillomavirus (HPV) in head and neck carcinogenesis as a separate etiologic factor has been firmly established (Gillison et al, 2000;Dahlgren et al, 2003;Braakhuis et al, 2004a). Human papillomaviruses are epitheliotropic DNA viruses with a genome of approximately 8 kb.…”