Cyclin D1 Amplification and p16(MTS1/CDK4I) Deletion Correlate With Poor Prognosis in Head and Neck Tumors

Namazie, Ali; Alavi, Sassan; Olopade, Olufunmilayo I.; Pauletti, Giovanni M.; Aghamohammadi, Neema; Aghamohammadi, Mazda; Gornbein, Jeffrey; Calcaterra, Thomas C.; Slamon, Dennis J.; Wang, Marilene B.; Srivatsan, Eri S.

doi:10.1097/00005537-200203000-00013

Cited by 123 publications

(127 citation statements)

References 28 publications

(37 reference statements)

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“…Several studies report that patients with HPV-positive head and neck tumours have an improved prognosis (Ritchie et al, 2003;Schlecht, 2005), whereas amplification of 11q13 has been associated with a more rapid and frequent recurrence of disease (Fujii et al, 2001) and poorer survival (Akervall et al, 1997;Rodrigo et al, 2000;Namazie et al, 2002). Weinberger et al (2006) has shown that patients with HPV-positive tumours which express high levels of p16 protein and low levels of p53 protein present with a favourable prognosis.…”

Section: Discussionmentioning

confidence: 99%

11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours

et al. 2006

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Two distinct etiologies of head and neck squamous cell carcinoma (HNSCC) have been proposed, DNA damage owing to tobacco and alcohol exposure and human papillomavirus (HPV) oncogene-mediated transformation. Common genetic alterations in HNSCC include TP53 mutations, 11q13 amplification (amp) and CDKN2A/p16 mutations or promoter methlyation. However, in HPV þ HNSCC it is frequent to observe wild-type TP53 and expression of p16. The relationship of this unusual pattern with 11q13 amp has not been tested. In a retrospective study on 125 HNSCC patients, only 17% (five out of 30) of HPV þ vs 44% (39 out of 89) of HPV À tumours expressed 11q13 amp (adjusted odds ratio (OR) ¼ 0.2, 95% confidence interval (CI) ¼ 0.1 -0.6). A subpopulation of tumours (n ¼ 69) were classified according to the three molecular markers, TP53, p16 and 11q13 amp. In addition to wild-type TP53, and p16 expression, HPV þ tumours were more likely not to be amplified at 11q13 (OR ¼ 6.5, 95% CI ¼ 1.8 -23.9). As HPV þ HNSCC lack the genetic alterations which are common in other tumours, we hypothesise that HPV infection may represent an early event in the HNSCC carcinogenic process, thus suggesting a distinct molecular pathway.

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Section: Discussionmentioning

confidence: 99%

11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours

et al. 2006

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“…28 The second, p14(ARF), activates TP53 (tumor protein p53) through mediation of MDM2, an inhibitor of TP53, and CIP1(p21), an inhibitor of cyclin-dependent kinase CDK2, and results in cell cycle arrest at both G1 and G2/M. In 103 HNSCC tumors, Namazie et al 29 found CDKN2A deletions in 52% of cases and also observed that CYCLIN-D13CDK4 amplification had a significant correlation with recurrence, distant metastasis and survival. Bazan et al 11 reported that LOH at 9p21 and CDKN2A point mutations were associated with shorter survival in 64 cases of laryngeal squamous cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma

Coon

Savera

Zarbo

et al. 2004

Intl Journal of Cancer

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Loss of heterozygosity (LOH) in chromosomal regions that harbor tumor suppressor genes from tumor tissue may lead to decreased survival time in cancer patients with squamous cell carcinoma of the head and neck (HNSCC). We studied 8 regions frequently lost in HNSCC in 150 patients having a primary diagnosis of HNSCC. Tumor and normal tissue DNA were genotyped for microsatellite repeat markers in 8 unlinked chromosomal regions. The association between LOH and death from HNSCC was investigated, weighted by number of informative markers per region and adjusted for age at diagnosis, self-reported race, tumor stage and current smoking status. LOH at 3 chromosomal regions were independently associated with reduced survival. A greater risk for cancer mortality was observed for LOH at chromosomal regions 3p24. Cure rates for patients with squamous cell carcinoma of the head and neck (HNSCC) are low. According to Surveillance, Epidemiology and End Results (SEER) data, the 5-year survival rate for cancers of the larynx is 65.9% and for cancers of the oral cavity and pharynx only 58.8%. 1 Few reliable postdiagnosis prognostic indicators exist. TNM tumor staging, which incorporates information regarding the size of the tumor (T) as well as descriptions of the regional nodes (N) and distant metastases (M), is the most common clinical method for assessing prognosis and aides the clinician in the selection of an appropriate treatment regimen for the individual patient. 2 To illustrate, SEER 5-year survival rates decrease from 81.9% for localized to 46.7% for regional and 23.4% for distant metastatic tumors of the pharynx and oral cavity with a similar trend seen in laryngeal tumors: 82.0%, 51.0% and 37.7%, respectively. 1 Although SEER data demonstrate the strong correlation between tumor stage and survival, there is much variation in outcome within each tumor stage that remains unresolved.Other established clinical factors that contribute to the treatment decision-making process include tumor site, pathologic grading of differentiation, performance status and overall treatment time. 3,4 Nevertheless, such indicators alone do not adequately predict outcome. Additional patient-specific prognostic indicators, such as genetic biomarkers, are needed to allow the physician to better identify those who are most likely to benefit from aggressive therapy. 5 Loss of heterozygosity (LOH) at specific markers may offer additional prognostic information to aid in the selection of an appropriate treatment course.Numerous genetic changes accumulate in HNSCC tumors, but the relative importance of specific genetic sites to patient survival remains uncertain. Our previous work had shown a high frequency of cytogenetic abnormalities, most commonly visible chromosomal deletions, at the following 8 chromosomal regions: 3p14. 2-p13, 3p24.3-p14.3, 5q11.2-q31.3, 8p21.3-11.21, 9p21-p24, 10p12.1-p11.22, 18q12.3-q23 and 21q21.1-q22.2. 6 We continue this work by examining allelic loss at the molecular level. Several of these regions have been supported ...

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“…Whether these differences (or other molecular differences not explored in our study) underlie prognosis in our patients remains unclear. Evidence for a prognostic effect of 11q13.3 amplification in HNSCC is inconsistent (Ruiz et al, 2012;Muller et al, 1997;Klussman et al, 2009;Hermsen et al, 2005;Rodrigo et al, 2000;Namazie et al, 2002;Ashman et al, 2003;Wreesmann et al, 2004;Xavier et al, 2012), but recent meta-analysis identified ANO1 (along with FADD) as the strongest potential host prognostic biomarkers across HNSCC (Reddy et al, 2016).…”

Section: Genes Chromosomes and Cancermentioning

confidence: 99%

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

Pattle¹,

Utjesanovic²,

Togo

et al. 2016

Genes Chromosomes & Cancer

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Squamous cell carcinomas of the hypopharynx (HPSCC) and oropharynx (OPSCC) have markedly different patient outcomes. Differences in HPV prevalence between these two patient groups may account for some of this difference, but other molecular markers of prognosis or pathological phenotype have not been established. Copy number gain of oncogenes is a well-established molecular change contributing to HNSCC development. Quantitative PCR was used to explore copy number gains of specific genes (3q -PIK3CA, TP63; 11q13.3 -CCND1, ANO1) in tumour DNA recovered from HPSCC (n=48) and OPSCC (n=52) patients. Associations between copy number gain, patient demographics, HPV/p16INK4a status and pathological stage were examined.HPV/p16 prevalence in HPSCC and OPSCC groups was 2.1% and 46.0% respectively. HPSCCs had frequent gains of CCND1 (56.3%) and ANO1 (56.3%) but few gains of PIK3CA (6.3%). By contrast, OPSCCs had significantly fewer CCND1 (23.1%) and ANO1 (17.3%) gains, and significantly more PIK3CA (26.9%) gains. A mutually exclusive relationship between HPV/p16 and 11q13.3 gains was observed in OPSCCs, while PIK3CA and TP63 gains were similar across HPVassociated and smoking/alcohol-associated patients. ANO1 gain was significantly linked to tumour pathology in HPSCC, associating with nodal metastasis and smaller and less invasive tumours at presentation (p=0.010). Our results provide a convincing link between a specific molecular change and disease phenotype that appears unique to our HPSCC population, supporting a model of 11q13.3 in promoting metastatic disease progression in HNSCC, and suggest a role for ANO1 as a molecular marker of metastatic disease. words

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Cyclin D1 Amplification and p16(MTS1/CDK4I) Deletion Correlate With Poor Prognosis in Head and Neck Tumors

Abstract: We demonstrate that FISH is a simple and sensitive method for detecting cyclin D1 amplification and p16 deletion in head and neck cancer. Our results suggest that these two genetic aberrations together portend a poorer outcome than either of the abnormalities alone in head and neck cancer.

Cited by 123 publications

References 28 publications

11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours

11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours

Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

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