Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Abstract

Human papillomavirus (HPV) DNA sequences are associated with the large majority of invasive cervical carcinoma but the role of specific genotype(s) in the outcome of the disease is still debated. To determine the viral epidemiology in the French population of patients and the prognostic value of HPV genotypes in cervical cancer, we performed a retrospective study in 515 patients treated in our Institution from 1985 to 2005. Ninety-six percent of the cases were found associated with HPV DNA whereas 4% remained HPV negative. High-risk HPV 16/18 genotypes were found in 70% of the cases. HPV 18 was more frequently associated with adenocarcinoma (40.6%) than HPV 16 (10.4%) and found in tumours developed in younger women (mean age, 45.8 years) than HPV 16 (48.3 years) or other HPV types (53.6 years). In multivariate analysis, node involvement (p < 0.0001), parametria invasion (p 5 0.009), tumour size (p 5 0.01) and HPV status (p 5 0.02) were associated with disease-free survival (median follow-up 95 months). Disease outcome was better in tumours associated with intermediate risk HPV types (HPV 31,33,35,39, 52, 53, 58, 59, 73) than in tumours with high oncogenic types (HPV 16, 18, 45) (p 5 0.03). Node status and tumour size remained prognostic factor for overall survival. Our data show that HPV genotype is one of the biological factors associated with the outcome of cervical cancer. One third of invasive carcinoma were not associated with HPV 16/18, indicating that the screening for cervical neoplasia should be maintained after prophylactic vaccination against these HPV genotypes. ' 2008 Wiley-Liss, Inc.Key words: cervical cancer; HPV; prognosis Human papillomavirus (HPV) DNA sequences are associated with most of invasive cervical carcinoma worldwide 1 and the role of HPV as a causative agent of cervical neoplasia is well documented. 2 There is a large plurality of HPV types since more than 100 different genotypes have been identified 3 among which more than 40 infect ano-genital mucosa. Histological and virological analyses have shown that 3 groups of genital HPV could be identified according to their oncogenic properties. Low-risk HPVs (HPV6,11,42,43, 44. . .), present in low grade cervical intraepithelial neoplasia (CIN) but rare in invasive cancer, intermediaterisk HPVs (HPV 31,33,35, 51, 52, 58. . .), more prevalent in CIN than in invasive cancer, and high-risk HPVs (HPV16, 18, 45, 56. . .), more frequently found in invasive carcinoma than in CIN. 4 Experimental data have disclosed that high-risk E6 and E7 oncoprotein act in the tumour process by interfering with cell cycle G1-S checkpoint. 5 Virological epidemiology data show that HPV16 and HPV18 are the most prevalent genotypes found in invasive carcinoma worldwide but that there are significant geographic variations in the prevalence of less common genotypes. 6 In the perspective of prophylactic vaccination, it is thus necessary to accurately determine the prevalence of the different HPV types in cervical cancer at country level. Moreover, controversial data...

Prevalence and Distribution of High-Risk Human Papillomavirus Genotypes in Invasive Carcinoma of the Uterine Cervix in Uruguay

“…The higher prevalence of HPV16/18/45 in tumors developed in younger patients compared with intermediate-risk HPV genotypes could be explained by different oncogenicity of HPV genotypes. Similar results were observed by De Cremoux et al 14 It was reported that ICCs related to HPV types 16, 18, and 45, irrespective of histological type, are diagnosed an average of 4 years earlier than are those caused by other high-risk HPV types. 18 That is in agreement with the observation that HPV types 16, 18, and 45 are more likely to be integrated into the human genome than are the other HPV types and that precancerous lesions induced by these HPV genotypes progress to ICC in a substantially shorter time compared with lesions induced by HPV types 31 and 33.…”

“…Total DNA was extracted by a commercially available kit (QIA amp DNA mini kit, Qiagen, Valencia, CA) following the manufacturer's recommendations and stored at j20-C until use. All samples were then screened for the presence of HPV 14 Polymerase chain reaction amplification using generic primers was done in a 50-HL volume, and included 1Â enzyme buffer, 2-mmol/L MgCl 2 , 0.2 mmol/L of deoxyribonucleotide triphosphate dNTP, 1.25 U Taq Gold DNA polymerase (Applied Biosystems, Foster City, CA) and 1 Hmol/L of each HPV type 3 ¶ and 5 ¶ primers. The amplification ramp included 1 minute at 94-C, then 2 minutes at 40-C and 1 minute 30 seconds at 72-C for 40 cycles.…”

Region-Wise Distribution of High-Risk Human Papillomavirus Types in Squamous Cell Carcinomas of the Cervix in India

“…The global rate of HPV-negative invasive carcinoma is 10.1%, ranging from 2% to 26.1%. 10 Although several reasons may be evoked to account for the potential false negativity of viral analysis (rare or not yet cloned HPV, loss of viral DNA sequences during the tumor process, DNA degradation in some of the samples, lack of methodology, etc), it has also been hypothesized that a small proportion of ICC, particularly in the population of older women, may be driven by HPVindependent oncogenic mechanisms, 10 the prognosis of which has been shown to be poor. 11 There were many similarities in HPV type-specific distribution across the regions studied.…”

Metastatic squamous-cell carcinoma of the lung arising in a 12-year-old boy with juvenile recurrent respiratory papillomatosis of neonatal onset

“…Positive control-plasmids and two independent negative controls were amplified in each run. All samples were tested for DNA integrity by PCR using primers for the human GAPDH gene (9). The presence of HPV 6/11 was demonstrated by five independent PCR analysis, on formalin-fixed paraffin-embedded tumor tissue from the bone metastatic lesion.…”