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Human papillomavirus typing of invasive cervical cancers in Italy

Human papillomavirus typing of invasive cervical cancers in Italy Background: Human papilloma viruses (HPV) are the necessary cause of invasive cervical cancer (ICC). Of the many different types identified so far, only a few of them account for the great majority of cases worldwide, with geographical differences in their distribution. Data on the local distribution are now of interest in view of the soon-to-come introduction of HPV type-specific prophylactic vaccines. Results: We have investigated HPV type distribution in samples of 48 ICC cases occurred in women living in North-East Italy in the years 1997–1999. Cases were extracted from the Venetian Tumour Registry files, as incident cases whose specimens had been processed in two Pathology Departments. Search and typing were performed by polymerase chain reaction (PCR) using GP5+/ GP6+ primers, followed by direct sequencing or reverse dot blot. Three cases were PCR negative using the housekeeping primers and hence excluded. One case was negative by all HPV tests used. HPV 16 was present in 32 (72.7%) cases, as single infection in 28, in mixed infection in 4. Of the 44 positive cases, HPV 16 and HPV 18 accounted for 33 (75%), as single or mixed infections. The other high risk HPV types accounted for 11 (25%) of the remaining infections. Of the 32 HPV 16 positive cases, sequencing of the E6 gene could be performed in 25; the prototype isolate was identified in 7, and the variant T350G in 18; in 4 cases one or more additional mutations were present. Conclusions: Our results suggest that HPV 16 has a very high prevalence among women with invasive cervical cancer in Italy; therefore, the use of a prophylactic vaccine for HPV types 16 and 18 could prevent up to 75% of invasive cervical cancers in Italy. Findings graphical variation [1]. Limited data on HPV type Persistent infection with high risk HPV is a necessary cause distribution among ICC cases from Italy are available to for invasive cervical cancer; studies on HPV type distribu- date [2]; this information is useful in view of the availabil- tion among ICC cases worldwide have shown some geo- ity of type-restricted prophylactic vaccines in the very near Page 1 of 3 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:9 http://www.infectagentscancer.com/content/1/1/9 future. We retrieved consecutive incident cases of ICC fied fragment could not be successfully sequenced. The E6 occurred during the years 1997–1999 in Italian women pattern corresponded to the prototype in 7 cases, while living in the North-East area from the Venetian Tumour the T350G mutation was present in 18; as single mutation Registry files, and selected the cases whose samples had in 14, with another mutation in 3 (T256C, A257G, been processed in the Pathology Departments of Padova A442C, respectively), and with three additional muta- and Vicenza. tions in 1 (T286A, A289G, C335T). A total of 48 ICC cases were selected; 43 squamous cell Overall, 44 out of the 45 valuable ICC Italian cases cancers (SCC) and 5 adenocarcinomas. Median age at occurred during 1997–1999 were HPV positive. HPV 16 diagnosis was 55 yrs (range 28–89). DNA was extracted was detected in 32 cases (72.7%), a result indicating a very from formalin-fixed paraffin-embedded samples by using high prevalence in Italy, in keeping with other studies the QIAamp DNA minikit (Qiagen GmbH, Germany), [2,7,8]. Indeed, in our region HPV 16 is the most preva- according to the manufacturer's instructions. To verify lent type also in high grade lesions; 40% of samples cyto- DNA quality, amplification of a 268 bp fragment of the logically diagnosed as high grade squamous Beta-globin gene was performed using PC04/GH20 prim- intraepithelial lesions [9], and 65.5% (36/55) of histolog- ers. HPV detection was conducted using GP5+/GP6+ gen- ically confirmed CIN3/CIS (data not shown). These data eral consensus primers (which amplify a fragment of are in line with the notion that HPV 16 positive infections approximately 140–150 bp), as previously described [3], are at great risk of clinical progression and need a closer and 0.5 U of AB SuperTaq (AB Analitica, Padova, Italy). follow-up, as recommended also by other authors [10]. HPV types were identified by direct sequencing; PCR This implies that when searching for HPV sequences in products were purified by ExoSAP-IT (USB Corporation, clinical samples, careful attention must be paid to the Ohio, USA) and subjected to cycle sequencing by ABI detection of type 16; in our experience, testing by HPV 16 PRISM Big Dye Terminator Cycle Sequencing kit (Applera, type-specific PCR in adjunct to consensus primers PCR is Foster City, CA, USA), and sequencing reactions were run very useful to guarantee high sensitivity for this type, since on the ABI PRISM 310 Genetic Analyzer (Applied Biosys- HPV 16 infections can sometimes be missed by consensus tems). The BLAST server was used to match all sequences primers in cases of mixed infections and/or low viral load. available in GenBank [4]. HPV 16 type specific primers A mixed infection was detected in 5 (11.4%) of our cases; H16L1/H16R3 were used to amplify a 323 bp fragment in this result is somehow surprising, but mixed infections the E6 gene, as previously described [5], and the frag- have been detected in invasive cervical cancers also by ments subjected to direct sequencing (from both direc- other authors [11]. Indeed, different data have been tions) to characterize the isolates; variants were defined by obtained so far on the frequency and the role in cervical comparison to HPV 16 prototype sequences. HPV 16 and neoplasia development of coinfections with multiple HPV 18 type specific primers amplifying fragments of 98 HPV types. This can be due to differences in the studied bp and 118 bp, respectively, were also used, as previously population or in the typing methodology used. In our described [6]. Samples resulted negative for HPV DNA or study the five double infections were all found by nested untypable by direct sequencing and type-specific PCRs PCR followed by reverse dot blot, and it is known that were further tested by nested PCR and reverse dot blot by using the HPV-HS BIO and HPV Strip Detection kits (AB Analitica, Padova, Italy), according to the manufacturer's Table 1: HPV type distribution in relation to histology among 44 instructions, which allow the detection of HPV types 6, HPV positive invasive cervical cancers. 11, 34, 40, 43, 44, 53, 54, 61, 69, 70, 16, 18, 31, 33, 35, HPV types Histology 39, 45, 51, 52, 56, 58, 59, 66. Squamous cell carcinoma Adenocarcinoma Of the 48 cases analyzed, 3 SCC resulted negative for the housekeeping gene and were excluded, and 1 SCC was HPV 16 26 2 negative for HPV DNA with all the tests used. The remain- HPV 16 + HPV 18 3 ing 44 cases (97.8%) were positive for HPV sequences; 39 HPV 16 + HPV 31 1 single infections and 5 (11.4%) double infections, as HPV 18 1 HPV 33 2 2 described in Table 1. In 8 cases the type could be deter- HPV 35 1 mined only by nested PCR followed by reverse dot blot, HPV 45 2 and all the 5 mixed infections were in this group. Overall, HPV 52 1 the most frequently detected types were HPV 16, 18 and HPV 56 + HPV 70 1 33 (cumulatively, 37/44, 84.1%). HPV 16 E6 gene could HPV 58 2 be sequenced in 25 cases; in 6 cases amplification with the E6 type specific primers was negative, and in 1 the ampli- Page 2 of 3 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:9 http://www.infectagentscancer.com/content/1/1/9 3. de Roda Husman AM, Walboomers JMM, van den Brule AJC, Meijer reverse hybridization methods are more sensitive than CJLM, Snijders PJF: The use of general primers GP5 and GP6 sequencing in detecting multiple genotypes [12]. elongated at their 3' ends with adjacent highly conserved sequences improves human papillomavirus detection by PCR. J Gen Virol 1995, 76:1057-1062. Sequence analysis of the E6 gene in 25 HPV 16 positive 4. National Center for Biotechnology Information [http:// ICC cases showed the presence of the T350G mutation in www.ncbi.nlm.nih.gov/] 5. Giaquinto C, Del Mistro A, De Rossi A, Bertorelle R, Giacomet V, the great majority (18/25, 72%), in 4 cases also accompa- Ruga E, Minucci D: Vulvar carcinoma in a 12-year-old girl with nied by other mutations; among the mutations identified, vertically acquired human immunodeficiency virus infection. A257G, C335T, T350G, A442C lead to amino acid Pediatrics 2000, 106(4):e57. 6. Biederman K, Dandachi N, Trattner M, Vog G, Doppelmayr H, Morè changes (I52V, H78Y, L83V, E113D, respectively), while E, Staudach A, Dietze O, Hauser-Kronberger C: Comparison of C256T, T286A, A289G are silent not leading to amino real-time PCR signal-amplified in situ hybridization and con- acid changes [13,14]. Interestingly, the A257G mutation ventional PCR for detection and quantification of human papillomavirus in archival cervical cancer tissue. J Clin Micro- has been firstly described very recently, and occurred in biol 2004, 42:3758-3765. combination with the T350G variant [14], as in our case. 7. Clifford GM, Smith JS, Aguado T, Franceschi S: Comparison of HPV type distribution in high-grade cervical lesions and cervical Variations in the viral genes leading to amino acid substi- cancer: a meta-analysis. Br J Cancer 2003, 89:101-105. tutions can alter the biological functions of the encoded 8. Medeiros R, Prazeres H, Pinto D, Macedo-Pinto I, Lacerda M, Lopes proteins or their antigenic properties. Of the naturally C, Cruz E: Characterization of HPV genotype profile in squa- mous cervical lesions in Portugal, a southern European pop- occurring HPV 16 viral variants, the T350G (L83V) is the ulation at high risk of cervical cancer. Eur J Cancer Prev 2005, most commonly found among invasive cancers [15], and 14:467-471. 9. Del Mistro A, Bonaldi L, Bertorelle R, Minucci D, Franzetti M, Catte- has been linked to an increased risk for cervical disease lan A, Bonoldi E, Sposetti R, Torrisi A, Chieco-Bianchi L: Genital progression [14]. human papillomavirus types in immunocompetent and immunodepressed women in Northeast Italy: prevalence and cytomorphological correlations. J Lower Gen Tract Dis 2001, HPV 33 was detected in 4 cases, resulting the second most 5:12-20. frequent type (together with type 18), a result observed 10. Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, also in The Netherlands [16]. Rush BB, Glass AG, Schiffman M: The elevated 10-year risk of cervical precancer and cancer in women with human papil- lomavirus (HPV) type 16 or 18 and the possible utility of In conclusion, our results suggest that HPV 16 has a very type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005, 97:1072-1079. high prevalence among women with invasive cervical can- 11. Stevens MP, Tabrizi SN, Quinn MA, Garland SM: Human papillo- cer living in Italy, implying that a prophylactic vaccine for mavirus genotype prevalence in cervical biopsies from types 16 and 18 could prevent up to 75% of cancer cases women diagnosed with cervical intraepithelial neoplasia or cervical cancer in Melbourne, Australia. Int J Gynecol Cancer in Italy. 2006, 16:1017-1024. 12. Molijn A, Kleter B, Quint W, van Doorn LJ: Molecular diagnosis of human papillomavirus (HPV) infections. J Clin Virol 2005, Abbreviations 32S:S43-S51. HPV (Human papilloma viruses); ICC (invasive cervical 13. Zehbe I, Wilander E, Delius H, Tommasino M: Human papilloma- cancer); SCC (squamous cell carcinoma); CIN3 (cervical virus 16 E6 variants are more prevalent in invasive cervical carcinoma than prototype. Cancer Res 1998, 58:829-833. intraepithelial neoplasia); CIS (carcinoma in situ); PCR 14. Grodzki M, Besson G, Clavel C, Arslan A, Franceschi S, Birembaut P, (polymerase chain reaction). Tommasino M, Zehbe I: Increased risk for cervical disease pro- gression of French women infected with the human papillo- mavirus type 16 E6-350G variant. Cancer Epidemiol Biomarkers Authors' contributions Prev 2006, 15:820-822. ADM planned and coordinated the study, analyzed the 15. Tornesello ML, Duraturo ML, Salatiello I, Buonaguro L, Losito S, Botti data and drafted the manuscript. HFS and RT performed G, Stellato G, Greggi S, Piccoli R, Pilotti S, Stefanon B, De Paolo G, Franceschi S, Buonaguro FM: Analysis of human papillomavirus the molecular analyses. RB participated in the sequence type-16 variants in Italian women with cervical intraepithe- alignment and helped to draft the manuscript. AP, EB, PZ lial neoplasia and cervical cancer. J Med Virol 2004, 74:117-126. 16. Bulkmans NWJ, Bleeker MCG, Berkhof J, Voorhorst FJ, Snijders PJF, and DM participated in the design and coordination of Meijer CJLM: Prevalence of types 16 and 33 is increased in the study, and in the collection, assembly and review of high-risk human papillomavirus positive women with cervi- the patients' data. All authors read and approved the final cal intraepithelial neoplasia grade 2 or worse. Int J Cancer 2005, 117:177-181. manuscript. References 1. World Health Organization, International Agency for Research on Cancer: IARC Handbooks of Cancer Prevention. Cervix Cancer Screening, Lyon 2005:10. 2. Voglino G, Poso F, Privitera S, Parisio F, Ghiringhello B, Gordini G, Chiara G, Massobrio M, Fessia L: The role of human papillomavi- rus in cyto-histological practice: distribution and prevalence of high-risk strains (16, 18, 31, 33 and 35) in intraepithelial lesions and neoplasia of the uterine cervix. Pathologica 2000, 92:516-523. 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Human papillomavirus typing of invasive cervical cancers in Italy

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Springer Journals
Copyright
Copyright © 2006 by Del Mistro et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
DOI
10.1186/1750-9378-1-9
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17192187
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Abstract

Background: Human papilloma viruses (HPV) are the necessary cause of invasive cervical cancer (ICC). Of the many different types identified so far, only a few of them account for the great majority of cases worldwide, with geographical differences in their distribution. Data on the local distribution are now of interest in view of the soon-to-come introduction of HPV type-specific prophylactic vaccines. Results: We have investigated HPV type distribution in samples of 48 ICC cases occurred in women living in North-East Italy in the years 1997–1999. Cases were extracted from the Venetian Tumour Registry files, as incident cases whose specimens had been processed in two Pathology Departments. Search and typing were performed by polymerase chain reaction (PCR) using GP5+/ GP6+ primers, followed by direct sequencing or reverse dot blot. Three cases were PCR negative using the housekeeping primers and hence excluded. One case was negative by all HPV tests used. HPV 16 was present in 32 (72.7%) cases, as single infection in 28, in mixed infection in 4. Of the 44 positive cases, HPV 16 and HPV 18 accounted for 33 (75%), as single or mixed infections. The other high risk HPV types accounted for 11 (25%) of the remaining infections. Of the 32 HPV 16 positive cases, sequencing of the E6 gene could be performed in 25; the prototype isolate was identified in 7, and the variant T350G in 18; in 4 cases one or more additional mutations were present. Conclusions: Our results suggest that HPV 16 has a very high prevalence among women with invasive cervical cancer in Italy; therefore, the use of a prophylactic vaccine for HPV types 16 and 18 could prevent up to 75% of invasive cervical cancers in Italy. Findings graphical variation [1]. Limited data on HPV type Persistent infection with high risk HPV is a necessary cause distribution among ICC cases from Italy are available to for invasive cervical cancer; studies on HPV type distribu- date [2]; this information is useful in view of the availabil- tion among ICC cases worldwide have shown some geo- ity of type-restricted prophylactic vaccines in the very near Page 1 of 3 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:9 http://www.infectagentscancer.com/content/1/1/9 future. We retrieved consecutive incident cases of ICC fied fragment could not be successfully sequenced. The E6 occurred during the years 1997–1999 in Italian women pattern corresponded to the prototype in 7 cases, while living in the North-East area from the Venetian Tumour the T350G mutation was present in 18; as single mutation Registry files, and selected the cases whose samples had in 14, with another mutation in 3 (T256C, A257G, been processed in the Pathology Departments of Padova A442C, respectively), and with three additional muta- and Vicenza. tions in 1 (T286A, A289G, C335T). A total of 48 ICC cases were selected; 43 squamous cell Overall, 44 out of the 45 valuable ICC Italian cases cancers (SCC) and 5 adenocarcinomas. Median age at occurred during 1997–1999 were HPV positive. HPV 16 diagnosis was 55 yrs (range 28–89). DNA was extracted was detected in 32 cases (72.7%), a result indicating a very from formalin-fixed paraffin-embedded samples by using high prevalence in Italy, in keeping with other studies the QIAamp DNA minikit (Qiagen GmbH, Germany), [2,7,8]. Indeed, in our region HPV 16 is the most preva- according to the manufacturer's instructions. To verify lent type also in high grade lesions; 40% of samples cyto- DNA quality, amplification of a 268 bp fragment of the logically diagnosed as high grade squamous Beta-globin gene was performed using PC04/GH20 prim- intraepithelial lesions [9], and 65.5% (36/55) of histolog- ers. HPV detection was conducted using GP5+/GP6+ gen- ically confirmed CIN3/CIS (data not shown). These data eral consensus primers (which amplify a fragment of are in line with the notion that HPV 16 positive infections approximately 140–150 bp), as previously described [3], are at great risk of clinical progression and need a closer and 0.5 U of AB SuperTaq (AB Analitica, Padova, Italy). follow-up, as recommended also by other authors [10]. HPV types were identified by direct sequencing; PCR This implies that when searching for HPV sequences in products were purified by ExoSAP-IT (USB Corporation, clinical samples, careful attention must be paid to the Ohio, USA) and subjected to cycle sequencing by ABI detection of type 16; in our experience, testing by HPV 16 PRISM Big Dye Terminator Cycle Sequencing kit (Applera, type-specific PCR in adjunct to consensus primers PCR is Foster City, CA, USA), and sequencing reactions were run very useful to guarantee high sensitivity for this type, since on the ABI PRISM 310 Genetic Analyzer (Applied Biosys- HPV 16 infections can sometimes be missed by consensus tems). The BLAST server was used to match all sequences primers in cases of mixed infections and/or low viral load. available in GenBank [4]. HPV 16 type specific primers A mixed infection was detected in 5 (11.4%) of our cases; H16L1/H16R3 were used to amplify a 323 bp fragment in this result is somehow surprising, but mixed infections the E6 gene, as previously described [5], and the frag- have been detected in invasive cervical cancers also by ments subjected to direct sequencing (from both direc- other authors [11]. Indeed, different data have been tions) to characterize the isolates; variants were defined by obtained so far on the frequency and the role in cervical comparison to HPV 16 prototype sequences. HPV 16 and neoplasia development of coinfections with multiple HPV 18 type specific primers amplifying fragments of 98 HPV types. This can be due to differences in the studied bp and 118 bp, respectively, were also used, as previously population or in the typing methodology used. In our described [6]. Samples resulted negative for HPV DNA or study the five double infections were all found by nested untypable by direct sequencing and type-specific PCRs PCR followed by reverse dot blot, and it is known that were further tested by nested PCR and reverse dot blot by using the HPV-HS BIO and HPV Strip Detection kits (AB Analitica, Padova, Italy), according to the manufacturer's Table 1: HPV type distribution in relation to histology among 44 instructions, which allow the detection of HPV types 6, HPV positive invasive cervical cancers. 11, 34, 40, 43, 44, 53, 54, 61, 69, 70, 16, 18, 31, 33, 35, HPV types Histology 39, 45, 51, 52, 56, 58, 59, 66. Squamous cell carcinoma Adenocarcinoma Of the 48 cases analyzed, 3 SCC resulted negative for the housekeeping gene and were excluded, and 1 SCC was HPV 16 26 2 negative for HPV DNA with all the tests used. The remain- HPV 16 + HPV 18 3 ing 44 cases (97.8%) were positive for HPV sequences; 39 HPV 16 + HPV 31 1 single infections and 5 (11.4%) double infections, as HPV 18 1 HPV 33 2 2 described in Table 1. In 8 cases the type could be deter- HPV 35 1 mined only by nested PCR followed by reverse dot blot, HPV 45 2 and all the 5 mixed infections were in this group. Overall, HPV 52 1 the most frequently detected types were HPV 16, 18 and HPV 56 + HPV 70 1 33 (cumulatively, 37/44, 84.1%). HPV 16 E6 gene could HPV 58 2 be sequenced in 25 cases; in 6 cases amplification with the E6 type specific primers was negative, and in 1 the ampli- Page 2 of 3 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:9 http://www.infectagentscancer.com/content/1/1/9 3. de Roda Husman AM, Walboomers JMM, van den Brule AJC, Meijer reverse hybridization methods are more sensitive than CJLM, Snijders PJF: The use of general primers GP5 and GP6 sequencing in detecting multiple genotypes [12]. elongated at their 3' ends with adjacent highly conserved sequences improves human papillomavirus detection by PCR. J Gen Virol 1995, 76:1057-1062. Sequence analysis of the E6 gene in 25 HPV 16 positive 4. National Center for Biotechnology Information [http:// ICC cases showed the presence of the T350G mutation in www.ncbi.nlm.nih.gov/] 5. Giaquinto C, Del Mistro A, De Rossi A, Bertorelle R, Giacomet V, the great majority (18/25, 72%), in 4 cases also accompa- Ruga E, Minucci D: Vulvar carcinoma in a 12-year-old girl with nied by other mutations; among the mutations identified, vertically acquired human immunodeficiency virus infection. A257G, C335T, T350G, A442C lead to amino acid Pediatrics 2000, 106(4):e57. 6. Biederman K, Dandachi N, Trattner M, Vog G, Doppelmayr H, Morè changes (I52V, H78Y, L83V, E113D, respectively), while E, Staudach A, Dietze O, Hauser-Kronberger C: Comparison of C256T, T286A, A289G are silent not leading to amino real-time PCR signal-amplified in situ hybridization and con- acid changes [13,14]. Interestingly, the A257G mutation ventional PCR for detection and quantification of human papillomavirus in archival cervical cancer tissue. J Clin Micro- has been firstly described very recently, and occurred in biol 2004, 42:3758-3765. combination with the T350G variant [14], as in our case. 7. Clifford GM, Smith JS, Aguado T, Franceschi S: Comparison of HPV type distribution in high-grade cervical lesions and cervical Variations in the viral genes leading to amino acid substi- cancer: a meta-analysis. Br J Cancer 2003, 89:101-105. tutions can alter the biological functions of the encoded 8. Medeiros R, Prazeres H, Pinto D, Macedo-Pinto I, Lacerda M, Lopes proteins or their antigenic properties. Of the naturally C, Cruz E: Characterization of HPV genotype profile in squa- mous cervical lesions in Portugal, a southern European pop- occurring HPV 16 viral variants, the T350G (L83V) is the ulation at high risk of cervical cancer. Eur J Cancer Prev 2005, most commonly found among invasive cancers [15], and 14:467-471. 9. Del Mistro A, Bonaldi L, Bertorelle R, Minucci D, Franzetti M, Catte- has been linked to an increased risk for cervical disease lan A, Bonoldi E, Sposetti R, Torrisi A, Chieco-Bianchi L: Genital progression [14]. human papillomavirus types in immunocompetent and immunodepressed women in Northeast Italy: prevalence and cytomorphological correlations. J Lower Gen Tract Dis 2001, HPV 33 was detected in 4 cases, resulting the second most 5:12-20. frequent type (together with type 18), a result observed 10. Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, also in The Netherlands [16]. Rush BB, Glass AG, Schiffman M: The elevated 10-year risk of cervical precancer and cancer in women with human papil- lomavirus (HPV) type 16 or 18 and the possible utility of In conclusion, our results suggest that HPV 16 has a very type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005, 97:1072-1079. high prevalence among women with invasive cervical can- 11. Stevens MP, Tabrizi SN, Quinn MA, Garland SM: Human papillo- cer living in Italy, implying that a prophylactic vaccine for mavirus genotype prevalence in cervical biopsies from types 16 and 18 could prevent up to 75% of cancer cases women diagnosed with cervical intraepithelial neoplasia or cervical cancer in Melbourne, Australia. Int J Gynecol Cancer in Italy. 2006, 16:1017-1024. 12. Molijn A, Kleter B, Quint W, van Doorn LJ: Molecular diagnosis of human papillomavirus (HPV) infections. J Clin Virol 2005, Abbreviations 32S:S43-S51. HPV (Human papilloma viruses); ICC (invasive cervical 13. Zehbe I, Wilander E, Delius H, Tommasino M: Human papilloma- cancer); SCC (squamous cell carcinoma); CIN3 (cervical virus 16 E6 variants are more prevalent in invasive cervical carcinoma than prototype. Cancer Res 1998, 58:829-833. intraepithelial neoplasia); CIS (carcinoma in situ); PCR 14. Grodzki M, Besson G, Clavel C, Arslan A, Franceschi S, Birembaut P, (polymerase chain reaction). Tommasino M, Zehbe I: Increased risk for cervical disease pro- gression of French women infected with the human papillo- mavirus type 16 E6-350G variant. Cancer Epidemiol Biomarkers Authors' contributions Prev 2006, 15:820-822. ADM planned and coordinated the study, analyzed the 15. Tornesello ML, Duraturo ML, Salatiello I, Buonaguro L, Losito S, Botti data and drafted the manuscript. HFS and RT performed G, Stellato G, Greggi S, Piccoli R, Pilotti S, Stefanon B, De Paolo G, Franceschi S, Buonaguro FM: Analysis of human papillomavirus the molecular analyses. RB participated in the sequence type-16 variants in Italian women with cervical intraepithe- alignment and helped to draft the manuscript. AP, EB, PZ lial neoplasia and cervical cancer. J Med Virol 2004, 74:117-126. 16. Bulkmans NWJ, Bleeker MCG, Berkhof J, Voorhorst FJ, Snijders PJF, and DM participated in the design and coordination of Meijer CJLM: Prevalence of types 16 and 33 is increased in the study, and in the collection, assembly and review of high-risk human papillomavirus positive women with cervi- the patients' data. All authors read and approved the final cal intraepithelial neoplasia grade 2 or worse. Int J Cancer 2005, 117:177-181. manuscript. References 1. World Health Organization, International Agency for Research on Cancer: IARC Handbooks of Cancer Prevention. Cervix Cancer Screening, Lyon 2005:10. 2. Voglino G, Poso F, Privitera S, Parisio F, Ghiringhello B, Gordini G, Chiara G, Massobrio M, Fessia L: The role of human papillomavi- rus in cyto-histological practice: distribution and prevalence of high-risk strains (16, 18, 31, 33 and 35) in intraepithelial lesions and neoplasia of the uterine cervix. Pathologica 2000, 92:516-523. Page 3 of 3 (page number not for citation purposes)

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Infectious Agents and Cancer – Springer Journals

Published: Dec 27, 2006

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