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Scientific Backgrounder

Prevention of cervical cancer is a major undertaking in the United States with complex patient management guidelines developed by medical professional societies. The ASCCP and ACOG consensus recommendations utilize repeat cervical cytology testing followed by HPV testing, colposcopy and biopsy as appropriate management based on the abnormal Pap test results, creating a framework for patient care by practicing Ob/Gyn physicians.1-4

Clinical research has demonstrated that no single test or technology is capable of both accurately and precisely identifying which women will develop cervical cancer. Therefore, consensus care guidelines utilize a combination of diagnostic testing and visual examination to identify cervical cancer and its pre-cursors. The use of the Pap test as an initial screening tool has successfully reduced the incidence of cervical cancer in the US since its introduction, but a single Pap test lacks the specificity to precisely identify which patients are in the early stages of cervical disease.5-7 The discovery of HPV and its requirement for the development of cervical cancer was a major advance. The incorporation of HPV testing in clinical practice has improved the identification of women at risk for developing cervical disease. Although, the widespread prevalence of high-risk HPV infections presents a challenge to clinicians since the majority of women with HPV will not develop advanced cervical dysplasia or cancer.8,9

Cervical cancer screening programs are a significant part of women’s health care throughout the United States and have resulted in a significant reduction in cervical cancer incidence over the last several decades. Current programs include liquid-based cervical cytology followed by testing for infection with high-risk human papillomavirus (HPV) types when equivocal or mild cytological abnormalities are identified. More severe cytological abnormalities are followed up with colposcopic examination and invasive procedures.

Colposcopy with directed biopsy is used to detect disease and make treatment decisions, but its utility is limited. Effectiveness of the procedure depends on clinician training, the site of biopsy, and the number of biopsies taken.10,11 Evaluation of the tissue pathology also has its challenges. Clinical studies have shown significant inter-pathologist variability and reliability.12,13 The NCI-sponsored ASCUS/LSIL Triage Study (ALTS) study showed colposcopy-directed biopsies only detected 60% of the disease present within the study subjects.14-17

More than 99% of cervical cancers have detectable high-risk HPV sub-types.6,19,23,32 Infection by a high-risk HPV sub-type is required but it is not sufficient to cause cervical cancer. While the prevalence of high-risk HPV infections is high within women in the United States, the vast majority of these infections regress, or resolve, within two years.9,14-17 Cervical carcinogenesis is a multi-step process that, typically, occurs over a long time frame.18 Transformation of cervical cells requires the long-term expression of the viral oncoproteins E6 and E7 which interact with and de-regulate the Rb and p53 tumor suppressor pathways resulting in genomic instability.20 This instability may result in damage to the cervical cell DNA and the cell accumulates genetic changes which drive carcinogenesis and tumor development.21

The detection of abnormalities in chromosomal DNA has been shown to be an effective tool for the detection and diagnosis of many cancers. Abnormal chromosomal number (aneuploidy) is a hallmark of cancer. Chromosome regions 3q & 5p are two of the most frequently amplified regions in all cancer cells.19,20 Research suggests the amplification of these chromosomal locations results in increase telomerase activity within the cells.20 The Telomerase RNA Component (TERC) gene is located at 3q26 and the Telomerase Reverse Transcriptase (TERT) gene is located at 5p15.19 The amplification of 3q and 5p within cells results in gain of both of these Telomerase subunit genes.20 With increased DNA copy number at 3q26 (TERC) and 5p15 (TERT), cells may promote carcinogenesis through a growth advantage.21,22 A recurrent pattern of chromosomal aberrations has been documented to play a role in cervical carcinogenesis, with the amplification of 3q26 (TERC) and 5p15 (TERT) being critical markers of disease progression.21-33 Numerous research studies have shown gains of 3q26 (TERC) and 5p15 (TERT) are present in the vast majority of both squamous and adenocarcinoma cervical cancers.21-33 The gain of 3q26 (TERC) has been shown to be associated with the transition from pre-malignant cervical intra-epithelial neoplasia (CIN) to invasive disease.22,24-30 The gain of 5p15 (TERT) is frequently present in high grade cervical squamous intraepithelial lesion (HSIL) specimens and is associated with marked dysplasia and cancer.22,24,25 Patients with amplifications at these loci have been shown to have a great risk of lymph node metastases.18,33,34 These data indicate that the presence of extra copies of these chromosomal loci drive the initial steps of cervical carcinogenesis.21-33

In addition, both 3q26 (TERC) and 5p15 (TERT) are amplified in vaginal and vulvar cancer and cancer cell lines, although gain of 5p15 (TERT) is three times more likely to be gained in these specimen types than 3q26 (TERC).25

References:

  1. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. Am J Obstet Gynecol 2007;197:340–5.
  2. Wright TC, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, and for the 2006 ASCCP-Sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007; 197:346-55.
  3. Management of abnormal cervical cytology and histology. ACOG Practice Bulletin No. 99 American College of Obstetricians and Gynecologists. Obstet Gynecol 2008; 112:1419-44.
  4. Cervical Cytology Screening. ACOG Practice Bulletin No. 109 American College of Obstetricians and Gynecologists. Obstet Gynecol 2009; 114:1409-20.
  5. Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, Ratnam S, Coutlée F, Franco EL; Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. 2007 N Engl J Med. 357:1579-88.
  6. Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, Rådberg T, Strander B, Johansson B, Forslund O, Hansson BG, Rylander E, Dillner J. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. 2007 N Engl J Med. 357:1589-97.
  7. Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, Voorhorst FJ, Verheijen RH, van Groningen K, Boon ME, Ruitinga W, van Ballegooijen M, Snijders PJ, Meijer CJ. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. 2007 Lancet. 370:1764-72.
  8. Herrero R, Munoz N. Human papillomavirus and cancer. 1999 Cancer Surv 33:75–98.
  9. Dunne EF, Unger ER, Sternberg M, McQuillian G, McSwan DC, Patel SS, Markowitz LE. Prevalence of HPV Infection Among Females in the United States. JAMA. 2007;297:813-819.
  10. Gage JC, Hanson VW, Abbey K, Dippery S, Gardner S, Kubota J, Schiffman M, Solomon D, Jeronimo J; ASCUS LSIL Triage Study (ALTS) Group. Number of cervical biopsies and sensitivity of colposcopy. 2006 Obstet Gynecol. 108:264-72.
  11. Jeronimo J, Schiffman M. Colposcopy at a crossroads. Am J Obstet Gynecol. 2006 195:349-53. Epub 2006 May 3.
  12. Stoler MH, Schiffman M; Atypical Squamous Cells of Undetermined Significance-Low-grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study.2001 JAMA. 285):1500-5.
  13. Carreon JD, Sherman ME, Guillén D, Solomon D, Herrero R, Jerónimo J, Wacholder S, Rodríguez AC, Morales J, Hutchinson M, Burk RD, Schiffman M. CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples. 2007 Int J Gynecol Pathol. 26:441-6.
  14. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188:1383–92.
  15. Cox JT, Schiffman M, Solomon D, for the ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol 2003; 188:1393–400.
  16. Guido R, Schiffman M, Solomon D, Burke L, for the ASCUS-LSIL Triage Study (ALTS) Group. Post-colposcopy management strategies for patients with low-grade squamous intraepithelial lesions or human papillomavirus DNA-positive atypical squamous cells of undetermined significance: two-year prospective study. Am J Obstet Gynecol 2003; 188:1401-1405.
  17. ASCUS-LSIL Triage Study (ALTS) Group. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol 2003; 188:1406-1412.
  18. Kanao H, Enomoto T, Kimura T, Fujita M, Nakashima R, Ueda Y, Ueno Y, Miyatake T, Yoshizaki T, Buzard G, Tanigami, Yoshino K, Murata Y. Overexpression of LAMP3/TSC403/DC-LAMP Promotes Metastasis in Uterine Cervical Cancer. 2005 Cancer Res. 65:8640-5.
  19. Baudis M. Genomic analysis in 5918 malignant epithelial tumors: an explorative meta-analysis of chromosomal data. 2007 BMC Cancer. 7:226-241.
  20. Cao Y, Bryan TM, Reddel RR. Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. 2008 Cancer Sci. 99:1092-1099.
  21. Mitra AB. Genetic Deletion and Human Papillomavirus Infection in Cervical Cancer: Loss of Heterozygosity Sites at 3p and 5p are Important Genetic Events. 1999 Int. J. Cancer. 72:322-324.
  22. Heselmeyer K, Schröck E, du Manior S, Blegen H, Shah K, Steinbeck R, Auer G, Ried T. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. 1996 PNAS. 93:479-484.
  23. Narayan G, Murty VV. Integrative genomic approaches in cervical cancer: implications for molecular pathogenesis. 2010 Future Oncol. 6:1643-1652.
  24. Scotto L, Narayan G, Nandula SV, Subramaniyam S, Kaufmann AM, Wright JD, Pothuri B, Mansukhani M, Schneider, Arias-Pulido H, Murty VV. Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha. 2008 Molecular Cancer. 7:58-68.
  25. Heselmeyer K, Macville M, Schröck E, Blegen H, Hellström AC, Shah K, Auer G, Ried T. Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q. 1997 Genes Chromosomes Cancer. 19:233-40.
  26. Heselmeyer-Haddad K, Janz V, Castle PE, Chaudhri N, White N, Wilber K, Morrison LE, Auer G, Burroughs FH, Sherman ME, Ried T. Detection of genomic amplification of the human telomerase gene (TERC) in cytologic specimens as a genetic test for the diagnosis of cervical dysplasia. 2003 Am J Pathol. 163:1405-16.
  27. Heselmeyer-Haddad K, Sommerfeld K, White NM, Chaudhri N, Morrison LE, Palanisamy N, Wang ZY, Auer G, Steinberg W, Ried T. Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer. 2005 Am J Pathol. 166:1229-38.
  28. Andersson S, Wallin KL, Hellstrom AC, Morrison LE, Hjerpe A, Auer G, Ried T, Larsson C, Heselmeyer-Haddad K. Frequent gain of the human telomerase gene TERC at 3q26 in cervical adenocarcinomas. 2006 Br. J. Cancer. Doi:10.1038/sj.bjc.6603253.
  29. Andersson S, Sowjanya P, Wangsa D, Hjerpe A, Johanson B, Auer G, Gravitt PE, Larsson C, Wallin KL, Ried T, Heselmeyer-Haddad K. Detection of genomic amplification of the human telomerase gene TREC, a potential marker for triage of women with HPV-positive, abnormal pap smears. 2009 Am J Pathol. 175:1831-1847.
  30. Fitzpatrick MA, Funk MC, Gius D, Huettner PC, Zhang Z, Bidder M, Ma D, Powell MA, Rader JS. Identification of chromosomal alterations important in the development of cervical intraepithelial neoplasia and invasive carcinoma using alignment of DNA microarray data. 2006 Gynecol Oncol. 103:458-62. Epub 2006 May 2.
  31. Lando M, Holden M, Bergersen LC, Svendsrud DH, Stokke T, Sundfør K, Glad IK, Kristensen GB, Lyng H. Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer. 2009 PLoS Genet. 5:e1000719. Epub 2009 Nov 13.
  32. Wilting SM, Steenbergen RDM, Tijssen M, van Wieringen WN, Helmerhorst TJM, van Kemenade FJ, Bleeker MCG, van de Wiel MA, Carvalho B, Meijer GA, Ylstra B, Meijer CJLM, Snijders PJF. Chromosomal signatures of a subset of high-grade premalignant cervical lesions closely resemble invasive carcinomas. 2009 Cancer Res. 69:647-55.
  33. Wangsa D, Heselmeyer-Haddad K, Ried P, Eriksson E, Schaffer AA, Morrison LE, Luo J, Auer G, Munck-Wikland E, Ried T, Lundqvist EA. Fluorescence in situ hybridization markers for the prediction of cervical lymph node metastases. 2009 Am. J. Pathol. 175:2637-45.
  
 
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