Cervical infection with high-risk human papillomavirus (hrHPV) is the necessary cause of cervical cancer. Secondary prevention of the disease relies on the accurate identification and treatment of high-grade precursors to prevent progression to invasive disease. Inclusion of hrHPV typing tests in cytology-based screening programs has clearly improved the sensitivity with which precancerous lesions are detected. Indeed, women testing hrHPV-negative have an extremely low risk of cancer over 3-5 years. The management of women testing hrHPV-positive in the setting of a normal cytology or abnormal cells of undetermined significance (ASC-US) however, is much less clear. About 90% of HPV infections will be cleared within 1-2 years and only a minority of precancerous lesions will progress to a higher grade lesion (5-year risk of progression is reported to be about 4-6%). Women diagnosed with a low grade squamous intraepithelial lesion (LSIL) have a marginally higher risk of progression but hrHPV testing does allow any additional benefit in risk assessment since most are hrHPV-positive. It is in these clinical settings that integration of additional biomarkers in the triage process is much needed in order to limit unnecessary colposcopies and excisional procedures and identify those women with lesions that are at risk of progression to a higher grade.
Associated with such progression is the appearance of host oncogenic events, such as non-random chromosomal abnormalities including genomic gain . The FISH-Based HPV-Associated Cancer Test (FHACTÂ®) assesses these genomic alterations. Fluorescence in situ hybridization (FISH) analysis is performed on nuclei of cells derived from a liquid pap specimen, using the FHACTÂ® combination probe (CGI Italia): 3q26 (TERC) (red), 5p15 (D5S2095) (green), 20q13 (D20S911) (gold) and CEP7 (aqua).
Gain of 3q26 (TERC) has been detected with increasing frequency in cervical lesions with increasing severity and ultimately is observed in about 75% of cervical cancers [2-5]. Gain of 5p15, 20q13, and chromosome 7 share a similar pattern of appearance in precancerous cytology specimens by FISH but with lower frequencies, consistent with their lower occurrence in cervical cancer (40-45% for 5p15 and 20q13, and 15% for chromosome 7) [6-8]. Gain of any one of the four loci is detected in up to 90% of all cervical cancers .
FHACTÂ® is indicated for hrHPV-positive normal or ASC-US, and LSIL cytology specimens.
1. The Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov)
2. Heselmeyer-Haddad K, et al. (2005) Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer. Am J Pathol, 166, 1229-1238.
3. Caraway NP, et al. (2008) Gain of the 3q26 region in cervicovaginal liquid-based pap preparations is associated with squamous intraepithelial lesions and squamous cell carcinoma. Gynecol Oncol, 110, 37-42.
4. Andersson S, et al. (2009) Detection of genomic amplification of the human telomerase gene TERC, a potential marker for triage of women with HPV-positive, abnormal Pap smears. Am J Pathol, 175, 1831-1847.
5. Seppo A., et al. (2009) Gain of 3q26: a genetic marker in low-grade squamous intraepithelial lesions (LSIL) of the uterine cervix. Gynecol Oncol, 114, 80-83.
6. Scotto, L., et al. (2008) Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha. Mol Cancer, 7, 58.
7. Scotto L., et al. (2008) Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: Potential role in progression. Genes Chromosomes Cancer, 47, 755-765.
8. Luhn P, et al. (2013) Chromosomal gains measured in cytology samples from women with abnormal cervical cancer screening results. Gynecol Oncol, 130, 595-600.