One of the greatest challenges in cervical cancer screening is the sensitivity of the Pap test. The addition of high risk HPV to the Pap greatly improves sensitivity, at the cost of specificity. As described in this issue, an attempt at isolating patients at greater risk for advanced cervical disease is through genotyping for HPV types 16/18. However, this is by no means predictive of future disease and may cause a false sense of security, or unnecessary follow-up. A predictive test, which can help identify patients at more foreseeable risk for high grade cervical disease is desperately needed. Testing for genetic abnormalities, using the HPV-4C®fluorescent in-situ hybridization (FISH) test, may provide the answer. Non-random chromosomal abnormalities are associated with the progression of cervical disease. These abnormalities are detected by observing increased numbers, or “gains” of chromosomal regions which are identified with different colored fluorescent probes (please see figures 1-3.) The HPV-4C®test is a highly sensitive and specific 4-color FISH test which examines 4 chromosomal regions; 3q, 5p, 20q and Centromere 7. Gain of 3q26 (the TERC gene) is seen in approximately 75% of cervical cancers1. Gains of 5p, 20q and centromere 7 have lower frequencies, consistent with their lower occurrence in cervical cancer although these are often associated with more advanced lesions.2-4 Gain of any one of the four loci is detected in up to 90% of all cervical cancers.5 What does this mean? In short, women with a positive test are showing evidence of chromosomal abnormalities, or “DNA damage”, which is strongly associated with the presence of, or the progression to, high grade cervical disease (CIN 3 or above.) Conversely, women who are not showing these abnormalities have not yet acquired this damage; it is therefore conceivable that this lesion may regress and the patient can be managed accordingly.

FIGURE 1: Two cell nuclei, each with normal (diploid, or 2) copy numbers of each chromosomal region (3q26 = red, 5p15 = green, CEN7= aqua, 20q = gold.)

FIGURE 2: Four cell nuclei, each with abnormal copies of 3q26 (red) and 5p15 (green)

FIGURE 3: A single nucleus with abnormal copies (3 or more) of all probes

BIBLIOGRAPHY 1 Andersson S et al. 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. 2009 Nov;175(5):1831-47. 2 Scotto L et al. Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over- expressed genes, including Drosha. Mol Cancer. 2008 Jun 17;7:58. 3 Scotto L et al. 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. 2008 Sep;47(9):755-65. 4 Luhn P et al. Chromosomal gains measured in cytology samples from women with abnormal cervical cancer screening results. Gynecol Oncol. 2013 Sep;130(3):595-600. 5 Heselmeyer-Haddad et al. Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer. Am J Pathol. 2005 Apr;166(4):1229-38.