FHACT: the FISH-based HPV-associated cancer test that detects nonrandom gain at four genomic loci as biomarkers of disease progression

Abstract

Despite implementation of screening programs for human papillomavirus (HPV)-associated cancers, in particular cervical, scientific studies continue to uncover viral and host biomarkers that could serve to further optimize the detection of individuals with underlying or at risk for developing precancer or cancer. Nonrandom host somatic chromosomal alterations are frequently shared across HPV-associated cancers, but with varying frequencies, potentially with functional roles. At least for 3q26 gain, there is firm preliminary evidence to support that this genomic alteration can serve as a biomarker of disease progression of cervical cancer. In the current review, the FISH-based HPV-associated cancer test is described that enables detection of genomic imbalance at four loci (3q26, 5p15, 20q13, centromere 7) in a single hybridization on a cell-by-cell basis in cytology specimens. When implemented as a secondary screening assay, the FISH-based HPV-associated cancer test could assist in the detection of clinically relevant HPV-associated disease and help guide patient management decisions.

Keywords::

• biomarker
• cancer
• chromosome
• FHACT
• gain
• HPV
• screening

Financial & competing interests disclosure

J Houldsworth is an employee and stockholder of Cancer Genetics, Inc. Funding was provided by Cancer Genetics, Inc. and National Cancer Institute. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Within current cervical cancer screening, about 80% of women with mildly abnormal/low grade or equivocal cytology findings referred to colposcopic-directed biopsy will not have clinically relevant disease, primarily due to the relatively poor sensitivity and reproducibility measures of the Pap test and reduced specificity and positive predictive value of high-risk human papillomavirus (HPV) DNA testing.

• Additional biomarker discovery and validation studies have been undertaken to improve the efficiency within this group of women to stratify those most likely to have underlying high-grade lesions and to better differentiate those low-grade lesions that will regress, persist or progress.

• Nonrandom somatic gain of genomic regions are shared across HPV-associated cancers perhaps as functional drivers of disease progression, and represent potential host biomarkers of HPV-associated immediate precancers and cancers.

• FHACT was introduced as a secondary screening assay to detect the gain of 3q26, 5p15, cen7 and 20q13 by FISH on a cell-by-cell basis in leftover cytology specimens, and at least for gain of 3q26 has exhibited higher sensitivity then the Pap test and higher specificity than high-risk HPV testing to detect underlying high-grade disease.

• As for other biomarkers currently being considered for secondary screening, well-designed, adequately-powered longitudinal studies are required to further validate and realize the true clinical utility of nonrandom chromosomal gain as a robust biomarker of HPV-associated disease progression.

Notes