Page 94 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman
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Chapter 4
Interestingly, 3q gain can occur based on tetrasomy, in which four copy numbers are found, or aneusomy, in which three or more than four copy numbers are found. It is unclear whether there is a clinical difference between these two forms of 3q gain, in terms of the risk of disease persistence or progression. Both tetrapoidy and aneuploidy are frequent events in CIN development. The frequency of tetraploid cells is significantly increased in CIN lesions compared to normal cervical tissue and is considered an early event in cervical carcinogenesis.[28] Aneuploidy is more often found in more advanced lesions and cervical carcinoma.[15] Although it is still debated whether aneuploidy results from genomic instability of diploid cells or from chromosomal losses from tetraploid cells, evidence in CIN lesions suggests that aneuploidy is preceded by tetraploidy. [28] This would indicate that aneuploidy in CIN lesions associates with later stages of cervical oncogenesis, possibly indicated a more high-risk CIN lesion. Based on these findings, one may argue that 3q26/hTERC gain based on aneuploidy imposes a greater risk of disease persistence or progression than 3q26/hTERC gain based on tetraploidy. In our study, the only purely aneusomic lesion showed disease regression. Our study shows no difference in disease regression or persistence based on 3q26 gain in tetrasomic or aneusomic lesions, but numbers are small and the follow-up term was relatively short. The reviewed studies show conflicting results regarding the prognostic value of 3q gain based on either aneuploidy or tetraploidy. One study showed a positive predictive value of 100% for gain based on aneuploidy for disease progression.[20] Two other studies could not confirm this finding, but compared progression to non-progression (including persistence), which makes comparison of the studies difficult.[22, 24] Interestingly, Lan et al. found a higher progression risk for tetraploid lesions.[23] In conclusion, current evidence shows that lesions with 3q26 gain based on both tetrasomy and aneusomy can show either regression, persistence or progression. Based on these results, it remains unclear whether there is a clinical difference between 3q26/hTERC gain based on tetrasomy or aneusomy, in terms of the risk of disease persistence or progression.
Only five out of eight reviewed studies performed HPV typing, of which only one study reported on the association between HPV and 3q gain: a non-significant association was found between viral load and 3q gain.[21] As discussed before, this limits the overall interpretation of the study results, since high-risk HPV in itself is a risk factor for disease progression/persistence. Regarding the relation between HPV infection and 3q26/hTERC gain, it is debated whether 3q26/hTERC gain is a direct cause of HPV infection, or an independent risk factor in high-grade CIN. It has been shown that genomic integration of HPV (with increased expression of E6 and E7) and gain of hTERC are important associated genetic events in the progression of CIN to cervical cancer.[16] On the other hand, 3q gains have also been detected in non-HPV-associated squamous cell cancers of the lower genital tract and other malignancies.[12] Assessment of HPV status is therefore vital in future studies on the prognostic properties of 3q26/hTERC. Furthermore, future studies should clarify the association between HPV genotype and 3q gain, with regard to the natural prognosis of high-grade CIN.
Limitations of the current clinical study include the small patient population. The patient population was extracted from a historical cohort of patients from a previous study, based upon the availability of sufficient biopsy material. Another limitation of our study may be the use of
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