Abstract
AimsSOX17 expression has not been studied in glandular lesions of the uterine cervix like adenocarcinoma in situ (AIS) and invasive adenocarcinomas (AdC), whereas SOX17 promoter CpG island methylation has been reported. Therefore, the aim of this study was to relate the topographical distribution of SOX17 expression and SOX17 methylation status to each other, and to SOX2 expression, human papillomavirus (HPV) type, and physical status of the virus.Methods and resultsImmunohistochemistry was used in 45 cases to assess expression of SOX17 and SOX2. SOX17 promoter methylation was determined in 25 cases by means of bisulphite conversion and methylation‐specific polymerase chain reaction. SOX17 and SOX2 showed a mutually exclusive expression pattern in normal epithelium, with a sharp delineation in the squamocolumnar junction. SOX17 was found in endocervical columnar and reserve cells, whereas SOX2 was exclusively found in squamous epithelium. In both glandular lesions and cases with coexisting glandular and squamous intraepithelial components, a complex combination of SOX17 and SOX2 expression patterns was seen and mutually exclusive expression was lost. Frequently, gain of expression of SOX2 was found and expression of SOX17 was lost. Methylation of the CpG island in the SOX17 promoter was shown to be strongly associated with loss of expression of SOX17 (P = 0.0016).ConclusionsIn this study, we show for the first time a direct correlation between the topographical distribution of SOX17 expression and the methylation status of its gene promoter. This explains the heterogeneity of SOX17 expression in the glandular lesions of the cervix. No correlation was found between HPV type and physical status of the virus on the one hand and methylation status on the other.
Highlights
Cervical cancer is the fourth most frequent cancer in women, with an estimated 570 000 new cases in 2018
We immunohistochemically examined the expression pattern of the transcription regulator protein SRY-box containing gene 17 (SOX17) in normal cervical glandular epithelium and in the lesions derived therefrom
SOX2 expression, Human papillomavirus (HPV) typing of the lesions, chromogenic in-situ hybridisation (CISH) and several molecular markers were used for correlation with SOX17 expression and SOX17 promoter methylation
Summary
Cervical cancer is the fourth most frequent cancer in women, with an estimated 570 000 new cases in 2018. The majority of endocervical adenocarcinoma (AdC) and AdC in situ (AIS) is K17-positive, suggesting a role for these cells in the development of such endocervical (pre)malignancies.[14,15] Both squamous and glandular carcinomas develop in the cervical transformation zone which is an important argument for the hypothesis that the reserve cells play a central role in the pathogenesis of both squamous and glandular cervical lesions.[16,17,18,19,20,21]. The promoter CpG island region of SOX17 has been reported to be methylated in the majority of squamous and glandular (pre)malignant lesions of the uterine cervix.[26] As a single marker, promoter CpG island methylation of SOX17 has been shown to be associated with progression of high-grade SIL (HSIL) into carcinoma.[27] Another transcription regulator protein from the SRY-box gene family, SOX2, has been shown to play an important role during the progression of SIL lesions. SOX2 expression, HPV typing of the lesions, chromogenic in-situ hybridisation (CISH) and several molecular markers were used for correlation with SOX17 expression and SOX17 promoter methylation
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