Cellular context determines DNA methylation profiles in SWI/SNF‐deficient cancers of the gynecologic tract

Abstract

SWI/SNF (SWItch/Sucrose Non-Fermentable) complex deficiency has been reported in a wide variety of cancers and is often associated with an undifferentiated phenotype. In the gynecologic tract SWI/SNF-deficient cancers are diagnostically challenging and little is known about their cellular origins. Here we show that undifferentiated endometrial carcinoma (UDEC), SMARCA4-deficient uterine sarcoma (SDUS), and ovarian small cell carcinoma, hypercalcemic type (SCCOHT) harbor distinct DNA methylation signatures despite shared morphology and SWI/SNF inactivation. Our results indicate that the cellular context is an important determinant of the epigenetic landscape, even in the setting of core SWI/SNF deficiency, and therefore methylation profiling may represent a useful diagnostic tool in undifferentiated, SWI/SNF-deficient cancers. Furthermore, applying copy number analyses and group-wise differential methylation analyses including endometrioid endometrial carcinomas and extracranial malignant rhabdoid tumors, we uncover analogous molecular features in SDUS and SCCOHT in contrast to UDEC. These results suggest that SDUS and SCCOHT represent chromosomally stable SWI/SNF-deficient cancers of the gynecologic tract, which are within the broader spectrum of malignant rhabdoid tumors.

Small‐cell carcinoma of the ovary hypercalcaemic type shows a wild‐type immunohistochemical staining pattern of p53

“…Our findings are consistent with prior DNA sequencing studies of SCCOHT which did not identify mutations or significant copy number variations in TP53 6–8 . Our results show that an abnormal p53 staining pattern renders a diagnosis of SCCOHT highly unlikely.…”

“…Our findings are consistent with prior DNA sequencing studies of SCCOHT which did not identify mutations or significant copy number variations in TP53. [6][7][8] Our results show that an abnormal p53 Correspondence 155 staining pattern renders a diagnosis of SCCOHT highly unlikely. Instead, immunohistochemical evidence of TP53 mutations would suggest other highgrade ovarian neoplasms, such as a high-grade serous carcinoma or even metastatic disease.…”

Teratoma‐associated and so‐called pure Wilms tumour of the ovary represent two separate tumour types with distinct molecular features

“…Cancer cells harbour DNA methylation profiles that reflect both the cell of origin and somatically acquired DNA methylation changes 40 . We have previously shown that this technique allows the tracing of the distinct cellular origins of various cancers in the gynaecological tract 41–43 . In the current study, we show that teratoma‐associated ovarian WTs mostly share a DNA methylation cluster with mature cystic teratomas, which is distinct from primary renal WT (including three renal WT with DICER1 alterations).…”

“…40 We have previously shown that this technique allows the tracing of the distinct cellular origins of various cancers in the gynaecological tract. [41][42][43] In the current study, we show that teratoma-associated ovarian WTs mostly share a DNA methylation cluster with mature cystic teratomas, which is distinct from primary renal WT (including three renal WT with DICER1 alterations). Furthermore, the two so-called pure ovarian WTs clustered with the recently described DNA methylation cluster of SARC DICER1, which is distinct from both the clusters of primary renal WT and conventional DICER1-associated SLCT.…”

Mesonephric‐like adenocarcinoma harbours characteristic copy number variations and a distinct DNA methylation signature closely related to mesonephric adenocarcinoma of the cervix

“…DNA methylation profiles of cancer cells reflect both somatically acquired DNA methylation changes and inherent features that reflect the cell of origin [15]. The latter enables, for example, the tracing of the distinct cellular origins in undifferentiated SWI/SNF (SWItch/Sucrose Non‐Fermentable)‐deficient cancers of the gynaecological tract [16]. Conversely, a significant overlap in the epigenome of tumours of various histological origins indicates a biological relatedness, as has recently been shown for DICER1‐associated neoplasms and for high‐grade endometrial stromal sarcomas with different types of genetic fusions [17,18].…”