DNA Methylome Analyses Implicate Fallopian Tube Epithelia as the Origin for High-Grade Serous Ovarian Cancer

Abstract

High-grade serous ovarian cancer (HGSC) is the most common and lethal form of epithelial ovarian cancer (EOC). Two distinct tissues have been suggested as the tissue of origin: ovarian surface epithelia (OSE) and fallopian tube epithelia (FTE). We hypothesized that the DNA methylome of HGSC should more closely resemble the methylome of its tissue of origin. To this end, we profiled HGSC (n=10), and patient-matched OSE and FTE (n=5) primary fresh-frozen tissues, and analyzed the DNA methylome using Illumina 450K arrays (n=20) and Agilent Sure Select methyl-seq (n=7). Methylomes were compared using statistical analyses of differentially methylated CpG sites (DMC) and differentially methylated regions (DMR). In addition, methylation was evaluated within a variety of different genomic contexts, including CpG island shores and Homeobox (HOX) genes, due to their roles in tissue specification. Publically-available HGSC methylome data (n=628) were interrogated to provide additional comparisons with FTE and OSE for validation. These analyses revealed that HGSC and FTE methylomes are significantly and consistently more highly conserved than are HGSC and OSE. Pearson correlations and hierarchal clustering of genes, promoters, CpG islands, CpG island shores, and HOX genes all revealed increased relatedness of HGSC and FTE methylomes. Thus, these findings reveal that the landscape of FTE more closely resembles HGSC, the most common and deadly EOC subtype.

Epigenetics in ovarian cancer

“…In addition to genomic characteristics, these EOC histotypes have different epidemiologic risk factors [2–4], expression signatures [5–7], clinical responses to therapy [8] and distinct precursor sites. HGSOC appears to originate from fallopian tube or ovarian surface epithelium [9], shows few mutational events compared with other histotypes [10] and generally have gross chromosomal instability exhibiting copy number variations [11,12]. LGSOC are considered to arise from borderline tumors [13] and commonly possess mutations in the Ras family of genes ( KRAS, BRAF, NRAS, ERBB2 , and PTEN ) and are chromosomally stable [14].…”

Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling

“…As evidence of an FTE origin, several studies identified putative precursor lesions in the fallopian tube of women undergoing prophylactic oophorectomy called p53 signatures, which were patches of secretory epithelium that express mutant p53 protein [2–4]. The transcriptomic profile of HGSOC tumors significantly correlated with that of the fallopian tube [5], and the genomic methylation patterns of HGSOC were more similar to the FTE than the OSE [6]. A recent retrospective analysis found salpingectomy was associated with a 45% decrease in ovarian cancer risk [7].…”

Epigenetic reprogramming towards mesenchymal-epithelial transition in ovarian cancer-associated mesenchymal stem cells drives metastasis

“…We downloaded and reprocessed external DNA methylation data on normal cell types from prior publications (Patch et al 2015;Klinkebiel et al 2016) (methods), including normal FTE and ovary stroma, profiled on the earlier generation of the Infinium platform, Infinium HumanMethylation450 (450K) array. The intersect between the two platforms (450,161 CpGs) were used in joint analysis with these external normal controls.…”

“…Public available data resources DNA methylation data (Illumina HM450 array) of ovarian stroma samples (N=4; samples annotated as ovary and pathologist evaluation of available slides confirms ovarian stroma histology) were downloaded from the Genomic Data Commons (GDC) Data Portal (https://portal.gdc.cancer.gov), together with that of Uterine Carcinosarcoma (UCS; N=57) and Sarcoma (SARC; N=261). Pure, uncultured fallopian tube epithelium samples (FTE; N=4) were downloaded through GEO database, with one sample GSM2146822 taken from Series GSE81224 (Klinkebiel et al 2016), and the other three samples (GSM1606969, GSM1606970, and GSM1606973) from Series GSE65820 (Patch et al 2015). Other FTE samples in the same studies either had insufficient epithelial purity or had undergone in vitro culturing and therefore not included.…”