Project description:BackgroundSerous borderline ovarian tumour (SBOT) is the most common type of BOT. Fertility sparing surgery (FSS) is an option for patients with SBOT, though it may increase the risk of recurrence. The clinical and molecular features of its recurrence are important and need to be investigated in detail.MethodsAn internal cohort of 319 patients with SBOT was collected from Aug 1, 2009 to July 31, 2019 from the Obstetrics and Gynecology Hospital of Fudan University in China. An external cohort of 100 patients with SBOT was collected from Aug 1, 2009 to Nov 30, 2019 from the Shandong Provincial Hospital in China. The risk factors for the recurrence were identified by multivariate cox analysis. Several computational methods were tested to establish a prediction tool for recurrence. Whole genome sequencing, RNA-seq, metabolomics and lipidomics were used to understand the molecular characteristics of the recurrence of SBOT.FindingsFive factors were significantly correlated with SBOT recurrence in a Han population: micropapillary pattern, advanced stage, FSS, microinvasion, and lymph node invasion. A random forest-based online recurrence prediction tool was established and validated using an internal cohort and an independent external cohort for patients with SBOT. The multi-omics analysis on the original SBOT samples revealed that recurrence is related to metabolic regulation of immunological suppression.InterpretationOur study identified several important clinical and molecular features of recurrent SBOT. The prediction tool we established could help physicians to estimate the prognosis of patients with SBOT. These findings will contribute to the development of personalised and targeted therapies to improve prognosis.FundingJL was funded by MOST 2020YFA0803600, 2018YFA0801300, NSFC 32071138, and SKLGE-2118 to Jin Li; JY was funded by the Initial Project for Young and Middle-aged Medical Talents of Wuhan City, Hubei Province ([2014] 41); HH was funded by MOST 2019YFA0801900 and 2020YF1402600 to He Huang; JS was funded by NSFC 22,104,080; CG was funded by Natural Science Foundation of Shanghai 20ZR1408800 and NSFC82171633; BL was funded by Natural Science Foundation of Shanghai 19ZR1406800.

Project description:Epithelial ovarian cancer is morphologically and clinically heterogeneous. Transcriptional profiling has revealed molecular subtypes (referred to as M-bM-^@M-^\C-signaturesM-bM-^@M-^]) that correlate to biological as well as clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and to investigate similarities to the intrinsic molecular subtypes of breast cancer. Global gene expression profiling was performed using Illumina's HT12 Bead Arrays and applied to 59 fresh-frozen ovarian tumors. SAM analysis revealed enrichment of cell cycel processes among the malignant tumors, in line with malignant tumors being highly proliferative. The borderline tumors were split between the malignant and benign tumor clusters, indicating that borderline tumors have both malignant and benign features. Furthermore, nearest centroid classification was performed applying previously published gene profiles for the ovarian cancer C-signatures and the intrinsic breast cancer subtypes, respectively, and showed significant correlations between the malignant serous tumors and the highly aggressive C1, C2 and C4 ovarian cancer signatures, and the basal-like breast cancer subtype. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer C3 signature. The borderline tumors, on the other hand, correlated significantly to the Luminal A breast cancer subtype. These findings remained when analyzed in a large, independent dataset. The data in this study link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, including an aggressive phenotype, frequent TP53 mutations and a high degree of genomic instability, and suggest that biomarkers and targeted therapies may overlap between these subsets of ovarian and breast cancers. Finally, the link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers. Total RNA obtained from serous ovarian adenocarcinomas, adenomas and borderline tumors. Gene expression profiling using Illumina's HT12 v4 bead arrays. Application of ovarian cancer molecular subtypes and intrinsic breast cancer subtypes using nearest centroid classification. KRAS and BRAF mutation analyses in the malignant and borderline tumors.

Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Gene expression analysis was performed on five serous borderline tumors with BRAF mutation and five serous borderline tumors without BRAF mutation randomly. RNA was extracted from microdissected tumor cells. Expression profiling was carried out with Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays

Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed.

Project description:Epithelial ovarian cancer is morphologically and clinically heterogeneous. Transcriptional profiling has revealed molecular subtypes (referred to as “C-signatures”) that correlate to biological as well as clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and to investigate similarities to the intrinsic molecular subtypes of breast cancer. Global gene expression profiling was performed using Illumina's HT12 Bead Arrays and applied to 59 fresh-frozen ovarian tumors. SAM analysis revealed enrichment of cell cycel processes among the malignant tumors, in line with malignant tumors being highly proliferative. The borderline tumors were split between the malignant and benign tumor clusters, indicating that borderline tumors have both malignant and benign features. Furthermore, nearest centroid classification was performed applying previously published gene profiles for the ovarian cancer C-signatures and the intrinsic breast cancer subtypes, respectively, and showed significant correlations between the malignant serous tumors and the highly aggressive C1, C2 and C4 ovarian cancer signatures, and the basal-like breast cancer subtype. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer C3 signature. The borderline tumors, on the other hand, correlated significantly to the Luminal A breast cancer subtype. These findings remained when analyzed in a large, independent dataset. The data in this study link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, including an aggressive phenotype, frequent TP53 mutations and a high degree of genomic instability, and suggest that biomarkers and targeted therapies may overlap between these subsets of ovarian and breast cancers. Finally, the link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.

			Action	DRS
	SRR17179873_1.fastq.gz	Fastqsanger.gz
	SRR17179873_2.fastq.gz	Fastqsanger.gz
	SRR17179874_1.fastq.gz	Fastqsanger.gz
	SRR17179874_2.fastq.gz	Fastqsanger.gz
	SRR17179875_1.fastq.gz	Fastqsanger.gz

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Identification of clinical and molecular features for recurrent serous borderline ovarian tumor

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