Whole exome sequence analysis of serous borderline tumors of the ovary

Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, USA. Electronic address: .
Gynecologic Oncology (Impact Factor: 3.77). 06/2013; 130(3). DOI: 10.1016/j.ygyno.2013.06.007
Source: PubMed


Serous borderline tumor (SBT) is a unique histopathologic entity of the ovary, believed to be intermediate between benign cystadenoma and invasive low-grade serous carcinoma. While somatic mutations in the KRAS or BRAF, and rarely ERBB2, genes have been well characterized in SBTs, other genetic alterations have not been described. Toward a more comprehensive understanding of the molecular genetic architecture of SBTs, we undertook whole exome sequencing of this tumor type.

Following pathologic review and laser capture microdissection to enrich for tumor cells, whole exomes were prepared from DNA of two independent SBTs and subjected to massively parallel DNA sequencing.

Both tumors contained an activating mutation of the BRAF gene. A total of 15 additional somatic mutations were identified, nine in one tumor and six in the other. Eleven were missense mutations and four were nonsense or deletion mutations. Fourteen of the 16 genes found to be mutated in this study have been reported to be mutated in other cancers. Furthermore, 12 of these genes are mutated in ovarian cancers. The FBXW7 and KIAA1462 genes are noteworthy candidates for a pathogenic role in serous borderline tumorigenesis.

These findings suggest that a very small number of somatic genetic mutations are characteristic of SBTs of the ovary, thus supporting their classification as a relatively genetically stable tumor type. The mutant genes described herein represent novel candidates for the pathogenesis of ovarian SBT.

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    • "Low grade serous carcinomas have a DNA content and level of copy number alterations which more closely resembles SBTs than high grade serous carcinomas and are intermediate between the two [88] [89]. A recent study involving a whole exome analysis of low grade serous carcinomas of the ovary identified an average of only 10 somatic mutations per tumor [90] [91]. "
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    ABSTRACT: Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas. The carcinogenesis of endometrioid and clear cell carcinoma (CCC) arising from endometriotic cysts is significantly influenced by the free iron concentration, which is associated with cancer development through the induction of persistent oxidative stress. A subset of mucinous carcinomas develop in association with ovarian teratomas; however, the majority of these tumors do not harbor any teratomatous component. Other theories of their origin include mucinous metaplasia of surface epithelial inclusions, endometriosis, and Brenner tumors. Low grade serous carcinomas are thought to evolve in a stepwise fashion from benign serous cystadenoma to a serous borderline tumor (SBT). With regard to high grade serous carcinoma, the serous tubal intraepithelial carcinomas (STICs) of the junction of the fallopian tube epithelium with the mesothelium of the tubal serosa, termed the "tubal peritoneal junction" (TPJ), undergo malignant transformation due to their location, and metastasize to the nearby ovary and surrounding pelvic peritoneum. Other theories of their origin include the ovarian hilum cells.
    BioMed Research International 04/2014; 2014(5-6):934261. DOI:10.1155/2014/934261 · 2.71 Impact Factor
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    ABSTRACT: There is debate as to whether peritoneal implants associated with serous borderline tumors/atypical proliferative serous tumors (SBT/APSTs) of the ovary are derived from the primary ovarian tumor or arise independently in the peritoneum. We analyzed 57 SBT/APSTs from 45 patients with advanced stage disease identified from a nation-wide tumor registry in Denmark. Mutational analysis for hotspots in KRAS and BRAF was successful in 55 APSTs and demonstrated KRAS mutations in 34 (61.8%) and BRAF mutations in 8 (14.5%). Mutational analysis was successful in 56 peritoneal implants and revealed KRAS mutations in 34 (60.7%) and BRAF mutations in 7 (12.5%). Mutational analysis could not be performed in 2 primary tumors and in 9 implants either because DNA amplification failed or there was insufficient tissue for mutational analysis. For these specimens we performed VE1 immunohistochemistry, which was shown to be a specific and sensitive surrogate marker for a V600E BRAF mutation. VE1 staining was positive in one of 2 APSTs and 7 of 9 implants. Thus, among 63 implants for which mutation status was known (either by direct mutational analysis or by VE1 immunohistochemistry), 34 (53.9%) had KRAS mutations and 14 (22%) had BRAF mutations of which identical KRAS mutations were found in 34 (91%) of 37 SBT/APST-implant pairs and identical BRAF mutation in 14 (100%) of 14 SBT/APST-implant pairs. Wild-type KRAS and BRAF (at the loci investigated) were found in 11(100%) of 11 SBT/APST-implant pairs. Overall concordance of KRAS and BRAF mutations was 95% in 59 of 62 SBT/APST-implant (non-invasive and invasive) pairs (p< 0.00001). In conclusion, this study provides cogent evidence that the vast majority of peritoneal implants, non-invasive and invasive, harbor the identical KRAS or BRAF mutations that are present in the associated SBT/APST, supporting the view that peritoneal implants are derived from the primary ovarian tumor.
    The Journal of Pathology 01/2014; 232(1). DOI:10.1002/path.4293 · 7.43 Impact Factor
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    ABSTRACT: Objectives Borderline ovarian tumors (BOT) are premalignant lesions. Approximately 10% of all epithelial ovarian cancers are known to be hereditary with hereditary breast and ovarian cancer (HBOC) accounting for approximately 90% of cases; the remaining 10% are attributable to Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). The aim of our study is to estimate this risk based on screening immunohistochemistry (IHC). Methods Thirty-four patients diagnosed with BOT were identified. Family history, clinical characteristics, and IHC data (breast cancer 1, early onset [BRCA1], breast cancer 2, early onset [BRCA2], mutS homolog 2 [MSH2], mutL homolog 1 [MLH1]) were collected for all cases from the patients' medical charts. Nuclear staining of the tumor was scored as negative and positive. Results Among 32 patients, 14 (44%) had serous type and 18 (56%) had mucinous type. The mean patient age was 44 years (range 19-86).The number of patients with weak IHC staining for MSH2 and BRCA2 was 1 (3%) and 6 (19%) respectively. The median follow up was 21.8 months. Conclusion According to the results, we discovered that 3% and 19% of patients with BOT had a risk of hereditary cancer based on IHC analysis respectively. This pilot study may help clinician to counsel effectively for confirmative tests.
    04/2014; 20(1):14-20. DOI:10.6118/jmm.2014.20.1.14
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