CCNE1  Amplification and Centrosome Number Abnormality in Serous Tubal Intraepithelial Carcinoma- Further Evidence Supporting its Role as a Precursor of Ovarian High-Grade Serous Carcinoma

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Abstract

Aberration in chromosomal structure characterizes almost all cancers and has profound biological significance in tumor development. It can be facilitated by various mechanisms including overexpression of cyclin E1 and centrosome amplification. Since ovarian high-grade serous carcinoma has pronounced chromosomal instability, in this study we sought to determine if increased copy number of CCNE1 which encodes cyclin E1 and centrosome amplification (> 2 copies) occur in its putative precursor, serous tubal intraepithelial carcinoma. We found CCNE1 copy number gain/amplification in 8 (22%) of 37 serous tubal intraepithelial carcinomas and 12 (28%) of 43 high-grade serous carcinomas. There was a correlation in CCNE1 copy number between serous tubal intraepithelial carcinoma and high-grade serous carcinoma in the same patient (p <0.001). There was no significant difference in the percentage of CCNE1 gain/amplification between serous tubal intraepithelial carcinoma and high-grade serous carcinoma (p= 0.61). Centrosome amplification was recorded in only 5 (14%) of 37 serous tubal intraepithelial carcinomas, and in 10 (40%) of 25 high-grade serous carcinomas. The percentage of cells with centrosome amplification was higher in high-grade serous carcinoma than serous tubal intraepithelial carcinoma (p< 0.001). Induced expression of cyclin E1 increased the percentage of fallopian tube epithelial cells showing centrosome amplification. Our findings suggest that gain/amplification of CCNE1 copy number occurs early in tumor progression and precedes centrosome amplification. The more prevalent centrosome amplification in high-grade serous carcinoma than serous tubal intraepithelial carcinoma supports the view that serous tubal intraepithelial carcinoma precedes the development of many high-grade serous carcinomas.

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Most cited references 29

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TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions.

Ann Sehdev, Elisabetta Kuhn, Tian-da Wang … (2012)

Serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of ovarian, tubal and 'primary peritoneal' (pelvic) high-grade serous carcinoma (HGSC). As somatic mutation of TP53 is the most common molecular genetic change of ovarian HGSC, occurring in more than 95% of cases, we undertook a mutational analysis of 29 pelvic HGSCs that had concurrent STICs to demonstrate the clonal relationship of STICs and HGSCs. In addition, we correlated the mutational data with p53 immunostaining to determine the role of p53 immunoreactivity as a surrogate for TP53 mutations in histological diagnosis. Somatic TP53 mutations were detected in all 29 HGSCs analysed and the identical mutations were detected in 27 of 29 pairs of STICs and concurrent HGSCs. Missense mutations were observed in 61% of STICs and frameshift/splicing junction/nonsense mutations in 39%. Interestingly, there were two HGSCs with two distinctly different TP53 mutations each, but only one of the mutations was detected in the concurrent STICs. Missense mutations were associated with intense and diffuse (≥ 60%) p53 nuclear immunoreactivity, while most of the null mutations were associated with complete loss of p53 staining (p < 0.0001). Overall, this p53 staining pattern yielded a sensitivity of 87% and a specificity of 100% in detecting TP53 missense mutations. In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Are all pelvic (nonuterine) serous carcinomas of tubal origin?

Robert Kurman, Chris G Przybycin, Russell Vang … (2010)

It has been proposed that the presence of tubal intraepithelial carcinoma (TIC), in association with one-third to nearly half of pelvic serous carcinomas, is evidence of fallopian tube origin for high-grade serous carcinomas that would have been otherwise classified as primary ovarian or peritoneal. To address this hypothesis, we evaluated a series of 114 consecutive pelvic (nonuterine) gynecologic carcinomas at our institution (2006 to 2008) to determine the frequency of TIC in 52 cases in which all the resected fallopian tube tissue was examined microscopically. These 52 cases were classified as ovarian (n=37), peritoneal (n=8), or fallopian tube (n=7) in origin as per conventional criteria based on disease distribution. The presence of TIC and its location and relationship to invasive carcinoma in the fallopian tubes and ovaries were assessed. Among the 45 cases of ovarian/peritoneal origin, carcinoma subtypes included 41 high-grade serous, 1 endometrioid, 1 mucinous, 1 high-grade, not otherwise specified, and 1 malignant mesodermal mixed tumor. TIC was identified in 24 cases (59%) of high-grade serous carcinoma but not among any of the other subtypes; therefore, the term serous TIC (STIC) is a more specific appellation. STICs were located in the fimbriated end of the tube in 22 cases (92%) and in the ampulla in 2 (8%); they were unilateral in 21 (88%) and bilateral in 3 (13%). STICs in the absence of an associated invasive carcinoma in the same tube were detected in 7 cases (30%) and with invasive carcinoma in the same tube in 17 (71%). Unilateral STICs were associated with bilateral ovarian involvement in 15 cases and unilateral (ipsilateral) ovarian involvement in 5 (the remaining case with a unilateral STIC had a primary peritoneal tumor with no ovarian involvement); the bilateral STICs were all associated with bilateral ovarian involvement. Six of the 7 primary tubal tumors were high-grade serous carcinomas, and 4 of these 6 (67%) had STICs. Based on conventional criteria, 70%, 17%, and 13% of high-grade serous carcinomas qualified for classification as ovarian, peritoneal, and tubal in origin, respectively; however, using STIC as a supplemental criterion to define a case as tubal in origin, the distribution was modified to 28%, 8%, and 64%, respectively. Features of tumors in the ovary that generally suggest metastatic disease (bilaterality, small size, nodular growth pattern, and surface plaques) were identified with similar frequency in cases with and without STIC and were, therefore, not predictive of tubal origin. The findings, showing that nearly 60% of high-grade pelvic (nonuterine) serous carcinomas are associated with STICs, are consistent with the proposal that the fallopian tube is the source of a majority of these tumors. If these findings can be validated by molecular studies that definitively establish that STIC is the earliest form of carcinoma rather than intraepithelial spread from adjacent invasive serous carcinoma of ovarian or peritoneal origin, they will have important clinical implications for screening, treatment, and prevention.

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Centrosome amplification, chromosome instability and cancer development.

Kenji Fukasawa (2005)

During mitosis, two centrosomes form spindle poles and direct the formation of bipolar mitotic spindles, which is an essential event for accurate chromosome segregation into daughter cells. The presence of more than two centrosomes (centrosome amplification), severely disturbs mitotic process and cytokinesis via formation of more than two spindle poles, resulting in an increased frequency of chromosome segregation errors (chromosome instability). Destabilization of chromosomes by centrosome amplification aids acquisition of further malignant phenotypes, hence promoting tumor progression. Centrosome amplification occurs frequently in almost all types of cancer, and is considered as the major contributing factor for chromosome instability in cancer cells. Upon cytokinesis, each daughter cell receives one centrosome, and thus centrosome must duplicate once, and only once, before the next mitosis. If centrosomes duplicate more than once within a single cell cycle, centrosome amplification occurs, which is frequently seen in cells harboring mutations in some tumor suppressor proteins such as p53 and BRCA1. The recent studies have provided critical information for understanding how loss of these proteins allows multiple rounds of centrosome duplication. In this review, how centrosome amplification destabilizes chromosomes, how loss of certain tumor suppressor proteins leads to centrosome amplification, and the role of centrosome amplification in cancer development will be discussed.

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Journal

Journal ID (nlm-journal-id): 8806605

Journal ID (pubmed-jr-id): 6644

Journal ID (nlm-ta): Mod Pathol

Journal ID (iso-abbrev): Mod. Pathol.

Title: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

ISSN (Print): 0893-3952

ISSN (Electronic): 1530-0285

Publication date Nihms-submitted: 1 June 2019

Publication date (Electronic): 22 July 2016

Publication date (Print): October 2016

Publication date PMC-release: 10 June 2019

Volume: 29

Issue: 10

Pages: 1254-1261

Affiliations

[1 ]Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

[2 ]Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, USA

[3 ]Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu, Japan,

[4 ]Legacy Health Systems, Portland, OR, USA

[5 ]Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Author notes

Correspondence: I-M Shih, MD, PhD, Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA, ishih@ 123456jhmi.edu and E. Kuhn, MD, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA, elisabettakuhn@ 123456hotmail.it

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Manuscript ID: NIHMS781271

DOI: 10.1038/modpathol.2016.101

PMC ID: 6557162

PubMed ID: 27443516

SO-VID: 90adf5a2-9b9f-471c-a1b9-a18e56d8d04a

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CCNE1 Amplification and Centrosome Number Abnormality in Serous Tubal Intraepithelial Carcinoma- Further Evidence Supporting its Role as a Precursor of Ovarian High-Grade Serous Carcinoma

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Most cited references 29

TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions.

Are all pelvic (nonuterine) serous carcinomas of tubal origin?

Centrosome amplification, chromosome instability and cancer development.

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