Epithelial ovarian tumors pathogenesis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]


DNA damage and repair mechanisms.
DNA damage and repair mechanisms.[1]

Secondary Müllerian system

  • Although ovarian surface epithelium is not a derivative of Müllerian ducts but ovarian epithelial cancers are characterized by presence of Müllerian lesions.[2]
  • Serous carcinoma of ovary is though to originate from fallopian tubes while clear cell, endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis. Similarly Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives..[3][4]
  • Secondary Müllerian system is a hypothesis that tries to explain this apparent enigma of existence of Müllerian epithelial lesions in locations not derived from Müllerian ducts such as ovaries and peritoneal cavity.[5][4]
  • According to this hypothesis, Müllerian tissues, considered as vestigial, are found in locations such as para-tubal and para-ovarian locations and these tissues or cysts, not the ovarian epithelium itself, give rise to epithelial ovarian neoplasms.[3][4]

Hereditary ovarian carcinoma: An understanding of genome

  • More than one fifth cases of ovarian epithelial cancers are found to have hereditary causes. These hereditary diseases/syndromes appear to possess heterogeneous, both in genetic anomalies and in clinical manifestations.[6][7]
  • Majority of these hereditary cancers are caused by two genetic anomalies: a defect in so-called mismatch repair genes named as MLH1, MSH2, MSH6 and PMS2, and in DNA defects repair genes named as BRCA1 and BRCA2.[6][7][1][8]

The role of BRCA1 gene in DNA repair

  • BRCA1 is a protein that, through a complex interaction with other proteins such as tumor suppressors, regulators of cell cycle and other DNA repair genes, is involved in DNA repair pathways.[6][7] [9]
  • This protein has two domains: amino-terminal RING domain and a BRCT domain. The former posses E3 ubiquitin ligase activity and the later facilitates phospho-protein binding.[9]
  • Tumor suppressor role of both domains is highlighted by the fact that mutations in both domains have been found in breast and gynecological malignancies.[9]
  • The major role of BRCA1 appears to sense and repair double stranded DNA breaks in homologous recombination.[9]

Binding of BRCA1 to double stranded DNA breaks through its association with the abraxas–RAP80 macro-complex → processing of double stranded DNA breaks through interaction of BRCA1 with CtIP (transcription factor) and the MRN complex → The BRCA1–CtIP complex → CtIP-mediated 5′-end resection of double stranded DNA breaks

  • Another role of BRCA1 in Non-homologous end joining (NHEJ) pathway has also been proposed. Though still controversial, it has been suggested that BRCA1 plays a critical function by removal of Non-homologous end joining proteins such as p53-binding protein 1 (53BP1) from double stranded DNA breaks.[9]
  • G1/S, S-phase and G2/M checkpoints activation during cell cycle has also been found defective in cells lacking or having mutated BRCA1. A brief interaction of BRCA1 with cell cycle is given below:[9]

Phosphorylation of BRCA1 by ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related protein (ATR) → phosphorylation of p53 → transcriptional induction of the cyclin dependent kinase (CDK) inhibitor p21.

[10]A summary of BRCA1 activity and function in DNA damage repair

The role of BRCA2 gene in DNA repair

  • BRCA2, as opposed to BRCA1 that functions in multiple pathways involving DNA repair, has its primary role in homologous recombination (HR).[6][7][9]
  • DNA-binding domain (DBD) of BRCA2 binds single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) and eight BRC repeats. The eight BRC repeats bind RAD51 (a recombinase).[9][11]
  • The binding of BRCA2 to RAD51 leads to recruitment of RAD51 to double stranded DNA breaks, an essential step in homologous recombination double stranded DNA repair.[9][11][12]
  • After recruitment, BRCA2 helps RAD51 in displacement of replication protein A (RPA) in single stranded DNA. It then prevents nucleation of RAD51 at double stranded DNA and promotes RAD51 filament formation on single stranded DNA.[9][12]

The connection between BRCA1 and BRCA2

  • The common pathway that seems to link both BRCA! and BRCA2 proteins is homologous recombination mediated repair.[9][13][14]
  • Partner and localizer of BRCA2 (PALB2) physically connects BRCA1 and BRCA2 through N-terminal coiled-coil domain and the C terminus.[9][13][14]
  • The interaction between BRCA2 and PALB2 is observed for two critical function in homologous recombination mediated repair: interaction of RAD51 with replication protein A (RPA) in single stranded DNA and recruitment of BRCA2 and RAD51 on the site of DNA damage.[9]

The role of mismatch repair genes

  • Mismatch repair genes mutated in pathogenesis of hereditary epithelial ovarian cancer include human MutS homolog (MSH2 and 6), the human MutL homolog (MLH1 and 3), and post-meiotic segregation MutL homolog (PMS2) genes.[6][7][1][8]
  • A simplified version of repair mechanism by mismatch repair genes products is described below:[8][15]

MutS homologs (MSHs) recognize the DNA mismatch → MutS homologs (MSHs) recruit MutL homologs (MLHs) → excision of mismatched DNA → DNA polymerase re-synthesizes DNA.

  • Cells deficient in mismatch repair mechanism develop high rate of mutations including DNA sequences that include microsatellite repeats, resulting in microsatellite instability. This microsatellite instability has been implicated in impaired or defective signaling transduction, DNA repair and apoptosis, transcriptional regulation and protein translocation, and immune regulation.[1][8][15]

TP53 mutations and loss of tumor suppression

  • TP53 is a tumor suppressor gene that encodes for a transcription factor. The transcription factor encoded by TP53, known as p53, is a major regulator of cell cycle.[16][17]
  • Called by some as “Guardian of the Genome”, it is involved in variety of cellular functions such as cellular proliferation and cell cycle, apoptosis, and stability & integrity of the genome.[18][17]
Downstream effect of p53 mutation
Downstream effect of p53 mutation.[19]

Template:Epithelial ovarian cancer

An insight on molecular pathogenesis of epithelial ovarian cancer

Genetic alterations in cell cycle genes in epithelial ovarian cancer types.
Genetic alterations in cell cycle genes in epithelial ovarian cancer types.[20]

Dualistic Model

  • This model attempts to explain clinicopathological and molecular genetic features of epithelial tumors by diving them in two subgroups: type I and type II epithelial ovarian tumors.[21][22]
  • Another advantage of this classification is that it tries to group precursor lesions with their putative malignant lesions.[21][22]
  • Type I tumors generally arise from endometriosis or fallopian tubal related serous epithelium. They are clinically stable, exhibit less aggressive clinical course and a different genetic than that of Type II.[23][24]
  • Type II tumors generally arise from fallopian tubal epithelium. They exhibit more aggressive clinical course and a different genetic profile relative to Type I.[23][24]
  • Type I tumors are generally characterized by chromosomal stability and somatic mutations that may include KRAS, BRAF, PTEN, PIK3CA, CTNNB1, ARID1A and PPP2R1A. BRCA1 mutation, on the other hand, has not been observed and TP53 mutation is very rare.[21][22][25]
  • Type II tumors are characterized by chromosomal instability. The mutations characteristic of high grade tumors, especially TP53 are common. TP53 has been reported in more than 90% of these tumors and a high proportion contains either BRCA mutations or BRCA related mutations such as RAD51, PALB2.[21][26][27]
  • A simplified version of this classification is provided below:
Epithelial Ovarian Cancer
Type I Type II
  • Low-grade serous carcinoma
  • Endometrioid carcinoma
  • Clear cell carcinoma
  • Mucinous carcinoma
  • Malignant Brenner tumor
  • Seromucinous carcinoma
  • High-grade serous carcinoma
  • Undifferentiated carcinoma
  • Carcinosarcoma

Dualistic model for serous tumor

  • Serous tumor provides, perhaps the most, evidence for the proposed model. Studies suggest that it exhibits distinct morphological and genetic types/stages that may explain the progression from benign tumor (cystadenoma) to low grade serous tumor.[21][22]
  • This idea is supported by advances in discovery and understanding of so-called borderline serous tumors. These advances demonstrated that one type of these borderline tumors resembled benign serous tumors in their cinicopathological behavior and were named as “atypical proliferative serous tumor (APST)”. The other type behaved in way closer to low grade serous cancer and were termed as “micropapillary serous carcinoma (MPSC)”.[21][22][28]
  • The absence of KRAS and BRAF mutation in serous cystadenoma but presence of these mutations in atypical proliferative serous tumor indicates that these mutations occur somewhat early in transformation of serous cystadenoma into atypical proliferative serous tumor.[21][29]
  • More support was provided by studies that showed that genes involved in MAPK pathway were expressed more in micropapillary serous carcinoma than in atypical proliferative serous tumor. In addition, micropapillary serous carcinoma exhibited more chromosomal instability than atypical proliferative serous tumor.[21][28]
  • This indicates the step-wise development of low grade serous carcinoma from benign cystadenoma with developemnet of abnormalities in KRAS, BRAF and MAPK pathways. A simplistic version is given below:[21][30][31][32]

ERRB2 (mutation) → PI3K → AKT → mTOR → Cyclin D1 → cell cycle control and cellular survival → Tumor initiation and progression

KRAS → BRAF → MEK → ERK → Cell cycle control and cellular survival → Tumor initiation and progression

PI3K (mutation) → AKT → Tumor initiation and progression

KRAS (mutation) → BRAF → MEK → ERK → Tumor initiation and progression

PI3K (mutation) → Tumor initiation and progression

BRAF (mutation) → MEK → ERK → Cell cycle control and cellular survival → Tumor initiation and progression

*ERK can directly promote tumor initiation, and cellular growth and survival or can promote these through activation of glucose transporter-1 and cyclin D1.[21]

  • High grade serous carcinoma, on the other hand, is characterized by mutations rarely found in either of low grade serous carcinoma, micropapillary serous carcinoma and atypical prolferative serous tumor. Of these mutations, TP53 is the most common mutation and is found in >90% of the cases.[21][27]
  • While BRCA1 and BRCA2 mutations occur in majority of familial high grade serous carcinoma, inactivation of BRCA1 and/or BRCA2 by indirect mechanisms such as mutation and/or inactivation of promoter occur more frequently in sporadic high grade serous cancer and have been observed in about half of these cancers.[21][33]
  • The most noteworthy feature in molecular pathogenesis of high grade serous carcinoma is high level of DNA copy number gains or losses. These gains or losses are diffuse and include foci such as CCNE1 (cyclin E1), NOTCH3, AKT2, RSF1, and PIK3CA.[21][34]
Pathogenesis of high grade serous carcinoma
Pathogenesis of high grade serous carcinoma[35] Normal fallopian tube epithelium comprises of both secretory and ciliated cells and stains negative for p53. The benign ‘p53 signature’: secretory cells that possess strong p53 expression and evidence of DNA damage but are not proliferative. When they progress to serous tubal intraepithelial carcinoma or ‘STIC’, they acquire nuclear pleomorphism, mitoses, and loss of polarity. Serous tubal intraepithelial carcinoma shares all these properties with invasive high grade serous epithelial ovarian cancer and clinical symptoms typically emerge with advanced disease.[35][36]

Genetic alterations in clear Cell

  • Inactivating mutation of ARID1A. ARID1A encodes for a product that functions in tumor suppression and is observed in half of clear cell cancers.[21][25][37]
  • Activating mutation of PIK3CA, also observed in about half of these tumors, results in actiavtion of PI3k pathway.[21][38]
  • Deletion of PTEN, observed in about 20% of the cases, results in loss of tumor suppressor gene.[21][39]
  • These alterations indicate the importance of PI3K/PTEN pathway in development of clear cell carcinoma of ovary.[21][39]
ARIDA loss and PIK3CA activation in clear cell cancer of ovaries.[40](A) ARID1A and PIK3CA alterations plot against TCGA datasets. Significance of association between ARID1A and PIK3CA mutations were determined using Fisher’s exact test. (B) Determination of CRE-deleted (Arid1aΔ) allele in samples of tumor DNA. (C) RT-PCR was used to detect ARID1A loss or (Gt)Rosa26Pik3ca*H1047R transcripts. (D and E) Expression of ARID1A in normal ovaries (E) Expression of ARID1A in the normal ovarian surface epithelium (arrowhead). (F) ARID1A expression is not observed in the tumors. (H, I) Highest expression of P-AKT S473 in surface epithelium of ovaries in normal ovaries (E, arrowhead) and are greatly increased in ovarian tumors (F, arrowhead). Asterisk in E denotes an oocyte. (J,K) Morbid Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R mouse at sacrifice with hemorrhagic ascites (inset), primary ovarian tumor of moderate size, and bilateral tumor metastases (arrowheads). (L,M) Morbid Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R mouse at sacrifice with hemorrhagic ascites (inset), large primary ovarian tumor, and no visible metastases. The mice shown in J-M were sacrificed at 7 and 9 weeks post-AdCRE, respectively, because of visible ascitic fluid burden. (N,O) Arid1afl/+;(Gt)Rosa26Pik3ca*H1047R mice at 11-weeks post-AdCRE showing no evidence for tumor formation. In K and M, dashed circles indicate primary ovarian tumor on injected ovary. In N, arrows denote the AdCRE injected ovary. In K, M, and O, asterisks denote the uninjected, control ovary.

Genetic alterations in endometrioid tumors

  • Low grade endometrioid cancer also exhibits dysregulated either PI3K/PTEN pathway or Wnt/b-catenin signaling pathway. Later has been observed in about 40% of the low grade endometrioid tumors.[21][41][42][43]
  • PI3K/PTEN pathway is deregulated either by activating mutations in PIK3CA or inactivation/deletion of PTEN, a tumor suppressor gene. Activating mutations of CTNNB1, that encodes β-catenin, are usually the cause for deregulated Wnt/b-catenin signaling pathway.[21][41][42][43]
  • High grade endometrioid carcinoma, on the other hand, dooes not exhibit dysregulated PI3K/PTEN pathway or Wnt/b-catenin signaling pathway but frequently has TP53 mutations present.[21][43]

Genetic alterations in mucinous tumors

  • KRAS mutations are present in up to two thirds of these tumors and have also been used as molecular marker.[21][44][45]


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