open access: The origin of ovarian cancer (including references to familial/non-familial ovarian cancer/inclusion cysts...)

"According to Hamilton,¹ the concept that epithelial ovarian cancers arise from ovarian surface epithelial (OSE) cells was proposed by Sir Spencer Wells in 1872. More than a century later, this hypothesis remains controversial....Over the last decade several fundamental observations have documented that epithelial ovarian cancers should no longer be considered as a single disease entity."

Conclusion and future directions

There is recent compelling evidence that histological subtypes of epithelial ovarian cancers represent different disease entities that are characterised by distinct molecular changes. Research into the biology of those cancers, including an investigation of their cell of origin, should therefore be subtype-specific.

The finding by Sharma et al. does not refute the hypothesis of the ovarian origin of epithelial ovarian cancer, but does provoke a discussion about the cellular origin of these cancers. The fallopian tube epithelium is very likely to play an important role in the development of HGSOCs in women with BRCA mutations, and in a subset of non-familial HGSOCs. This does not, however, explain the origin of the majority of sporadic ovarian cancers that may grow directly from the ovary without tubal involvement. It is interesting to note that the data from Sharma et al. show a trend towards an increased risk of epithelial ovarian cancer in women with ICs (inclusion cysts) (relative risk of 1.92), albeit a statistically non-significant increase in risk. It is possible that much smaller ICs may have been missed by pelvic ultrasound, and that those could have contributed to the development of a fraction of epithelial ovarian cancers in the IC-negative women. The evolving model of a tubal origin of ovarian cancer, however, has important implications for future clinical and research directions.

The role of prophylactic salpingectomy alone in reducing the risk of epithelial ovarian cancer should be evaluated only in prospective clinical studies. Novel imaging modalities for the detection of early tubal lesions are needed to investigate the value of early detection of tubal intraepithelial carcinomas in reducing the risk of development of invasive epithelial ovarian cancer.
It is also crucial that further characterisation of the molecular events that control orderly cell division and differentiation of tubal epithelium should be investigated to gain insights into the initiation and progression of pelvic serous cancers.

worth reading - Medical News: SGO: PARP Inhibitor Active in Ovarian Cancer - in Meeting Coverage, SGO from MedPage Today

......"Antitumor activity was observed in heavily pretreated BRCA1 and BRCA2 mutation carriers, and preliminary antitumor activity was seen in patients with sporadic cancers," said Robert Wenham, MD, of the H. Lee Moffitt Cancer Center in Tampa, Fla...........During the initial dose-escalation phase, the patient population was enriched with BRCA1/2 mutation carriers. In the dose-expansion phase of the trial, investigators enrolled patients with sporadic platinum-resistant high-grade serous ovarian cancer......cont'd

free full access: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients — Ann Oncol

PARP inhibition: targeting the Achilles' heel of DNA repair..PARP inhibition: targeting the Achilles' heel of DNA repair to treat germline and sporadic ovarian cancers

Genetic/Familial high-risk assessment: breast and ... [J Natl Compr Canc Netw. 2010] - PubMed result

Abstract

Overview
All cancers develop as a result of mutations in certain genes, such as those involved in the regulation of cell growth and/or DNA repair,(1,2) but not all of these mutations are inherited from a parent. For example, sporadic mutations can occur in somatic/tumor cells only, and de novo mutations can occur for the first time in a germ cell (i.e., egg or sperm) or in the fertilized egg itself during early embryogenesis. However, family studies have long documented an increased risk for several forms of cancer among first-degree (i.e., parents, siblings, and children) and second-degree relatives (i.e., grandparents, aunts or uncles, grandchildren, and nieces or nephews) of affected individuals. These individuals may have an increased susceptibility to cancer as the result of 1 or more gene mutations present in parental germline cells; cancers developing in these individuals may be classified as hereditary or familial cancers. Hereditary cancers are often characterized by mutations associated with a high probability of cancer development (i.e., a high penetrance genotype), vertical transmission through either mother or father, and an association with other types of tumors.(3,4) They often have an early age of onset and exhibit an autosomal dominant inheritance pattern (i.e., occur when the individual has a mutation in only 1 copy of a gene). Familial cancers share only some features of hereditary cancers. For example, although familial breast cancers occur in a given family more frequently than in the general population, they generally do not exhibit the inheritance patterns or onset age consistent.

Clinical Significance of Microsatellite Instability in Sporadic Epithelial Ovarian Tumors

Abstract: CONCLUSION: MSI was infrequent in ovarian tumors, including both borderline and malignant tumors. MSI was found to be uncommon in sporadic ovarian tumors, even by using additional MSI markers. The clinical significance of MSI is not strong in patients with sporadic ovarian tumors.

Link to full text (pdf file):

DISCUSSION
....MSI is caused by mutations in the mismatchrepair genes (MMR). MSI has been implicated in the pathogenesis of colon, endometrial, and gastric
carcinomas that occur in the setting of HNPCC (Lynch Syndrome), and also in a subset of sporadic cancers such as upper urinary tract, stomach, colon, andendometrial carcinomas.
In ovarian cancers, the reported incidence of MSI ranges from 0 to 37%, depending on the number and type of markers. Sood et al. first
reported the incidence of MSI in ovarian cancer using the NCI criteria.....Therefore, further study of molecular events that are correlated with ovarian tumors is needed."

media item: Study Makes Strides in Understanding Ovarian Cancer (cysts/BRCA/sporadic)

Important: see post April 26th -  full free access:
 PLOS One: Genetic Analysis of the Early Natural History of Epithelial Ovarian Carcinoma
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Media article: 
"This is the first study giving very strong evidence that a substantial number of ovarian cancers arise in inclusion cysts and that there is indeed a precursor lesion that you can see, put your hands on, and give a name to," lead author Jeff Boyd, chief scientific officer at Fox Chase Cancer Center in Philadelphia, said in a news release. "Ovarian cancer most of the time seems to arise in simple inclusion cysts of the ovary, as opposed to the surface epithelium."...cont'd

Increased Incidence of Visceral Metastases in Scottish Patients With BRCA1/2-Defective Ovarian Cancer: An Extension of the Ovarian BRCAness Phenotype

Note: see abstract for further information

Results:
Seventy-nine patients with EOC/PPC and germline BRCA1/2 mutations were identified. Fifteen had inadequate clinical data, two had carcinosarcoma, 27 had previous breast cancer, and 16 were in remission. Of the remaining 19 patients who were BRCA1/2 deficient, 14 patients (74%) developed visceral metastases compared with six (16%) of 38 patients in the control group. The percentages of liver, lung, and splenic metastases were 53%, 32%, and 32%, respectively, in the patients compared with 5%, 3%, and 5%, respectively, in the controls.
Conclusion:
Although sporadic EOC commonly remains confined to the peritoneum, BRCA1/2-deficient ovarian cancer frequently metastasizes to viscera. These data extend the ovarian BRCAness phenotype, imply BRCA1/2-deficient ovarian cancer is biologically distinct, and suggest that patients with visceral metastases should be considered for BRCA1/2 sequencing.

BRCA1 as a Therapeutic Target in Sporadic Epithelial Ovarian Cancer

Jan 2009 full free access - Development of PARP inhibitors in oncology; Expert Opinion on Investigational Drugs + Expert Opinion

Note: highly technical but worth reviewing (BRCAness, sporadic, specific therapies (combination/single agent/+radiotherapy), those in clinical studies (Table 1),
differing cancers etc