Possible involvement of hMLH1, p16INK4a and PTEN in the malignant transformation of endometriosis

Martini, Maurizio; Ciccarone, M; Garganese, Giorgia; Maggiore, Claudia; Evangelista, Antonella; Rahimi, Siavash; Zannoni, Gian Franco; Vittori, Giorgio; Larocca, Luigi Maria

doi:10.1002/ijc.10715

Cited by 134 publications

(111 citation statements)

References 37 publications

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“…[23][24][25][26][27][28][29] Marker cM 2165T 2165E 914T 914E 247T 247E 18542T 18542E 11MT 11ME 10MT 10ME 8872T 8872E 842T 842E Chrm 3q D3S1614 169.9…”

Section: Discussionunclassified

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer

Prowse

Manek

Varma

et al. 2006

Intl Journal of Cancer

146

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Histopathology and epidemiology studies have consistently demonstrated a strong link between endometriosis and endometriosisassociated ovarian cancers (EAOCs)-in particular, the endometrioid and clear cell subtypes. However, it is still unclear whether endometriosis is a precursor to EAOCs, or whether there is an indirect link because similar factors predispose to both diseases. In order to search for evidence of clonal progression, we analyzed 10 EAOCs (endometrioid 5 4; clear cell 5 6) with coexisting endometriosis for common molecular genetic alterations in both the carcinoma and corresponding endometriosis. We used 82 microsatellite markers spanning the genome to examine loss of heterozygosity (LOH) in the coexisting carcinoma and endometriosis samples. A total of 63 LOH events were detected in the carcinoma samples; twenty two of these were also detected in the corresponding endometriosis samples. In each case, the same allele was lost in the endometriosis and cancer samples. Interestingly, no marker showed LOH in the endometriosis alone. These data provide evidence that endometriosis is a precursor to EAOCs. ' 2006 Wiley-Liss, Inc.

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“…[23][24][25][26][27][28][29] Marker cM 2165T 2165E 914T 914E 247T 247E 18542T 18542E 11MT 11ME 10MT 10ME 8872T 8872E 842T 842E Chrm 3q D3S1614 169.9…”

Section: Discussionunclassified

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer

Prowse

Manek

Varma

et al. 2006

Intl Journal of Cancer

146

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“…Mutations of PTEN (chromosome 10p23.3) were identified in 20% of both EAC and ovarian endometriosis, suggesting that the PTEN inactivation is an early event in the malignant process of endometriosis (14,16). A separate study identified reduced PTEN protein expression in 15% of endometriosis cases (17). The second hit or carcinogenesis step could be represented by the reduced expression of hMLH1, MSI (17).…”

Section: Loh Involved In Endometrioid Adenocarcinoma (Eac) Of the Ovarymentioning

confidence: 99%

Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (Review)

Kobayashi¹

2009

Oncol Rep

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Abstract. Epithelial ovarian cancer (EOC) is the leading cause of death in women with gynecological malignancies. Among EOC, clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) differ from the other histological types with respect to their clinical characteristics and carcinogenesis. Both tumor types are often associated with endometriosis. EAC is recently reported to be characterized by K-RAS activation and PTEN dysfunction. However, the molecular changes in CCC remain largely unknown. The aim of this review is to summarize the current knowledge on the molecular mechanisms involved in CCC tumorigenesis. The present article reviews the English language literature for biological, pathogenetic and pathophysiological studies on endometriosis-associated CCC of the ovary. Several recent studies of loss of heterozygosity (LOH), allelic loss, comparative genomic hybridization, mutation, methylation status, microarray gene-expression profiling and proteomics are discussed in the context of CCC biology. Retrograde menstruation or ovarian hemorrhage carries highly prooxidant factors, such as heme and iron, into the peritoneal cavity or ovarian endometrioma. A histologically normal ectopic endometrium bears genetic damages caused by irondependent oxidative stress. DNA damage or LOH caused by oxidative stress is a critical factor in the carcinogenic process. LOH studies have implicated the involvement of specific chromosomal regions (5q, 6q, 9p, 10q, 11q, 17q and 22q). Furthermore, the PTEN and APC (early event), p53, polo-like kinases, Emi1 and K-RAS (late event) genes may be involved in CCC carcinogenesis. The molecular pathology of CCC is heterogeneous and involves various putative precursor lesions and multiple pathways of development, possibly via genetic alteration by oxidative stress. the candidate tumor suppressor genes 7. Microsatellite instability in CCC 8. Genes specifically up-regulated in CCC 9. Clear cell adenofibroma-CCC sequence 10. Iron, oxidative stress and carcinogenesis 11. Conclusions IntroductionEpithelial ovarian cancer (EOC) is the leading cause of death in women with gynecological malignancies worldwide. The majority of patients present with stage III and IV disease, for which the 5-year survival rates are less than 20%. Most of the patients with EOC present with advanced disease that is not cured by surgery. Ninety per cent of EOC are derived from epithelium within inclusion cysts or from the ovarian surface epithelium and these neoplasms are classified into serous, mucinous, endometrioid adenocarcinoma (EAC), clear cell carcinoma (CCC) and other types (1).Molecular genetic alterations play a key role in carcinogenesis (1). High-grade serous carcinoma arises in a de novo fashion and is characterized by p53 mutations and BRCA1 and/or BRCA2 dysfunction. In contrast, low-grade serous carcinomas are characterized by activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF in an adenoma-borderline tumor-carcinoma sequence. Similarly, mucinous carcinomas have also ...

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“…A separate study identified reduced PTEN protein expression in 15% of endometriosis cases (Martini et al 2002).…”

Section: Somatic Mutations In Tsgsmentioning

confidence: 99%

“…Hypermethylation of hMLH1 (whose gene product is a component of the DNA mismatch repair pathway), with concurrent absence of hMLH1 protein expression, is noted in 8.6% of endometriotic lesions (Martini et al 2002).…”

Section: Msimentioning

confidence: 99%

Endometriosis and the neoplastic process

Varma¹,

Rollason²,

Gupta³

et al. 2004

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186

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Endometriosis is a frequent disorder that commonly presents with infertility and pelvic pain. Although the precise aetiology of endometriosis is unclear, it is generally considered to involve multiple genetic, environmental, immunological, angiogenic and endocrine processes. Genetic factors have been implicated in endometriosis but the susceptibility genes remain largely unknown. Although endometriosis is a benign disorder, recent studies of endometriosis suggest endometriosis could be viewed as a neoplastic process. Evidence to support this hypothesis includes the increased susceptibility to develop ovarian clear-cell and endometrioid cancers in the presence of endometriosis, and molecular similarities between endometriosis and cancer. In this article we discuss (i) the evidence suggesting that endometriosis might be viewed as a neoplastic process, and (ii) the implications of this hypothesis for elucidating the pathogenesis of endometriosis and developing novel methods of diagnostic classification and individualised treatments.

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Possible involvement of hMLH1, p16^INK4a and PTEN in the malignant transformation of endometriosis

Cited by 134 publications

References 37 publications

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer

Molecular pathogenesis of endometriosis-associated clear cell carcinoma of the ovary (Review)

Endometriosis and the neoplastic process

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