Clinicopathological And Molecular Characteristics Of Ovarian Cancer And Fallopian Tube Cancer With Analysis Of Deregulation Of Parkin Gene And Its Significance

BACKGROUNDThe diagnosis and therapy of ovarian cancer(OC)is the key problems of gynecologic oncologists,and its mortality ranks first in gynecological cancer.OC have been categorized into two broad categories as types Ⅰ and Ⅱ.Tumors of the two types have different characteristics in morphology,immunohistochemical and molecular genetic phenotype,and clinical pathways.Type Ⅱ tumors are defined as high grade neoplasms with high-grade serous carcinoma(HGSC)as the most common histological type.Recent studies hypothesize that a large proportion of HGSC may arise from fallopian tube distal epithelium,with the main evidences that serous tubal intraepithelial carcinoma(STIC)was observed in the tubal fimbriae of prophylactic salpingo-oophorectomy from women carrying BRCA mutations and specimen of cytoreductive surgery for ovarian HGSCs.Almost all HGSCs have mutation in the P53 gene,and P53 mutation have been found in serous carcinogenesis as an important early event.The patterns of P53 staining with immunohistochemistry can serve as surrogate marker for P53 mutation in OC.Fallopian tube cancer(FTC)is a rare gynecological malignancy.The true incidence of FTC may have been underestimated.HGSC is the most common histological subtype of the ovaries and the fallopian tubes.STIC often associated with invasive FTC.Serous OC and FTC may be a common disease.Most clinical studies have investigated the characteristics of the OC and FTC independently,and did not consider the STIC.Therefore,it may result in an inaccurate description of the essence for these lesionsGermline mutations of Parkin gene can cause neuronal dysfunction,and is associated with risk of Autosomal Recessive Juvenile Parkinson’s Disease(ARJPD).Somatic Parkin mutations may contribute to oncogenesis.Deregulation of the Parkin gene,including mutation,mRNA and protein downregulation,copy number loss,has been found in many kinds of human cancers,suggesting that the Parkin gene may be a tumor suppressor gene.The function of Parkin involved in various signaling pathways in cancer.However,many aspects about the role of Parkin in tumorigenesis remain unexplored.Parkin is a P53 target gene,and inactivation of the Parkin gene is correlates with P53 mutations.It is unclear how the P53 and Parkin gene interact in the tumor development.Researches on Parkin gene in OC and FTC have important significance to elucidate how Parkin gene plays a role and how Parkin and P53 interplay in cancer-linked pathological contexts.OBJECTIVETo analyze the difference between the OC(especially type Ⅱ)and FTC;to examine the incidence of STIC in specimen of OC and FTC in Chinese population;to investigate the clinicopathological characteristics and prognostic factors of OC with STIC and/or oviduct intramucosal carcinoma in order to verify the hypothesis of"pelvic HGSC originated from epithelium of the fallopian tube";to delineate the difference of deregulation in Parkin gene,including loss of heterozygosity(LOH),mRNA and protein expression,between various histological subtype of OC and FTC;to study the correlation between the deregulation of Parkin gene in tumor tissue and clinicopathological and immunohistochemical features,and to explore the mechanism of Parkin gene act in the development of OC and FTC.MATERIALS AND METHODS419 cases of OC and FTC were retrospectively studied with morphology,tissue microarray,immunohistochemical staining with follow-up and review of the literatures.Loss of heterozygosity(LOH)analysis with polymerase chain reaction-capillary electrophoresis(PCR-CE)was applied to 157 cases.Quantitative real-time RT-PCR(qRT-PCR)was performed in 107 cases for detection the expression of Parkin mRNA.RESULTSThere were 141 cases of type Ⅰ OC,and 233 cases of type Ⅱ OC.The numbers of HGSC,clear cell carcinoma(CCC),endometrial adenocarcinoma(EC),mucinous adenocarcinoma(MC)and low-grade serous carcinoma(LGSC)were 219,39,31,40,21 respectively,and HGSC accounting for 58.56%.There were 45 cases of FTC,including 42 cases of HGSC.Age of onset for OC and FTC patients was lower than population of Europe and America in Chinese population,and also the prognosis is poor.We found a significant poorer survival for type Ⅰ OC compared to type Ⅱ OC with all patients in advanced stage.There were no difference in clinicopathological parameters,immunohistochemical expression profile,overall survival(OS)and progression free survival(PFS)between type Ⅱ OC and FTC.STIC were found in 43/103 cases of ovarian HGSC and 22/42 cases of tubal HGSC,but not found in cases of type Ⅰ OC.Most cases of HGSC with STIC and/or oviduct intramucosal carcinoma(HGSC with tubal lesions)were in advanced stage.It was very similar in many clinicopathological parameters between cases of HGSC with tubal lesions combined with FTC and cases of type Ⅱ OC without tubal lesions.Type Ⅰ OC was quite much different from the former two in clinicopathologic and prognostic factors.88 of 157 OC/FTC samples showed LOH of Parkin gene in at least one STS(sequence-tagged site)locus in the region of Parkin gene,and 7 cases showed microsatellite instability(MSI).LOH of Parkin gene was significantly correlated with histological subtype—HGSC,P53 intense positive staining and advanced stage.Patients in advanced stage with LOH of Parkin gene showed a longer OS and PFS,compared with patients of advanced stage with negative LOH detection.The mRNA and protein expression of Parkin was significantly downregulated in OC/FTC compared with benign tissue.Low levels of Parkin mRNA were associated with typeⅡ tumor,LOH of Parkin gene and P53 intense positive staining.The protein downregulation of Parkin gene correlated with high level of CA125,lymph node metastasis and advanced stage.Different from the type Ⅰ OC,deregulation of Parkin gene were very similar in tumor of HGSC with tubal lesion,FTC,and type Ⅱ OC without tubal lesions.CONCLUSION1)OC of type Ⅱ and FTC might be a common disease,or originated from the same organ,because there were no difference in many clinicopathological parameters,prognostic factors and genetic background.2)The analysis of clinicopathological parameters for the patients of HGSC with tubal lesions combined with FTC strongly supported the hypothesis that "all pelvic HGSC arise from epithelium of fallopian tube".3)LOH was a common form of Parkin gene mutation,which was significantly associated with longer survival in advanced patients of type Ⅱ OC.4)Deregulation of Parkin gene occurred frequently in OC/FTC,and was significantly correlated with the expression of tumor marker and the development of invisive phenotype for OC/FTC.