Showing papers by "Setsuko K. Chambers published in 2013"

Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium

Abstract: Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. LS is the most common presentation of hereditary colorectal cancer (CRC), accounting for about 2–5% of all CRC cases. More recently, it is found that a similar number of endometrial cancers is also due to one of the MMR gene mutations. There has been significant progress in LS-related CRC in terms of molecular pathogenesis, risks, genetic basis, and cancer prevention. In contrast, the advance about LS-related endometrial cancer (EC) is very much limited. In this commentary, we summarize the main clinicopathologic features of LS-related EC and propose universal screening for LS in individuals with endometrial cancer.

Tubal origin of ovarian low-grade serous carcinoma

Abstract: Ovarian low-grade serous carcinomas are thought to evolve in a stepwise fashion from ovarian epithelial inclusions, cystadenomas, and borderline tumors. The current study was designed to gain insight into the origins of low-grade serous carcinomas (tubal versus ovarian) by comparatively evaluating the morphologic (secretory and ciliated cell distribution) and immunophenotypic (using antibodies to PAX8, tubulin, calretinin, and Ki67) attributes of its putative precursor lesions, the normal tubal epithelium, and the overt malignancy. A total of 226 adnexal tissues from 178 patients were studied, including 98 adnexae removed for non-neoplastic indications, 48 serous cystadenomas, 42 serous borderline tumors, and 38 low-grade serous carcinomas. Normal distal tubal epithelium comprised an admixture of PAX8 þ/tubulinsecretory cells and PAX8� / tubulin þ ciliated cells with a proliferative index of B3%. The vast majority of ovarian surface epithelia displayed a mesothelial phenotype (calretinin þ/PAX8� /tubulin� ) and low proliferative index (0% (12 per 1000)), although 4% of cases also displayed foci with tubal phenotype (calretinin� /PAX8 þ/tubulin þ). In contrast, most (78%) of the ovarian epithelial inclusions displayed a tubal phenotype and had a significantly higher proliferative index (1%) than ovarian surface epithelium, indicating that in most cases, the ovarian surface epithelium and ovarian epithelial inclusions are of different lineages. There was a progressive decrease in the population of ciliated cells, as evidenced by increasing secretory/ciliated cell ratio, from ovarian epithelial inclusions/cystadenomas to borderline tumors to low-grade serous carcinoma, indicating that the latter is a clonal expansion of secretory cells. Overall, the findings make a strong argument that the ovarian epithelial inclusions with a tubal phenotype is likely derived from fallopian tube through an intraovarian endosalpingiosis rather than through Mullerian metaplasia from ovarian surface epithelium. Genetic and molecular studies are needed to further confirm this finding as tubal origination of ovarian serous cancers will have a significant impact on ovarian cancer prevention and management. Modern Pathology (2011) 24, 1488-1499; doi:10.1038/modpathol.2011.106; published online 24 June 2011

An unusual BRCA mutation distribution in a high risk cancer genetics clinic

Abstract: The Database of Individuals at High Risk for Breast, Ovarian, or Other Hereditary Cancers at the Arizona Cancer Center in Tucson, Arizona assesses cancer risk factors and outcomes in patients with a family history of cancer or a known genetic mutation. We analyzed the subset of clinic probands who carry deleterious BRCA gene mutations to identify factors that could explain why mutations in BRCA2 outnumber those in BRCA1. Medical, family, social, ethnic and genetic mutation histories were collected from consenting patients' electronic medical records. Differences between BRCA1 and BRCA2 probands from this database were analyzed for statistical significance and compared to published analyses. A significantly higher proportion of our clinic probands carry mutations in BRCA2 than BRCA1, compared with previous reports of mutation prevalence. This also holds true for the Hispanic sub-group. Probands with BRCA2 mutations were significantly more likely than their BRCA1 counterparts to present to the high risk clinic without a diagnosis of cancer. Other differences between the groups were not significant. Six previously unreported BRCA2 mutations appear in our clinic population. The increased proportion of probands carrying deleterious BRCA2 mutations is likely multifactorial, but may reflect aspects of Southern Arizona's unique ethnic heritage.

Review Article Cell origin of endometriosis: contribution by the fallopian tube epithelium

Abstract: Endometriosis is one of the most enigmatic diseases in women. Extensive research has been carried out in the past since endometriosis has a significant impact in women's life. However, the pathogenesis of endome - triosis remains unclear. In this review, we briefly summarized four main theories associated with the cell origin of endometriosis including retrograde menstruation, coelomic metaplasia from ovarian or peritoneal surface, embry- onic rests from Mullerian tissue, and endometrioid tissue induction by hematopoietic stem cells. In addition, we have added our recently proposed theory of tubal origin of ovarian endometriosis based on our clinicopathological observations and recent experimental results. It would be interesting to know if the tubal contribution in the genesis of ovarian endometriosis can be truly accepted in future after additional in depth studies in various clinical, patho- logical, and molecular levels.

Review Article From endometrial glandular dysplasia to endometrial serous carcinoma: insights into underlying biological aspects

Abstract: Endometrial serous carcinoma (ESC), a clinically aggressive gynecologic cancer, is the prototypical type II endometrial carcinoma. In 2004, we first proposed a model of endometrial serous carcinogenesis that has, with ad - ditional evidence, developed into a robust, step-wise model of ESC development based on the progressive accumu- lation of molecular alterations. In this model, the cancer progresses from a resting endometrium into endometrial glandular dysplasia (EmGD), then serous endometrial intraepithelial carcinoma (SEIC), and eventually advances into ESC. Though various studies have discussed the key molecular alterations involved in ESC development, the pathways and relationships between different players are unclear. In this review, we have summarized the current state of knowledge on key pathways and on relationships between the molecular factors involved in endometrial serous carcinogenesis and discussed potential prevention and therapeutic strategies.

Post-Transcriptional Regulation of Proto-Oncogene c-fms in Breast Cancer

Abstract: In the development and progression of breast cancers, both the c-fms proto-oncogene (which encodes the tyrosine kinase receptor for CSF-1) as well as CSF-1 (colony stimulating factor1), play an important role. Evidence from transgenic models suggests that c-fms encodes for the sole receptor for CSF-1 (Dai et al, 2002). We and others have found that c-fms and/or CSF1 are expressed by the tumor epithelium in several human epithelial cancers (Kacinski et al, 1988, 1990, 1991; Rettenmier et al, 1989; Filderman et al, 1992; Ide et al, 2002); elevated levels of c-fms and CSF-1 are associated with poor prognosis (Kacinski et al, 1988; Tang et al, 1990; Price et al, 1993; Chambers et al, 1997, 2009; Scholl et al, 1993; Kluger et al, 2004; Sapi 2004). In human breast cancer, 94% of in situ and invasive lesions express c-fms (Kacinski et al, 1991; Flick et al, 1997), while 36% express both CSF-1 and c-fms (Kacinski et al, 1991; Scholl et al, 1993). Among breast cancer patients, serum levels of CSF-1 are frequently elevated in those with metastases (Kacinski et al, 1991). In breast tumors, nuclear CSF-1 staining is associated with poor survival (Scholl et al, 1994), and c-fms expression confers an increased risk for local relapse (Maher et al, 1998). In a large breast cancer tissue array, c-fms (Kluger et al, 2004) is strongly associated with lymph node metastasis, and poor survival. This strong correlation with prognosis suggests an etiologic role for c-fms/CSF-1 in tumor invasion and metastasis.

Nucleolin Mediates MicroRNA-directed CSF-1 mRNA Deadenylation but Increases Translation

Abstract: CSF-1 mRNA 3′UTR contains multiple unique motifs, including a common microRNA (miRNA) target in close proximity to a noncanonical G-quadruplex and AU-rich elements (AREs). Using a luciferase reporter system fused to CSF-1 mRNA 3′UTR, disruption of the miRNA target region, G-quadruplex, and AREs together dramatically increased reporter RNA levels, suggesting important roles for these cis-acting regulatory elements in the down-regulation of CSF-1 mRNA. We find that nucleolin, which binds both G-quadruplex and AREs, enhances deadenylation of CSF-1 mRNA, promoting CSF-1 mRNA decay, while having the capacity to increase translation of CSF-1 mRNA. Through interaction with the CSF-1 3′UTR miRNA common target, we find that miR-130a and miR-301a inhibit CSF-1 expression by enhancing mRNA decay. Silencing of nucleolin prevents the miRNA-directed mRNA decay, indicating a requirement for nucleolin in miRNA activity on CSF-1 mRNA. Downstream effects followed by miR-130a and miR-301a inhibition of directed cellular motility of ovarian cancer cells were found to be dependent on nucleolin. The paradoxical effects of nucleolin on miRNA-directed CSF-1 mRNA deadenylation and on translational activation were explored further. The nucleolin protein contains four acidic stretches, four RNA recognition motifs (RRMs), and nine RGG repeats. All three domains in nucleolin regulate CSF-1 mRNA and protein levels. RRMs increase CSF-1 mRNA, whereas the acidic and RGG domains decrease CSF-1 protein levels. This suggests that nucleolin has the capacity to differentially regulate both CSF-1 RNA and protein levels. Our finding that nucleolin interacts with Ago2 indirectly via RNA and with poly(A)-binding protein C (PABPC) directly suggests a nucleolin-Ago2-PABPC complex formation on mRNA. This complex is in keeping with our suggestion that nucleolin may work with PABPC as a double-edged sword on both mRNA deadenylation and translational activation. Our findings underscore the complexity of nucleolin's actions on CSF-1 mRNA and describe the dependence of miR-130a- and miR-301a-directed CSF-1 mRNA decay and inhibition of ovarian cancer cell motility on nucleolin.

Investigation of bendamustine HCL in a phase 2 study in women with resistant ovarian cancer.

Abstract: We investigated the safety and efficacy of 90 mg/m2 bendamustine HCL, administered intravenously on days 1 and 2 every 28 days in 10 women with platinum and taxane resistant epithelial ovarian cancer. There were no objective tumor responses observed; 2 patients had stable disease. Plasma samples collected at pre-treatment and end of cycle one were analyzed for changes in circulating total cytokeratin 18 and caspase cleaved cytokeratin 18 as exploratory early biomarkers of bendamustine-induced tumor cell death. All patients had measureable levels of both total and cleaved caspase 3 cytokeratin 18, but no relationship with response was possible due to the lack of clinical benefit in treated patients. Due to the high incidence of adverse events and absence of objective responses, only ten patients were treated as predefined by the Simon Two-Stage Design in the protocol. Overall, the regimen was not well tolerated and was associated with fatigue and a greater number of gastrointestinal side effects as compared to previously reported experiences in different patient populations. However, our study subjects did experience less bone marrow suppression. The lack of tolerability could reflect the degree of tumor burden within the peritoneal cavity as well as the high number of prior regimens (median of 5) received by the patients participating in this study.