Does EIF2S3 Retrogene Activation Regulate Cancer/Testis Antigen Expression in Human Cancers?

Cancer/Testis (C/T) antigens are a group of antigens, expressed in almost all types of cancers, which can elicit an immune response in patients whose cancers express these antigens. They are currently of great interest as targets for the development of cancer biomarkers and the creation of immunotherapies that directly target tumors in patients. Currently there are 280 C/T antigens and their variants listed on the C/T antigen data base. All known C/T antigens are encoded for by genes which are normally only expressed in the male testis; specifically during the process of spermatogenesis. They are therefore only expressed in germ cells that are in the process of differentiating into sperm. Expression of C/T antigens in tumors is thus a biological anomaly as, with the exception of germ cell tumors, cancers arise from somatic tissues which are not known to express any of the genes specifically involved in spermatogenesis. How and why C/T antigens are expressed in tumors remains an enigma. In this paper we present a hypothesis which proposes a mechanism for the activation of C/T antigen encoding genes in tumors. We propose that aberrant activation of the human autosomal retrogene, EIF2S3B, which regulates initiation and maintenance of spermatogenesis in males, is responsible for C/T expression. Because both male and females have tumors that express C/T antigens activation of spermatogenesis genes in tumors must involve a non-sex specific pathway. This can be explained by the copy number of EIF2S3 genes uniquely present within the human genome.

Successful Pregnancy after Intervention for Spindle-Cell Embryonal Rhabdomyosarcoma: A Case Report.

BACKGROUND: Embryonal rhabdomyosarcoma, the most common soft tissue malignancy in childhood, is treated with surgery and chemotherapy. Because of the young age at the time of presentation, a discussion of future reproduction is appropriate and conservative management should be considered. We present a case of embryonal rhabdomyosarcoma that was successfully and conservatively managed with chemotherapy, allowing for future pregnancies. CASE: A 17-year-old nulliparous woman with embryonal rhabdomyosarcoma underwent 6 cycles of chemotherapy with adriamycin, dacarbazine, cyclophosphamide, and vincristine, resulting in radiographic resolution of the disease. She was able to conceive without medical intervention and to have successful vaginal deliveries. SUMMARY AND CONCLUSION: The standard of care for embryonal rhabdomyosarcoma is surgery and chemotherapy; however, conservative management should be considered when preservation of fertility is a goal.

Prevention of Recurrent Mucinous Borderline Ovarian Tumor with Aromatase Inhibitor.

BACKGROUND: Aromatase inhibitors (AIs) are used for estrogen-modulated conditions. Some borderline ovarian tumors (BOT) express estrogen receptors. We present 2 cases of progression from mucinous cystadenoma to mucinous BOT (mBOT) after prior cystectomies in whom an AI was used with recurrence prevention. CASES: Two patients underwent laparoscopic ovarian cystectomy for mucinous cystadenoma. Serial imaging demonstrated recurrent ovarian cysts for which both underwent fertility sparing surgery (FSS) with ovarian cystectomy for mBOT. Both patients were initiated on an AI and have been without recurrence. SUMMARY AND CONCLUSION: BOT predominantly occur in reproductive aged females. FSS with cystectomy is an option, but recurrence occurs in 12-36% of cases. The use of AI in prevention of recurrent BOT shows promise, and more studies are needed to explore this treatment.

Successful yolk-sac tumor treatment with fertility-sparing partial oophorectomy.

Yolk-sac tumors account for about 20% of ovarian germ cell tumors and occur predominantly in women below 35 years of age. Modern evidence-based treatment strategies have ensured long term post-treatment survival, but with increased survival, attention has been turned to an urgent need for developing fertility sparing treatment strategies. In this report we describe the successful treatment of a young woman who was able to conceive and deliver two children, in spite of the loss of one ovary two years prior to being diagnosed with an ovarian yolk-sac tumor on the remaining ovary.

Do some epithelial ovarian cancers originate from a fallopian tube ciliate cell lineage?

There is a general agreement that a large subpopulation of serous ovarian cancers arise from the fallopian tube mucosal epithelium. However, there is still some debate as to whether the cancers originate from a secretory or ciliate cell lineage. One well established method for determining the origin of a cell line is to document the expression of genes and proteins that are cell type specific. Lineage or tissue specific patterns of gene expression are evidence of direct decent from a given cell type within a tissue. It has recently been established that the Tumor Protein TAp73 gene (TP73) is expressed in basal epithelial cells that develop into multiciliate cells. TP73 expression is therefore a marker for basal stem cells that are predestined to differentiate into cells with motile cilia and its expression is maintained in fully differentiated multiciliate cells. Interestingly TP73 expression has also been observed in a high percentage of epithelial ovarian cancers. With this in mind, it is hypothesized that a high percentage of epithelial ovarian cancers which express TP73 originate from a ciliate cell lineage.

Does expression of the retrogene UTP14c in the ovary pre-dispose women to ovarian cancer?

It has been previously shown that the spermatogenesis associated retrogene, UTP14c, is expressed in over 50% of normal human ovaries and 80% of ovarian cancers. UTP14c is located on chromosome 13 as an intronless copy of the X-linked housekeeping gene, UTP14a. Like all spermatogenesis associated retrogenes, UTP14c is expressed in the testis and is essential for sperm production. It has no known role in the female and is not normally expressed in any cells or organs outside of the gonads. By comparison the protein encoded by UTP14a is found in all cell types and has a dual function. It is primarily involved in the biosynthesis of 18S ribosomal RNA in the nucleolus where it is a component of the U3 small nucleolar RNA associated protein complex. In addition, it down regulates TP53 in both the nucleus and cytoplasm by targeting it for proteolytic degradation. By analogy, we propose that the UTP14c peptide also targets TP53 for degradation. This in turn may prevent cells expressing UTP14c from entering apoptosis. The loss of TP53 in ovarian cells can also result in the down regulation of microRNA-145 (miR-145) expression. The loss of miR-145 can result in the activation of factors that promote oncogenesis and cellular pluripotency which in turn could lead to the development of ovarian cancer. We hypothesize that women, whose ovaries express UTP14c, are predisposed to ovarian cancer due to the disruption of protective signals that normally trigger TP53-mediated apoptosis and the dysregulation of genes that promote oncogenesis, such as c-Myc, that occurs when miR-145 synthesis is disrupted.

Spermatogenesis associated retrogenes are expressed in the human ovary and ovarian cancers.

BACKGROUND: Ovarian cancer is the second most prevalent gynecologic cancer in women. However, it is by far the most lethal. This is generally attributed to the absence of easily detectable markers specific to ovarian cancers that can be used for early diagnosis and specific therapeutic targets. METHODOLOGY/PRINCIPAL FINDINGS: Using end point PCR we have found that a family of retrogenes, previously thought to be expressed only in the male testis during spermatogenesis in man, are also expressed in normal ovarian tissue and a large percentage of ovarian cancers. In man there are at least eleven such autosomal retrogenes, which are intronless copies of genes on the X chromosome, essential for normal spermatogenesis and expressed specifically in the human testis. We tested for the expression of five of the known retrogenes, UTP14C, PGK2, RPL10L, RPL39L and UBL4B in normal human ovary and ovarian cancers. CONCLUSIONS/SIGNIFICANCE: We propose that the activation of the testis specific retrogenes in the ovary and ovarian cancers is of biological significance in humans. Because these retrogenes are specifically expressed in the ovary and ovarian cancers in the female they may prove useful in developing new diagnostic and/or therapeutic targets for ovarian cancer.

EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer.

BACKGROUND: EphA2 is a tyrosine kinase receptor in the ephrin family that is implicated in oncogenesis and angiogenesis. The objective of the current investigation was to study the role of EphA2 in endometrial cancer and its relation to steroid hormone receptor expression. METHODS: EphA2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 expression levels were evaluated using immunohistochemistry in 139 endometrioid endometrial carcinoma (EEC) samples and in 10 benign endometrial samples. Samples were scored by 2 investigators who were blinded to clinical outcome. The results were correlated with clinicopathologic characteristics using univariate and multivariate analysis. A P value <.05 was considered statistically significant. RESULTS: High expression of EphA2 was detected in 48% of EEC samples versus 10% of benign samples. EphA2 overexpression was associated significantly with high disease stage (P = .04), high tumor grade (P = .003), increased depth of myometrial invasion (P = .05), low ER expression (P = .01), low PR expression (P = .006), and high Ki-67 expression (P = .04). Low ER and PR expression levels were associated with high tumor grade, positive lymph nodes, high Ki-67 expression, and high EphA2 expression. On univariate analysis of all patients, high EphA2 expression was associated significantly with shorter disease-specific survival (DSS) (P < .001). On multivariate analysis, age (P < .001), high disease stage (P = .002), and high EphA2 expression (P = .04) were independent predictors of poor DSS. CONCLUSIONS: EphA2 overexpression was associated with aggressive phenotypic features in EEC and was associated inversely with ER and PR expression. Thus, EphA2 may be an important therapeutic target, especially in patients with hormone receptor-negative endometrial carcinoma.

Uteroovarian ligament torsion of the due to a paratubal cyst.

Paratubal cysts rarely undergo torsion. When they do, typically they involve the infundibulopelvic ligament and affect the ovary and fallopian tube. We present a case and discussion of torsion of the uteroovarian ligament secondary to a large paratubal cyst with preservation of the ovary and fallopian tube.

Conservative treatment of stage IA2 squamous cell carcinoma of the cervix during pregnancy.

BACKGROUND: The standard management of early-stage invasive cervical cancer in early pregnancy is radical hysterectomy with the fetus in situ. We describe a case of early invasive cervical cancer in pregnancy that was treated with a conservative surgical approach. CASE: A nulliparous pregnant women at 15 weeks of gestation was diagnosed with stage IA2 invasive cervical cancer. She declined a radical hysterectomy, desiring to continue the pregnancy. A repeat cervical conization with retroperitoneal lymph node dissection was followed by radical trachelectomy 6 weeks after delivery. Currently she has 2 children, and there is no evidence of recurrence. CONCLUSION: Conservative stepwise surgical management of early invasive cervical cancer in the first half of pregnancy was a feasible approach in this woman who wished to continue the pregnancy.

Langerhans cell histiocytosis of the vulva: two case reports.

This report describes the histopathologic results of Langerhans cell histiocytosis of the vulva and options for treatment. We present two new cases demonstrating vulvar manifestations of disease and their course of treatment with a review of the literature. Langerhans cell histiocytosis of the female genital tract is rare. The disease cannot be diagnosed without biopsy of cutaneous lesions. Langerhans cell histiocytosis of the vulva is a rare disorder with few options for treatment.

Gastrointestinal stromal tumor presenting as a pelvic mass.

Gastrointestinal stromal tumors (GISTs) are c-kit-positive tumors that may arise anywhere in the tubular gastrointestinal tract. Around 5% of the cases arise elsewhere in the abdominal cavity. Tumors originating in the omentum and mesentery have been reported.A 31-year-old woman presented with pelvic pain, a palpable pelvic mass, and elevated CA-125. Imaging showed innumerable pelvic and abdominal masses. Histopathology showed a GIST that was positive for c-kit and vimentin and negative for desmin and smooth muscle actin. The patient was started on imatinib mesylate. Six months after diagnosis the tumor has remained stable.GI stromal tumors (GIST) may initially present as pelvic mass with elevated CA-125. Imatinib mesylate is the current mainstay therapy for GISTs after surgery.

Functional outcomes and complications of continent urinary diversions in patients with gynecologic malignancies.

OBJECTIVE: The purpose of this study was to review our experience with continent urinary diversions in patients with gynecologic malignancies and evaluate the presentation and management of early and late complications. METHODS: A retrospective chart review was performed of all patients who underwent a continent urinary diversion on the Gynecologic Oncology Service at The University of Texas M. D. Anderson Cancer Center during the period January 1988 to March 2001. We analyzed our data to evaluate potential risk factors for complications. Renal status, conduit integrity, and overall patient outcomes were also studied. RESULTS: We identified 40 patients who underwent a continent urinary diversion using an ileocolonic segment (Miami pouch technique). All patients had a history of gynecologic malignancies. The median age at the time of the procedure was 50 years (range 24 to 76 years), and the median weight was 69.6 kg (range 47 to 125 kg). A total of 39 patients (98%) had a history of radiotherapy. Continent urinary diversion was performed as part of an anterior pelvic exenteration in 12 patients (30%), in conjunction with a total pelvic exenteration in 18 patients (45%), and as the main procedure in 10 patients (25%). The median estimated blood loss was 2100 ml (range 200 to 8500 ml). The median length of hospitalization was 19.5 days (range 7 to 56 days). A total of 24 patients (60.0%) had a postoperative complications unrelated to the reservoir. Complications directly related to the continent urinary diversion were seen in 26 (65.0%) of 40 patients. None of the patients in this study group developed chronic renal failure, and there were no perioperative deaths. At last evaluation, 36 (90%) of 40 patients reported normal continent conduit function. CONCLUSIONS: Continent urinary diversion using an ileocolonic segment is a reasonable alternative to the ileal and transverse colon conduit in bladder reconstruction in patients undergoing radical pelvic surgery. The routine use of postoperative total parenteral nutrition, the chronic use of antibiotics after discharge from the hospital, and the routine use of imaging studies remain controversial. In this group of patients, the majority of complications may be successfully managed conservatively.