Safety of fertility-sparing surgery in young women with stage I endometrioid epithelial and mucinous ovarian cancer: A population-based analysis.

INTRODUCTION: The aim of this study was to assess the safety of fertility-sparing surgery (FSS) in stage I endometrioid epithelial cancer (EEOC) and mucinous ovarian cancer (MOC). METHODS: A retrospective case‒controlled study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on stage I EEOC and MOC between 2000 and 2016. The effects of FSS on overall survival (OS) were compared using log-rank tests. Univariate and multivariate Cox analyses were performed to control for confounders. RESULTS: The study identified 970 patients with FIGO stage I EEOC and 810 with stage I MOC. Of these patients, 116 (12.0%) EEOC and 268 (33.1%) MOC patients underwent fertility-sparing surgery. The results showed that patients with G3 EEOC had a worse 5-year OS than patients with G1 EEOC (96.1% vs. 90.1%, p = 0.020). IC stage MOC patients had a worse prognosis than IA and IB stage patients (94.9% vs. 88.7%, p = 0.001). FSS did not significantly affect the 5-year OS of patients with EEOC (94.8% vs. 95.4%, p = 0.687) or MOC (95.9% vs. 92.3%, p = 0.071). Further subgroup analysis according to tumor stage and histological grade did not show a worse OS with FSS in stage I EEOC or MOC patients, even with high-risk types such as G3 histology and IC phase. In a multivariable analysis, the application of FSS was not associated with inferior OS in EEOC or MOC. CONCLUSIONS: FSS for patients with stage I EEOC or MOC does not lead to worse outcomes than radical surgery, making it a viable option for young patients with early-stage disease wishing to preserve fertility.

Bilateral Salpingo-Oophorectomy for Intracardiac Leiomyomatosis: A Case Report.

BACKGROUND Intracardiac leiomyomatosis (ICLM) is an extremely rare tumor which is benign but presents with aggressive behavior. To date, there is still no standard of care for ICLM therapy, and treatment for complicated ICLM has obtained even less attention. Radical surgery was usually recommended to remove the patients' tumors completely. Since initial complete surgical resection cannot be performed in all cases, bilateral salpingo-oophorectomy (BSO), via its effects of estrogen deprivation, may be a feasible primary step in the treatment of premenopausal women with unresectable ICLM. CASE REPORT We describe a case of a residual mass in the inferior vena cava and right atrium that shrank dramatically after BSO. The patient was a 41-year-old woman with initially unresectable ICLM. Total hysterectomy with BSO and excision of the retroperitoneal mass was performed, but the intracaval tumor above L5 was not removed. Pathology revealed a benign leiomyoma which was strongly positive for both estrogen receptor and progesterone receptor. Two weeks after the BSO, the patient's serum estradiol level had decreased to a postmenopausal level. At the same time, the proximal end of the intracaval tumor shrank dramatically from the level of the right atrium to the level of L3 only 2 weeks after the surgery. Therefore, this may provide a therapeutic window for a second reduction surgery. CONCLUSIONS BSO, via its estrogen deprivation effect, may provide a simple but effective initial treatment choice for premenopausal women who suffer from primary unresectable ICLM.

Genomic and expressional dynamics of ovarian cancer cell lines in PARPi treatment revealed mechanisms of acquired resistance.

BACKGROUND: Patients with epithelial ovarian cancer (EOC) can benefit from poly- (ADP ribose) polymerase inhibitors (PARPi) therapy. However, PARPi resistance has become a challenge in clinical practice, and its mechanism requires further exploration. METHODS: We established three PARPi-resistant cell strains following olaparib exposure. CCK-8, clonogenic survival, transwell, wound healing, cell cycle, RT-qPCR and western blot assays were performed to explore the functional phenotype of the resistant cells. Whole-exome sequencing and RNA-sequencing were performed to identify the altered genes. Stable knockdown and overexpression were used to investigate the role of EP300, an upstream regulator of E-cadherin and epithelial-mesenchymal transition (EMT), in cell lines. We further validated the finding in clinical ovarian cancer samples by immunohistochemistry. RESULTS: We combined public datasets to obtain an integrated PARPi sensitivity profile in EOC cells, which indicated that primary PARPi resistance could not be fully explained by mutations in BRCA1/2 or homologous recombination deficiency related genes. Genomic and transcriptome analyses revealed distinct mechanisms between primary and acquired resistance. Long-term PARPi treatment induced accumulation of de novo single nucleotide variants (SNV), and the complete frame-shift deletion of PARP1 was detected in the A2780 resistant strain. Additionally, the depressed histone acetyltransferase of EP300 could cause resistant phenotype through activated EMT process in vitro, and associated with PARPi-resistance in EOC patients. CONCLUSION: Long-term PARPi treatment led to evolutionary genomic and transcriptional alterations that were associated with acquired resistance, among which depressed EP300 partly contributed to the resistant phenotype.

Ryanodine receptor 1-mediated Ca2+ signaling and mitochondrial reprogramming modulate uterine serous cancer malignant phenotypes.

BACKGROUND: Uterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker ryanodine receptor 1 (RYR1) identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment. METHODS: TCGA USC dataset was analyzed to identify top genes that are associated with patient survival or disease stage, and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models. RESULTS: High expression level of RYR1 in the tumors is associated with advanced stage of the disease. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through Ca2+-dependent activation of AKT/CREB/PGC-1α and AKT/HK1/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression and survival in mouse models. CONCLUSIONS: These findings provided insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival.

PRKCI Mediates Radiosensitivity via the Hedgehog/GLI1 Pathway in Cervical Cancer.

Objective: Insensitivity to radiotherapy accounts for the majority of therapeutic failures in cervical cancer (CC) patients who undergo radical radiotherapy. We aimed to elucidate the molecular mechanisms underlying radiosensitivity to identify methods to improve the overall 5-year survival rate. The atypical protein kinase C iota (aPKCι) gene PRKCI exhibits tumor-specific copy number amplification (CNA) in CC. We investigated how PRKCI decreases radiosensitivity in CC and assessed the interplay between PRKCI and the Hedgehog (Hh)/GLI1 pathway in the present research. Methods: The biological functions of PRKCI in CC radiosensitivity were explored through immunohistochemistry, colony formation, Cell Counting Kit-8 (CCK-8), cell cycle, apoptosis assays, and xenograft models. qRT-PCR, Western blotting analysis, and immunofluorescence assays were utilized to evaluate the interplay between PRKCI and the Hh/GLI1 pathway and its mechanism in PRKCI-decreased radiosensitivity in CC. Furthermore, the effect of auranofin (AF), a selective inhibitor of PKCι, on CC cells was explored through biochemical assays in vitro and in vivo. Results: We found that high PRKCI expression was responsible for decreased survival in CC. PRKCI was intimately associated with radiation-triggered alterations in proliferation, the cell cycle, apoptosis, and xenograft growth. The Hh/GLI1 pathway was activated when PRKCI expression was altered. PRKCI functions downstream of the Hh/GLI1 pathway to phosphorylate and activate the transcription factor GLI1. AF acts as a radiosensitizer and showed biological effects in vitro and in vivo. Conclusions: PRKCI is a therapeutic target for regulating radiosensitivity in CC. This molecule regulates radiosensitivity by modulating GLI1 relocalization and phosphorylation in CC via the Hh/GLI1 pathway.

Detection of ovarian cancer using plasma cell-free DNA methylomes.

BACKGROUND: Ovarian cancer (OC) is a highly lethal gynecologic cancer, and it is hard to diagnose at an early stage. Clinically, there are no ovarian cancer-specific markers for early detection. Here, we demonstrate the use of cell-free DNA (cfDNA) methylomes to detect ovarian cancer, especially the early-stage OC. EXPERIMENTAL DESIGN: Plasma from 74 epithelial ovarian cancer patients, 86 healthy volunteers, and 20 patients with benign pelvic masses was collected. The cfDNA methylomes of these samples were generated by cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). The differentially methylated regions (DMRs) were identified by the contrasts between tumor and non-tumor groups, and the discrimination performance was evaluated with the iterative training and testing method. RESULTS: The DMRs identified for cfDNA methylomes can well discriminate tumor groups and non-tumor groups (ROC values from 0.86 to 0.98). The late-stage top 300 DMRs are more late-stage-specific and failed to detect early-stage OC. However, the early-stage markers have the potential to discriminate all-stage OCs from non-tumor samples. CONCLUSIONS: This study demonstrates that cfDNA methylomes generated with cfMeDIP-seq could be used to identify OC-specific biomarkers for OC, especially early OC detection. To detect early-stage OC, the biomarkers should be directly identified from early OC plasma samples rather than mix-stage ones. Further exploration of DMRs from a k larger early-stage OC cohort is warranted.

Round ligament suspension and vaginal purse-string suture: Newly optimized techniques to prevent tumor spillage in laparoscopic radical trachelectomy for cervical cancer.

AIM: The purpose of this study was to investigate the surgical techniques and clinical feasibility of nonuterine manipulator and enclosed colpotomy to avoid cancer cell spillages in laparoscopic radical trachelectomy (LRT) for patients with early-stage cervical cancer. METHODS: We performed the newly optimized surgical techniques of round ligament suspension and vaginal purse-string suture in LRT in 12 patients with early-stage cervical cancer from May 2019 to October 2020. Surgical information and postoperative results were recorded. RESULTS: All 12 patients successfully underwent LRT with round ligament suspension and vaginal purse-string suture, and no conversion to laparotomy was required. The median operation time was 268.5 min (range 200-320 min), including 5 min of round ligament suspension, and the median blood loss was 20 mL (range 5-50 mL). The median number of pelvic lymph nodes removed was 27 (range 19-35), and median amounts of paracervical tissue was 24 mm (range 21-26 mm) and vaginal tissue was 18 mm (range 16-26 mm). No intraoperative complication or serious postoperative complications were reported. CONCLUSION: Round ligament suspension and vaginal purse-string suture techniques are feasible and effective in LRT. They can replace uterine manipulator and unprotected colpotomy with satisfactory perioperative outcomes.

CircCASC15-miR-100-mTOR may influence the cervical cancer radioresistance.

BACKGROUND: Cervical cancer has ranked the top one in gynecological malignancies for incidence. Radioresistance is now becoming a leading reason of recurrence. METHODS: Our microRNA array data indicated that the miRNA-100 level decreased significantly during radioresistance. In this study, we up-regulated miR-100 in Hela and Siha cells by using miR-100 mimics and observed proliferation and invasion. RESULTS: It turned out that with overexpression of miR-100, the cells had less invasiveness as well as proliferation. It may target gene mTOR, and it deed reduced EMT. To examine the role of miR-100 in radioresistance, there was no significant result showed by BSP. While the circCASC15 has been identified with sponge function according to RNA pull down and ISH. CONCLUSION: The conclusions indicate miR-100 is a tumor suppressor gene and could be a therapeutic target in radio-resistant cervical cancers.

Feasibility of the "Cuff-Sleeve" Suture Method for Functional Neocervix Reconstruction in Laparoscopic Radical Trachelectomy: A Retrospective Analysis.

STUDY OBJECTIVES: The purpose of this study was to evaluate the feasibility of "cuff-sleeve" sutures for reconstructing a functional neocervix in laparoscopic radical trachelectomy (RT). DESIGN: A retrospective analysis of a case series. SETTING: A teaching hospital. PATIENTS: Twenty-five patients who were diagnosed as early-stage cervical cancer from June 2017 to October 2020 in Sun Yat-sen Memorial Hospital. INTERVENTIONS: Laparoscopic RT with the "cuff-sleeve" suture method for cervicovaginal reconstruction. MEASUREMENTS AND MAIN RESULTS: Twenty-five patients successfully underwent the laparoscopic RT with the "cuff-sleeve" suture method for cervicovaginal reconstruction, and no intraoperative complications occurred or conversion to laparotomy was needed. For all patients, approximately 80% of the cervical length was removed. Surgical radicality and negative surgical margins were also confirmed. During a median follow-up time of 29 months (range 8-48 months), no severe postoperative complications were observed. No cervical stenosis or secondary abnormal menstruation was reported. After the removal of the uterine stent 6 months after surgery, the neocervix length was approximately 14 mm (range 10-19 mm) and almost all the neocervixes were restored closely to the original anatomy. Four of 8 patients attempting actively to conceive were successful, and the cervical length of these pregnant patients was greater than or equal to 15 mm in all but one measurement at different gestational age. Three patients were ongoing pregnant, and the other had delivered successfully with a 16- mm cervix at term without cerclage. CONCLUSION: The "cuff-sleeve" suture method in cervicovaginal reconstruction is feasible in laparoscopic RT. This simplified suture technique can provide a functional neocervix to reduce cervical stenosis and incompetence.

N6-Methyladenosine Associated Silencing of miR-193b Promotes Cervical Cancer Aggressiveness by Targeting CCND1.

OBJECTIVE: Cervical cancer is a frequently encountered gynecological malignancy as a major contributor to cancer-related deaths in women. This study focuses on how miR-193b promotes cervical cancer aggressiveness as well as the role of m6A in miR-193b silencing. METHODS: Cervical cancer samples and the matching adjacent normal cervical tissues were used to determine the significance of miR-193b in cervical cancer. The CCK-8 assay, cell cycle analysis, qRT-PCR, Western blot assay, IHC, RIP, and xenograft models were utilized to explore the impact of miR-193b in cervical cancer and how m6A regulates miR-193b expression. Luciferase reporter assays, qRT-PCR, and Western blotting were enlisted to study the interaction between miR-193b and CCND1. RESULTS: Our study suggested that lower miR-193b expressions were strongly linked to more advanced cervical cancer stages and the presence of deeper stromal invasion. miR-193b functions as a tumor suppressor that is regulated by m6A methylation in cervical tumors. METTL3 modulates miR-193b mature process in an m6A-dependent manner. Reintroduction of miR-193b profoundly inhibits tumorigenesis of cervical cancer cells both in vivo and in vitro through CCND1 targeting. CONCLUSIONS: m6A associated downregulation of miR-193b promotes cervical cancer aggressiveness by targeting CCND1.

ALDH-1-positive cells exhibited a radioresistant phenotype that was enhanced with hypoxia in cervical cancer.

BACKGROUND: We have previously found there was a small subpopulation of cells with cancer stem cell-like phenotype ALDH-1 in cervical cancer. Radiotherapy has been applied in most of the cervical cancer. However,the mechanisms underlying radioresistance still remained elusive. Our study is to explore whether ALDH+ cell promotes radioresistance by hypoxia. METHODS: Cells were respectively cultured in hypoxia and normoxia environment and analyzed for marker stability, and cell cycle distribution. RESULTS: Cell growth, apoptosis, cell cycle, sphere formation were affected by hypoxia. ALDH-1 and CHK2 were upregulated after hypoxia. CONCLUSIONS: Here we show that ALDH-1 positive cells contribute to cervical carcinoma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of these cells is enriched after radiation in cervical carcinoma.

Growth arrest-specific 5 attenuates cisplatin-induced apoptosis in cervical cancer by regulating STAT3 signaling via miR-21.

Cervical cancer is the most common cause of female cancer-related mortality worldwide. Decreased expression of long noncoding RNA growth arrest-specific 5 (GAS5) is found in human cervical cancer tissues and associated with poor prognosis. However, the studies on associations between GAS5 level and malignant phenotypes, as well as sensitivity to chemotherapeutic drug in cervical cancer cells are limited. In this study, overexpression of GAS5 in cervical cancer cells resulted in prohibited cell proliferation and colony formation, which were promoted by siGAS5. Enhanced GAS5 increased cell percentage in the G0/G1 phase and decreased cells percentage in the S phase, whereas reduced expression did not. The malignant behaviors of cervical cancer cells, manifested by cell migration and invasion, could be weakened by the GAS5 overexpression and enhanced by siGAS5. Furthermore, in cisplatin-induced cell, overexpression of GAS5 reduced cells viability and enhanced apoptosis, whereas in cells transfected with siGAS5, apoptosis eliminated. We have reported the upregulation of microRNA-21 (miR-21) and its oncogenetic roles in cervical cancer previously. In this study, we found the negative relationship between the GAS5 and miR-21. Moreover, the decrease of miR-21 associated proteins phosphorylated STAT3 and E2F3 was seen in GAS5 overexpressed cells, both of which could be increased by siGAS5. The GAS5 deficiency also reduced miR-21 target proteins TIMP3 and PDCD4 expressions. Taken together, the GAS5 expression level is inversely associated with malignancy, but positively associated with sensitivity to cisplatin-induced apoptosis, suggesting that GAS5 could be a biomarker of cisplatin-resistance in clinical therapy of human cervical cancer.

SOX2 regulates radioresistance in cervical cancer via the hedgehog signaling pathway.

OBJECTIVE: Resistance to radiotherapy accounts for most treatment failures in cervical cancer patients who receive radical radiation therapy. To discover the possible mechanism of radioresistance and improve the 5-year survival rate, we focused on how sex-determining region Y-box 2 (SOX2) mediates radioresistance in cervical cancer as well as on the interaction between SOX2 and the hedgehog (Hh) signaling pathway in this study. METHODS: We established the acquired radioresistant subclone cells Hela-RR and Siha-RR. RT-qPCR, Western blot analysis, IHC, clonogenic survival assay, CCK-8 assay, apoptosis analysis, cell cycle analysis and xenograft models were used to explore the relationship between SOX2 expression and radiation resistance and to determine how SOX2 mediates radioresistance in cervical cancer. Furthermore, luciferase reporter and ChIP-PCR assays were utilized to assess the interaction between SOX2 and the Hh signaling pathway. RESULTS: Our research suggested that high expression of SOX2 was responsible for radioresistance in cervical cancer. SOX2 was observed to be closely related to irradiation-induced survival, proliferation, apoptosis, and cell cycle changes. The Hh signaling pathway was found to be activated in Hela-RR and Siha-RR, and the activation changed with SOX2 expression. IHC staining of SOX2 and Gli1 showed a close relationship between SOX2 and the Hh pathway. Luciferase reporter and ChIP-PCR assays demonstrated that SOX2 interacted with the Hh signaling pathway by occupying the HHAT promoter. CONCLUSIONS: SOX2 is a potential therapeutic target of irradiation resistance in cervical cancer. It mediates radioresistance in cervical cancer via the Hh signaling pathway.

Long non­coding RNA urothelial cancer associated 1 regulates radioresistance via the hexokinase 2/glycolytic pathway in cervical cancer.

Cervical cancer is one of the most common types of female malignant tumor. It is well established that radiotherapy (RT) is the first­line treatment of cervical cancer; however, radioresistance is a substantial obstacle to cervical cancer RT. At present, the mechanism underlying radioresistance remains unclear. Emerging evidence has demonstrated that long non­coding RNAs (lncRNAs) function as crucial regulators of diverse cancers. Aerobic glycolysis, which is a common phenomenon in cancer cells, is associated with various biological functions, including radioresistance. To the best of our knowledge, the present study is the first to explore the role of the lncRNA urothelial cancer associated 1 (UCA1) in cervical cancer radioresistance. In the present study, irradiation was used to establish irradiation­resistant (IRR) cells, after which a clonogenic survival assay was used to validate radioresistance, reverse transcription­quantitative polymerase chain reaction was used to evaluate the expression levels of UCA1 and western blotting was conducted to detect the expression levels of glycolysis­related proteins. In addition, a glucose/lactate assay kit was used to evaluate glucose/lactate concentrations and cells were transfected with small interfering RNA/pcDNA to regulate the expression of UCA1. Following the establishment of IRR cell lines (SiHa­IRR and HeLa­IRR), it was demonstrated that SiHa­IRR and HeLa­IRR cells exhibited increased expression levels of UCA1 and enhanced glycolysis. Dysregulation of UCA1 and inhibition of glycolysis affected radioresistance of cervical cancer cells. In addition, the results indicated that UCA1 promoted radioresistance­associated glycolysis in SiHa­IRR and HeLa­IRR cells, with the enzyme hexokinase 2 (HK2) acting as a significant regulator in this process. Inhibiting glycolysis by 2­DG reversed the effects of UCA1 overexpression on HK2 protein expression and radioresistance in SiHa and HeLa cells. Taken together, these findings suggested that UCA1 may have an important role in regulating radioresistance through the HK2/glycolytic pathway, providing novel potential targets to improve cervical cancer RT.

Non-malignant respiratory epithelial cells preferentially proliferate from resected non-small cell lung cancer specimens cultured under conditionally reprogrammed conditions.

The "conditionally reprogrammed cells" (CRC) method, using a Rho kinase inhibitor and irradiated mouse fibroblast cells has been described for the efficient growth of cells from malignant and non-malignant samples from primary tumor and non-malignant sites. Using the CRC method, four institutions independently cultured tumor tissues from 48 non-small cell lung cancers (NSCLC, mostly from primary resected tumors) and 22 non-malignant lungs. We found that epithelial cells could be cultured from tumor and non-malignant lung. However, epithelial cells cultured from tumors had features of non-malignant respiratory epithelial cells which include: 1) among 22 mutations found in the original tumors only two mutations were found in the CRC cultures with reduced frequency (31% to 13% and 92% to 15% from original tumor and CRC culture respectively); 2) copy number variation was analyzed in 9 tumor and their CRC cultures and only diploid patterns were found in CRC cultures; 3) mRNA expression profiles were similar to those of normal respiratory epithelial cells; and 4) co-culture of tumor and non-malignant lung epithelial cells resulted in mostly non-malignant cells. We conclude that CRC method is a highly selective and useful method for the growth of non-malignant respiratory epithelial cells from tumor specimens and only occasionally do such CRC cultures contain a small subpopulation of cancer cells marked by oncogenic mutations. While our findings are restricted to resected primary NSCLC, they indicated the necessity to fully characterize all CRC cultures and the need to develop culture technology that facilitates the growth of primary lung cancers.

RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers.

The tumor suppressor gene RASSF1A regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in approximately 50% of breast cancers. It has been shown previously that the polymorphism A133S in RASSF1A reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of RASSF1A A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 BRCA1 and BRCA2 (BRCA1/2) mutation carriers, 395 non-BRCA1/2 mutations carriers, and 120 untested for BRCA1/2 mutations. Patients with breast cancer had a higher frequency of A133S than the controls [P = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10-2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (P = 0.029; OR, 1.76; 95% CI, 1.06-2.92) and patients carrying BRCA1/2 mutations (P = 0.037, OR, 1.82; 95% CI, 1.04-3.18). Importantly, we found that the co-occurrence of a BRCA1 or BRCA2 mutation and A133S in RASSF1A was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002). Our data suggest that the presence of the RASSF1A A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers.