Falk C. Thiel

A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ∼2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79–0.86, Ptrend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73–0.81, Ptrend = 4.1 × 10−21).

Estrogen and progesterone receptors: from molecular structures to clinical targets

Research involving estrogen and progesterone receptors (ER and PR) have greatly contributed to our understanding of cell signaling and transcriptional regulation. In addition to the classical ER and PR nuclear actions, new signaling pathways have recently been identified due to ER and PR association with cell membranes and signal transduction proteins. Bio-informatics has unveiled how ER and PR recognize their ligands, selective modulators and co-factors, which has helped to implement them as key targets in the treatment of benign and malignant tumors. Knowledge regarding ER and PR is vast and complex; therefore, this review will focus on their isoforms, signaling pathways, co-activators and co-repressors, which lead to target gene regulation. Moreover it will highlight ER and PR involvement in benign and malignant diseases as well as pharmacological substances influencing cell signaling and provide established and new structural insights into the mechanism of activation and inhibition of these receptors.

Role of genetic polymorphisms and ovarian cancer susceptibility

The value of identifying women with an inherited predisposition to epithelial ovarian cancer has become readily apparent with the identification of the BRCA1, and BRCA2 genes. Women who inherit a deleterious mutation in either of these genes have a very high lifetime risk of ovarian cancer (10–60%) and to some extent, increased risks of fallopian tube and peritoneal cancer. These highly lethal cancers are almost completely prevented by prophylactic salpingoophorectomy. BRCA1/2 mutation testing has become the accepted standard of care in families with a strong history of breast and/or ovarian cancer. This approach has the potential to reduce ovarian cancer mortality by about 10%.

Association of complementary methods with quality of life and life satisfaction in patients with gynecologic and breast malignancies

Goals of workIn gynecological oncology, there is growing interest in the use of complementary and alternative medicine (CAM) methods. The lack of data regarding side effects, the lack of any survival advantages, and the costs of these methods appear to have no influence on patients’ decisions on whether to use CAM. Our interest was to evaluate the association between CAM use and the patients’ quality of life/life satisfaction (QoL/LS).Materials and methodsOne thousand thirty women with breast cancer of gynecologic malignancies were asked to participate in this study, which included a questionnaire and a personal interview on CAM. User status was compared with the patient’s own description of her QoL/LS and with the cancer type.Main resultsCAM was used by 48.7% of all women (n = 502). Breast cancer patients stated that they used CAM in 50.1% and women with gynecological cancer in 44.0%. The use of mistletoe was widespread (77.3%) and was more often seen in breast cancer patients than in gynecological cancer patients (74.4% vs 67.0%). CAM users less frequently stated an overall deterioration of their health status (35.1%) compared to nonusers (50.1%). CAM use resulted in a stated improvement in family conditions (6%) in comparison with the nonusers (2%).ConclusionsWith regard to patients’ perception of health status, CAM use is associated with a better coping with their disease. Most other categories of LS are not affected by CAM use. Patient-oriented information comparing standard therapies with CAM methods should be made widely available, and patients’ expectations of CAM use should be discussed between the physician and the patient.

Adjuvant Therapy in Lymph Node–Positive Vulvar Cancer: The AGO-CaRE-1 Study

Background: Women with node-positive vulvar cancer have a high risk for disease recurrence. Indication criteria for adjuvant radiotherapy are controversial. This study was designed to further understand the role of adjuvant therapy in node-positive disease. Methods: Patients with primary squamous-cell vulvar cancer treated at 29 gynecologic cancer centers in Germany from 1998 through 2008 were included in this retrospective exploratory multicenter cohort study. Of 1618 documented patients, 1249 had surgical groin staging and known lymph node status and were further analyzed. All statistical tests were two-sided. Results: Four hundred forty-seven of 1249 patients (35.8%) had lymph node metastases (N+). The majority of N+ patients had one (172 [38.5%]) or two (102 [22.8%]) positive nodes. The three-year progression-free survival (PFS) rate of N+ patients was 35.2%, and the overall survival (OS) rate 56.2% compared with 75.2% and 90.2% in node-negative patients (N-). Two hundred forty-four (54.6%) N+ patients had adjuvant therapy, of which 183 (40.9%) had radiotherapy directed at the groins (+/-other fields). Three-year PFS and OS rates in these patients were better compared with N+ patients without adjuvant treatment (PFS: 39.6% vs 25.9%, hazard ratio [HR] = 0.67, 95% confidence interval [CI[= 0.51 to 0.88, P = .004; OS: 57.7% vs 51.4%, HR = 0.79, 95% CI = 0.56 to 1.11, P = .17). This effect was statistically significant in multivariable analysis adjusted for age, Eastern Cooperative Oncology Group, Union internationale contre le cancer stage, grade, invasion depth, and number of positive nodes (PFS: HR = 0.58, 95% CI = 0.43 to 0.78, P < .001; OS: HR = 0.63, 95% CI = 0.43 to 0.91, P = .01). Conclusion: This large multicenter study in vulvar cancer observed that adjuvant radiotherapy was associated with improved prognosis in node-positive patients and will hopefully help to overcome concerns regarding adjuvant treatment. However, outcome after adjuvant radiotherapy remains poor compared with node-negative patients. Adjuvant chemoradiation could be a possible strategy to improve therapy because it is superior to radiotherapy alone in other squamous cell carcinomas.

Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell‐mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty‐three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15–1.74) and the HomOR = 1.63 (1.10–1.42), p‐trend = 0.0002] and [HetOR = 0.97 (0.80–1.17), HomOR = 0.74 (0.58–0.93), p‐trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele‐specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele‐specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.

Hysterectomy—A Comparison of Approaches

BACKGROUND The advantages and disadvantages of the various surgical techniques for hysterectomy are currently a topic of debate, with particular controversy over leaving the cervix in situ in the laparoscopic supracervical hysterectomy (LASH) procedure. METHODS In a retrospective single-center study, medical history and clinical characteristics were compared in patients who had undergone hysterectomy for benign disease in the period 2002-2008 at the Department of Obstetrics and Gynecology, Erlangen University Hospital. Postoperative satisfaction and the frequency of secondary operations for prolapse or incontinence in women with surgery between 2002 and 2007 were surveyed by means of a questionnaire. RESULTS The longest hospital stay was observed after abdominal hysterectomy (AH; 10 days), followed by vaginal hysterectomy (VH; 7.8 days) and laparoscopy-assisted vaginal hysterectomy (LAVH; 7.2 days). The shortest stays in hospital were seen after LASH (5.9 days) and total laparoscopic hysterectomy (TLH; 5.7 days). The shortest operating time was noted with VH (87 min) and the longest with LAVH (122 min). The lowest rates of blood loss were with LASH (1.38 g/dL) and TLH (1.51 g/dL). The highest rate of postoperative complications occurred after AH (8.9%). No differences were found in relation to postoperative satisfaction or surgery for prolapse or incontinence. CONCLUSION No postoperative benefits were found for leaving the cervix in situ when performing LASH. However, this was not a controlled randomized study.

Comparison of total laparoscopic hysterectomy (TLH) and laparoscopy-assisted supracervical hysterectomy (LASH) in women with uterine leiomyoma

OBJECTIVE To compare total laparoscopic hysterectomy (TLH) using the Hohl instrument with laparoscopy-assisted supracervical hysterectomy (LASH) in women with uterine leiomyoma. STUDY DESIGN 231 women underwent laparoscopic hysterectomy for the treatment of symptomatic leiomyoma between January 2005 and December 2007. A total of 113 women decided to undergo complete hysterectomy with removal of the cervix (TLH group) and 118 women wished to preserve the cervix; LASH was carried out in the latter group (LASH group). RESULTS No ureteral or bladder injury occurred in any of the patients. Two intraoperative complications and one postoperative complication occurred in the TLH group, while no complications occurred in the LASH group. When the TLH group was compared with the LASH group, the mean loss of hemoglobin was 1.6+/-1.1g/dL (95% CI 1.4-1.8) vs. 1.5+/-1.4g/dL (95% CI 1.2-1.7); the mean operating time was 114.0+/-33.8min (95% CI 107.6-120.2) vs. 116.5+/-40min (95% CI 109.3-124.0); and the mean uterus weight was 264.8+/-133.6g (95% CI 239.8-289.6) vs. 286.2+/-209.3g (95% CI 247.4-324.4). Hospital stay and use of analgesia in both groups were equal. No statistically significant differences were found. CONCLUSIONS TLH using the Hohl instrument is an option comparable with laparoscopy-assisted supracervical hysterectomy for women with uterine leiomyoma. However, the complication rates may be lower when LASH is performed.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

Background:Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Methods:Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.Results:FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20–0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10–3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25–0.94).Conclusions:FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Early aberrant insulin-like growth factor signaling in the progression to endometrial carcinoma is augmented by tamoxifen

Tamoxifen is an important selective estrogen receptor (ER) modulator for treatment of steroid hormone positive breast cancer. In addition to the beneficial effect, tamoxifen is one risk factor for endometrial carcinoma (EnCa) development. We hypothesized that, (1) dysregulation of gene expression and protein phosphorylation of the insulin‐like growth factor (IGF) and steroid hormone receptor‐signaling occur early in benign endometrial tissues and (2) signaling differences would be detected between patients with or without tamoxifen treatment. Seventy‐eight tissues, including 2 benign cohorts from patients treated with (n = 24) or without tamoxifen (n = 28) (hyperproliferative endometrium, hyperplasia, polyps), EnCa (n = 12) with endometrium controls (n = 14) were analyzed for expression of 15 genes from the IGF and steroid hormone receptor‐signaling, including the target genes Syncytin‐1, PAX2 and c‐myc. Total and phosphorylated protein expression were examined for ERα, PTEN, AKT, mTOR and Syncytin‐1. Compared to controls similar significant deregulation of IGF and steroid hormone receptor‐signaling, Syncytin‐1 and PAX2 occurred in both benign cohorts, irrelevant of tamoxifen treatment. Comparing both benign cohorts with and without tamoxifen significant expression differences were noted. Increased total protein and phosphorylation of pERα‐Ser118, pPTEN‐Thr380, pAKT‐Thr308, pAKT‐Ser473, pmTOR‐Ser2448 and Syncytin‐1 were noted in early benign tissue stages associating with tamoxifen, especially polyps. Functional kinetic studies following tamoxifen treatment of the PTEN mutated RL95‐2 EnCa cell line, demonstrated a doubling of phosphorylation of pERα‐Ser118 and a 4.2‐fold induction of pAKT‐Thr308 along with Syncytin‐1 induction. This study supports that dysregulated IGF and steroid hormone receptor signaling is prominent in endometrial benign stages and these alterations could represent clinical indicators for the risk of EnCa and also help in development of new therapies.