Small RNA sequencing reveals a comprehensive miRNA signature of BRCA1-associated high-grade serous ovarian cancer.

AIMS: BRCA1 mutation carriers are at increased risk of developing high-grade serous ovarian cancer (HGSOC), a malignancy that originates from fallopian tube epithelium. We aimed to identify differentially expressed known and novel miRNAs in BRCA1-associated HGSOC. METHODS: Small RNA sequencing was performed on eight normal tubal and five HGSOC samples of BRCA1 carriers. Differential expression of a subset of known and novel miRNAs was validated by qRT-PCR on the samples used for small RNA sequencing and a second sample cohort comprising normal and HGSOC tissue of matched BRCA1 and non-BRCA carriers. Data from The Cancer Genome Atlas were used to determine the clinical relevance of the validated differentially expressed miRNAs. RESULTS: 59 known and 20 novel miRNAs showed a significant >fourfold expression difference between normal tubal tissue and HGSOC. qRT-PCR validation confirmed a significant difference in expression levels for 10 out of 11 known miRNAs. Upregulation of two novel miRNAs could not be confirmed. Interestingly, for seven miRNAs a significant increase in expression was observed when comparing normal tubal tissue of postmenopausal women with premenopausal women. Expression levels of miR-145-5p significantly increased with International Federation of Gynecology and Obstetrics stage, while the expression levels of the other nine validated miRNAs were not associated with clinical characteristics. CONCLUSIONS: We report a comprehensive expression signature including both known and novel miRNAs of BRCA1-associated HGSOC. Comparison with previous profiling studies showed a good overlap and a large number of miRNAs not reported to be differentially expressed in HGSOC before underscoring the importance of this study.

Support of the 'fallopian tube hypothesis' in a prospective series of risk-reducing salpingo-oophorectomy specimens.

OBJECTIVE: To determine the prevalence, localisation and type of occult (non)invasive cancer in risk-reducing salpingo-oophorectomy (RRSO) specimens in BRCA-mutation carriers and high-risk women from BRCA-negative families. METHODS: A consecutive series of RRSO specimens of asymptomatic, screen-negative high-risk women were prospectively collected in our tertiary multidisciplinary cancer clinic from January 2000 until March 2012. All high-risk women in this study underwent genetic testing on BRCA-mutations. The surgico-pathological protocol comprised complete resection of ovaries and fallopian tubes, transverse sectioning at 2-3 mm (sectioning and extensively examining the fimbrial end [SEE-FIM] protocol from 2006) and double independent pathology review of morphologically deviant sections. RESULTS: Three hundred and sixty RRSOs were performed in 188 BRCA1-carriers, 115 BRCA2-carriers and 57 BRCA-negative women at a median age of 44.0 years. Four occult invasive cancers were detected in BRCA-carriers (1.3%, 95%-confidence interval (CI) 0.03-2.61), all in BRCA1-carriers >40 years of age. All cancers, of which two tubal and two ovarian cancers, were FIGO-stage I/II. Three non-invasive serous intraepithelial carcinomas (STICs) were detected in BRCA-carriers (1.0%, 95%-CI 0.00-2.10). In BRCA-negative women one STIC was found (1.8%, 95%-CI 0.00-5.16), however she carried an unclassified variant in BRCA2. Total follow-up after RRSO was 1691 woman-years, in which one BRCA1-carrier developed peritoneal cancer (0.3%, 95%-CI 0.00-0.82). CONCLUSIONS: A low prevalence of occult invasive cancer (1.1%) was found in young asymptomatic, screen-negative women at increased ovarian cancer risk undergoing RRSO. This study adds to the advice to perform RRSO in BRCA1-carriers before the age of 40. Our findings support the hypothesis of the fallopian tube as the primary site of origin of pelvic high-grade serous cancer.

Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers.

Serous endometrial intraepithelial carcinoma has been proposed to be a potential precursor lesion of pelvic high-grade serous carcinoma. If true, an increased incidence of uterine papillary serous carcinomas would be expected in BRCA1 and BRCA2 mutation carriers, who are at high-risk of developing pelvic high-grade serous carcinoma. This study explored particularly the occurrence of uterine papillary serous carcinoma, as well as other endometrial cancers, following risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 germline mutation attending a tertiary multidisciplinary clinic. A consecutive series of women with a BRCA1 or BRCA2 mutation who had undergone risk-reducing salpingo-oophorectomy without hysterectomy at the University Medical Center Groningen from January 1996 until March 2012 were followed prospectively. They were crossed with the histopathology list of endometrial cancer diagnoses reported by the Dutch nationwide pathology database PALGA. To assess the risk of endometrial cancer, a standardized incidence ratio was calculated comparing the observed with the expected number of endometrial cancer cases. Overall, 201 BRCA1 and 144 BRCA2 mutation carriers at a median age of 50 years (range, 32-78) were analyzed. After a median follow-up period of 6 years, after risk-reducing salpingo-oophorectomy, two cases of endometrial cancer were diagnosed, whereas the expected number was 0.94 cases (standardized incidence ratio 2.13; 95% confidence interval 0.24-7.69; P=0.27). Both endometrial cancer cases were of the endometrioid histological subtype. We showed that the incidence of endometrial cancer following risk-reducing salpingo-oophorectomy, especially uterine papillary serous carcinoma, in women at high-risk of developing pelvic high-grade serous carcinoma is not increased. On the basis of our data, the hypothesis of serous endometrial intraepithelial carcinoma being an important precursor lesion of pelvic high-grade serous carcinoma seems unlikely. There is no need to add a prophylactic hysterectomy to risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.

Clinicopathologic characteristics and survival in BRCA1- and BRCA2-related adnexal cancer: are they different?

OBJECTIVE: Our aim was to examine the clinicopathologic characteristics and survival of ovarian, tubal, and peritoneal (further denoted "adnexal") cancer in BRCA1 compared with BRCA2 carriers. METHODS: A consecutive series of adnexal cancers in BRCA1/2 mutation carriers diagnosed in 1980 to 2010 at the University Medical Center Groningen was analyzed. RESULTS: We evaluated 55 BRCA1- and 16 BRCA2-related adnexal cancers, consisting of 51 ovarian, 13 tubal, and 7 peritoneal cancers. Peritoneal cancer was restricted to BRCA1 carriers. Ovarian and tubal cancer was equally present in both carrier groups. Median age at diagnosis was younger in BRCA1 compared with BRCA2 carriers (50 vs 54 years; P = 0.03). No other clinicopathologic differences were found. Regarding survival, a nonsignificant trend was noted for BRCA2 carriers to have fewer relapses, a longer time to first relapse, and a longer disease-free and overall survival. CONCLUSIONS: Except for age at diagnosis and prevalence of peritoneal cancer, no significant clinicopathologic differences were found between BRCA1- versus BRCA2-associated adnexal cancer. On survival, it might be suggested that BRCA2 carriers have a more favorable outcome than BRCA1 carriers, marked by fewer relapses, a longer time to first relapse, and a longer disease-free and overall survival.

No (wo)man is an island--the influence of physicians' personal predisposition to labia minora appearance on their clinical decision making: a cross-sectional survey.

INTRODUCTION: Physicians are increasingly presented with women requesting a labia minora reduction procedure. AIM: To assess the influencing factor of personal predisposition in general practitioners, gynecologists, and plastic surgeons to labia minora appearance in relation to their willingness to refer for, or perform, a surgical labia minora reduction. METHODS: Cross-sectional self-administered questionnaire survey. Between May 2009 and August 2009, 210 physicians were surveyed. Primary care: general practitioners working in the north of the Netherlands. Secondary care: gynecologists and plastic surgeons working in five hospitals in the north of the Netherlands. MAIN OUTCOME MEASURES: A five-point Likert scale appraisal of four pictures showing a vulva, each displaying different sizes of labia minora, indicating a physician's personal predisposition, manifesting as willingness to refer for, or perform, a labia minora reduction. RESULTS: A total of 164/210 (78.1%) physicians completed the questionnaire, consisting of 80 general practitioners, 41 gynecologists, and 43 plastic surgeons (96 males, 68 females). Ninety percent of all physicians believe, to a certain extent, that a vulva with very small labia minora represents society's ideal (2-5 on the Likert scale). More plastic surgeons regarded the picture with the largest labia minora as distasteful and unnatural, compared with general practitioners and gynecologists (P < 0.01), and regarded such a woman as a candidate for a labia minora reduction procedure (P < 0.001). Irrespective of the woman's labia minora size and the absence of physical complaints, plastic surgeons were significantly more open to performing a labia minora reduction procedure than gynecologists (P < 0.001). Male physicians were more inclined to opt for a surgical reduction procedure than their female colleagues (P < 0.01). CONCLUSIONS: The personal predisposition of physicians (taking account of their specific gender and specialty) concerning labia minora size and appearance influences their clinical decision making regarding a labia minora reduction procedure. Heightened awareness of one's personal predisposition vis-à-vis referral and willingness to operate is needed.

[Diagnosing the onset of labour: more than a definition issue]. / De diagnose van het baringsbegin: meer dan een definitiekwestie.

Because the onset of labour represents a genuine diagnostic problem, labour at term is usually ascertained based on undefined subjective criteria. This can have far-reaching consequences. When the onset of labour is not duly diagnosed, dysfunctional labour may remain unrecognized and timely treatment could be wrongly withheld. Conversely, when a woman is declared to be in labour too early, erroneous interventions may follow. It is assumed that correct diagnosis of the onset of labour contributes to the effective correction of slow progression and to a reduction in the rising caesarean section rate. To diagnose the onset of labour, knowledge of physiology as well as pathophysiology in labour is required. A plea for verbal clarity amongst caregivers as well as consistent, evidence-based diagnosis of the onset of labour is made in this article.