Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium
卵巢癌中 PTEN 表达的临床和病理相关性: 来自卵巢肿瘤组织分析联盟的多中心研究
- 作者列表："Martins, Filipe Correia","Couturier, Dominique-Laurent","Paterson, Anna","Karnezis, Anthony N.","Chow, Christine","Nazeran, Tayyebeh M.","Odunsi, Adekunle","Gentry-Maharaj, Aleksandra","Vrvilo, Aleksandra","Hein, Alexander","Talhouk, Aline","Osorio, Ana","Hartkopf, Andreas D.","Brooks-Wilson, Angela","DeFazio, Anna","Fischer, Anna","Hartmann, Arndt","Hernandez, Brenda Y.","McCauley, Bryan M.","Karpinskyj, Chloe","Sousa, Christiani B.","Høgdall, Claus","Tiezzi, Daniel G.","Herpel, Esther","Taran, Florin Andrei","Modugno, Francesmary","Keeney, Gary","Nelson, Gregg","Steed, Helen","Song, Honglin","Luk, Hugh","Benitez, Javier","Alsop, Jennifer","Koziak, Jennifer M.","Lester, Jenny","Rothstein, Joseph H.","Andrade, Jurandyr M.","Lundvall, Lene","Paz-Ares, Luis","Robles-Díaz, Luis","Wilkens, Lynne R.","Garcia, Maria J.","Intermaggio, Maria P.","Alcaraz, Marie-Lyne","Brett, Mary A.","Beckmann, Matthias W.","Jimenez-Linan, Mercedes","Anglesio, Michael","Carney, Michael E.","Schneider, Michael","Traficante, Nadia"
Background PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression ( p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC ( p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC ( p value = 0.019) and associated with higher CD8 counts ( p value = 0.0016). Conclusions PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
背景 PTEN 缺失是卵巢癌组织类型 (高级别浆液性 (HGSOC) 、子宫内膜样 (ENOC) 、透明细胞 (CCOC) 、黏液性 (MOC) 、低级别浆液 (LGSOC))。我们的目的是在一项基于人群的大型研究中表征 PTEN 表达作为上皮性卵巢癌的生物标志物。方法来自卵巢肿瘤组织分析联盟的多中心观察性、前瞻性队列研究的 5400 例患者的肿瘤被用来评估免疫组化 PTEN 模式与总生存期、年龄、分期、分级之间的相关性,残余肿瘤，CD8 + 肿瘤浸润淋巴细胞 (TIL) 计数，雌激素受体 (ER) 表达,孕激素受体 (PR) 和雄激素受体 (AR) 通过 Cox 比例风险模型和广义 Cochran-Mantel-Haenszel 试验。结果: 细胞质 PTEN 表达下调在 ENOC (最常见于年轻患者; p 值 = 0.0001) 和 CCOC 中最常见，与 HGSOC 的总生存期延长相关 (风险比: 0.78，95% CI: 0.65-0.94，p值 = 0.022)。在 HGSOC 中，PTEN 表达与 ER 、 PR 和 AR 表达相关 (p值分别为 0.0008 、 0.062 和 0.0002)，在 CCOC 中，PTEN 表达与 CD8 计数较低相关 (p值 <0.0001)。PTEN 的异质性表达在晚期 HGSOC 中更普遍 (p 值 = 0.019)，并与较高的 CD8 计数相关 (p 值 = 0.0016)。结论 PTEN 缺失是卵巢癌中常见的驱动因子，与 HGSOC 和 CCOC 组织类型中激素受体和 CD8 + TIL 计数的表达明显相关。
METHODS:STUDY OBJECTIVE:To evaluate the differences in perioperative outcomes and immediate complication rates between laparoscopic myomectomy for submucous myomas and laparoscopic myomectomy for myomas in other locations. DESIGN:Retrospective cohort study. SETTING:University-affiliated hospital in London. PATIENTS:A total of 350 patients with symptomatic uterine myomas underwent laparoscopic myomectomy. Thirty-three of these were performed for submucous myomas (group 1), and 317 were for myomas in other uterine locations (group 2). INTERVENTIONS:Analysis of prospectively collected data on patient demographics, myoma characteristics, perioperative outcomes, and immediate complications. MEASUREMENTS AND MAIN RESULTS:Patient demographics, including age, body mass index, and parity, were similar in the 2 groups. No significant differences in myoma characteristics were seen between groups 1 and 2, including the mean dimension of largest myoma (7.1 vs 7.8 cm, respectively; p = .35), mean number of myomas removed (3.8 vs 4.1; p = .665), and mean mass of myomas removed (142.0 g vs 227.3 g; p = .186). There were also no significant between-group differences in any perioperative outcomes, including mean blood loss (226.8 mL vs 266.4 mL; p = .373), duration of surgery (103 minutes vs 113 minutes; p = .264), and duration of hospital stay (1.4 days vs 1.7 days; p = .057). No complications arose from laparoscopic resection of submucous myomas. CONCLUSION:Laparoscopic myomectomy for submucous myomas has similar perioperative outcomes and immediate complications as laparoscopic myomectomy for other myomas and can be considered for large or type 2 submucous myomas.
METHODS:INTRODUCTION:Laparoscopic myomectomy can be difficult when fibroids are large and numerous. This may result in extensive intraoperative bleeding and the need for a conversion to a laparotomy. Medical pretreatment prior to surgery might reduce these risks by decreasing fibroid size and vascularization of the fibroid. We compared pretreatment with ulipristal acetate (UPA) vs gonadotropin-releasing hormone agonists (GnRHa) prior to laparoscopic myomectomy on several intra- and postoperative outcomes. MATERIAL AND METHODS:We performed a non-inferiority double-blind randomized controlled trial in nine hospitals in the Netherlands. Women were randomized between daily oral UPA for 12 weeks and single placebo injection or single intramuscular injection with leuprolide acetate and daily placebo tablets for 12 weeks. The primary outcome was intraoperative blood loss. Secondary outcomes were reduction of fibroid volume, suturing time, total surgery time and surgical ease. RESULTS:Thirty women received UPA and 25 women leuprolide acetate. Non-inferiority of UPA regarding intraoperative blood loss was not demonstrated. When pretreated with UPA, median intraoperative blood loss was statistically significantly higher (525 mL [348-1025] vs 280 mL[100-500]; P = 0.011) and suturing time of the first fibroid was statistically significantly longer (40 minutes [28-48] vs 22 minutes [14-33]; P = 0.003) compared with GnRHa. Pretreatment with UPA showed smaller reduction in fibroid volume preoperatively compared with GnRHa (-7.2% [-35.5 to 54.1] vs -38.4% [-71.5 to -19.3]; P = 0.001). Laparoscopic myomectomies in women pretreated with UPA were subjectively judged more difficult than in women pretreated with GnRHa. CONCLUSIONS:Non-inferiority of UPA in terms of intraoperative blood loss could not be established, possibly due to the preliminary termination of the study. Pretreatment with GnRHa was more favorable than UPA in terms of fibroid volume reduction, intraoperative blood loss, hemoglobin drop directly postoperatively, suturing time of the first fibroid and several subjective surgical ease parameters.
METHODS:AIMS:Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS:We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION:Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.