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Paget's disease (PD) is an intraepidermal adenocarcinoma of the skin at the breast (mammary PD) or urogenital locations (extramammary PD [EMPD]). At present, there is lack of clarity on PD's pathogenesis, the relationship between its subtypes, and its lineage link with the underlying invasive carcinomas. Here we describe that mammary PD and EMPD have similar mutational profiles, with the most frequent recurrent mutations occurring in the chromatin remodeling genes, such as KMT2C (MLL3, 39%) and ARID2 (22%), with additional recurrent somatic mutations detected in genes previously not known to be mutated in cancers, such as CDCC168 (34%), FSIP2 (29%), CASP8AP2 (29%), and BIRC6 (24%). In paired mammary PD and underlying breast carcinoma samples, distinct gene mutations were detected, indicating that they represent independent oncogenic events. Finally, multistage EMPD tissue sequencing revealed KMT2C gene occurring early in EMPD oncogenesis, and that multifocal EMPD samples share the same early gene mutations, suggesting clonal origin of multifocal EMPD. Our results reveal similar genomic landscapes between mammary PD and EMPD, including early aberrations in chromatin remodeling genes. In addition, mammary PD and underlying breast ductal carcinomas represent independent oncogenic events. These findings provide approaches for developing diagnostic tools and therapeutic interventions for PD.

Background: Early embryonic arrest is one of the major causes of female infertility after in vitro fertilization (IVF), but the causal gene of arrest at the pronuclear (PN) zygote stage is largely unknown. Results: To understand this process, we recruited a family characterized by recurrent PN arrest during IVF cycles and performed whole-exome sequencing. The missense variant c.C1630T (p.R544W) in RGS12 was responsible for a phenotype characterized by paternal transmission. RGS12 controls Ca2+ oscillation, which is required for oocyte activation after fertilization. Single-cell transcriptome profiling of PN-arrest zygotes revealed defective established translation, RNA processing and cell cycle, which explained the failure of complete oocyte activation. Furthermore, we identified proximal genes involved in Ca2+ oscillation–cytostatic factor–anaphase-promoting complex (Ca2+ oscillation–CSF–APC) signaling, including upregulated CaMKII, ORAI1, CDC20, and CDH1 and downregulated EMI1 and BUB3. The findings indicated abnormal spontaneous Ca2+ oscillations leading to oocytes with prolonged low CSF and high APC level, which resulted in defective nuclear envelope breakdown and DNA replication. The changes in levels of critical genes were confirmed by examining other independent PN-arrest zygotes. However, the PN-arrest zygote phenotype was not consistent with that of RGS12-deficient mice, thereby indicating species-specific functions between human and mouse. Conclusion: Our findings expand our knowledge of the genetic determinants of human early embryonic arrest at the PN stage and provide guidance for selecting clinically infertile individuals with PN-arrest zygotes for Ca2+ intervention.

Uterine carcinosarcoma (UCS) is a rare aggressive malignancy. Several reports previously described UCS occurring after tamoxifen therapy for breast carcinoma. However, the genetic landscape of tamoxifen-related UCS remains unclear. We performed whole-exome sequencing of two UCSs after tamoxifen therapy for breast carcinoma to determine mutational profile of UCSs and those corresponding breast carcinomas. Our results demonstrated that 374 somatic variants in 141 genes were shared across the two UCSs, whereas no shared somatic variations across the breast carcinomas were found. Pathway analysis indicated the MAPK pathway, including the epithelial-mesenchymal transition (EMT) inducer gene TGF-β2 mutations (c. 1039G > A and c. 1040C > T, both p.A347T), recurrently occurred in UCS, while ER-related gene EP300 (p.P16L) and ESR1 (p.V355I) mutations were identified independently in breast carcinomas. These findings highlight the EMT-related gene TGF-β2 variants in the tumorigenesis of tamoxifen-related UCS, support the possibility that tamoxifen mediates its effect on UCS by enhancing mutations of driver genes, and also provides the rationale for clinical investigation in ER-related gene mutation in breast carcinoma to predict the risk for UCS after tamoxifen treatment.

// Ruiqin Mai 1,* , Songxia Zhou 2,* , Weixiang Zhong 3,* , Siming Rong 2 , Zhichao Cong 2 , Yunxian Li 2 , Qizhi Xie 2 , Huanming Chen 2 , Xiaoyun Li 2 , Shuhui Liu 2 , Yabin Cheng 4 , Yuanshen Huang 4 , Youwen Zhou 4 and Guohong Zhang 2,4 1 Department of Laboratory Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China 2 Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China 3 Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 4 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada * These authors have contributed equally to this work Correspondence to: Youwen Zhou, email: // Guohong Zhang, email: // Keywords : combing BRAF and MEK inhibition, targeted therapy, melanoma Received : May 01, 2015 Accepted : June 03, 2015 Published : June 08, 2015 Abstract Background: Several recent randomized clinical trials have preliminarily demonstrated that initial targeted therapy with combined BRAF and MEK inhibition is more effective in metastatic melanoma (MM) than single agent. To guide therapeutic decisions, we did a comprehensive network meta-analysis to identify evidence to robustly support whether combined BRAF and MEK inhibition is the best initial targeted therapeutic strategy for patients with MM. Methods: The databases of PubMed and trial registries were researched for randomized clinical trials of targeted therapy. Data of outcome were extracted on progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Network meta-analysis using a Bayesian statistical model was performed to evaluate relative hazard ratio (HR) for PFS and OS, odds ratio (OR) for ORR. Results: Finally, 16 eligible trials comprising 5976 participants were included in this meta-analysis. PFS were significantly prolonged in patients who received combined BRAF-MEK inhibition compared with those who received BRAF inhibition (HR: 0.58, 95%CI: 0.51-0.67, P < 0.0001) or MEK inhibition alone (HR: 0.29, 95%CI: 0.22-0.37, P < 0.0001). Combined BRAF-MEK inhibition also improved the OS over BRAF inhibition (HR: 0.67, 95%CI: 0.56-0.81, P < 0.0001) or MEK inhibition alone (HR: 0.48, 95%CI: 0.36-0.65, P < 0.0001). The ORR was superior in combined BRAF and MEK inhibition comparing with BRAF inhibition (OR: 2.00, 95%CI: 1.66-2.44, P < 0.0001) or MEK inhibition alone (OR: 20.66, 95%CI: 12.22-35.47, P < 0.0001). Conclusions: This study indicates that concurrent inhibition of BRAF and MEK improved the most effective therapeutic modality as compared as single BRAF or MEK inhibition for patients with MM.

Background and Objectives. Paget’s disease (PD) is a rare intraepithelial adenocarcinoma, which is composed of mammary (MPD) and extramammary Paget’s disease (EMPD). Currently, the published literature contains scant data on expression pattern of steroid hormone receptors in MPD and EMPD. Methods. Expression of estrogen receptor (ER) and androgen receptor (AR) was evaluated in 88 MPD and 72 EMPD by using immunohistochemical staining and H-score method. Results. Positive expression of AR was significantly higher in EMPD (61.11%, 44/72) than in MPD (32.95%, 29/88) (P<0.001), while ER expression was positive 19.44% (14/72) in EMPD and only 9.09% (8/88) in MPD (P=0.059). ER-AR expression pattern was significantly different between MPD (3.41%, 3/88) and EMPD (16.67%, 12/72) (P<0.001). No difference of AR (P=0.301) or ER (P=0.239) expression was identified between invasive (48.57%, 51/105 of AR, and 11.43%, 12/105 of ER) and noninvasive PD. In MPD, no difference of AR expression between MPD alone (7/18, 38.89%) and MPD with underling ductal carcinoma of breast (22/70, 31.43%) was identified (P=0.548). In EMPD, expression of AR was 63.33% (38/60) in penoscrotal EMPD. Conclusion. Our current results indicate that MPD and EMPD presented different expression pattern of AR and ER and would help to further identify the molecular subtype of MPD and EMPD for adjuvant hormonal therapy, especially for patients with penoscrotal EMPD.

Data of HPV genotype including 16 high-risk HPV (HR-HPV) and 4 low-risk HPV from 38,397 women with normal cytology, 1341 women with cervical cytology abnormalities, and 223 women with ISCC were retrospectively evaluated by a hospital-based study. The prevalence of high-risk HPV (HR-HPV) was 6.51%, 41.83%, and 96.86% in women with normal cytology, cervical cytology abnormalities, and ISCC, respectively. The three most common HPV types were HPV-52 (1.76%), HPV-16 (1.28%), and HPV-58 (0.97%) in women with normal cytology, whereas the most prevalent HPV type was HPV-16 (16.85%), followed by HPV-52 (9.55%) and HPV-58 (7.83%) in women with cervical cytology abnormalities. Specifically, HPV-16 had the highest frequency in ASC-H (24.16%, 36/149) and HSIL (35.71%, 110/308), while HPV-52 was the most common type in ASC-US (8.28%, 53/640) and LSIL (16.80%, 41/244). HPV-16 (75.78%), HPV18 (10.31%), and HPV58 (9.87%) were the most common types in women with ISCC. These data might contribute to increasing the knowledge of HPV epidemiology and providing the guide for vaccine selection for women in Shantou.

Uterine carcinosarcoma (malignant mixed Müllerian tumor, MMMT) is a rare aggressive malignant tumor, which demonstrates both malignant epithelial (carcinoma) and mesenchymal (sarcoma) components. Synchronous uterine carcinosarcoma and contralateral breast cancer in patient received tamoxifen treatment had not been reported. We present a case of uterine carcinosarcoma co-occurrenced with contralateral breast cancer in a 56-year-old nulliparous, obese breast cancer patient, who had been treated with tamoxifen for 5 years. The patient presented with palpable pelvic mass and vaginal bleeding. Histopathological evidence revealed that the tumor was comprised of an admixture of malignant epithelial and mesenchymal components. The epithelial component was endometrioid type adenocarcinoma, while sarcomatous component had heterologous elements including fusiform cell sarcoma and a prominent component of cartilage. The infiltrating ductal carcinoma has been diagnosed on her right breast. The patient died of disease 8 months after diagnosis. Postmenopausal patients, with adjuvant tamoxifen treatment for breast cancer, are at increased risk for the development of uterine carcinosarcoma and less benefit for contralateral breast cancer.