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Analysis of CARD10 and CARD11 Somatic Mutations in Patients with Ovarian Endometriosis

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ONCOLOGY LETTERS 16: 491-496, 2018 Analysis of CARD10 and CARD11 somatic mutations in patients with ovarian endometriosis YANG ZOU1,2, JIANG-YAN ZHOU1,3, FENG WANG1,2, ZI-YU ZHANG1,2, FA-YING LIU1,2, YONG LUO1,2, JUN TAN1,4, XIN ZENG1, XI-DI WAN1 and OU-PING HUANG1,3 1Key Laboratory of Women's Reproductive Health of Jiangxi Province; 2Central Laboratory; 3Department of Gynecology; 4Reproductive Medicine Center, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China Received October 11, 2017; Accepted March 27, 2018 DOI: 10.3892/ol.2018.8659 Abstract. Endometriosis is a complex and heterogeneous amongst 101 cases of ovarian endometriosis for the first time, pre-malignant inflammatory disease harboring multiple these mutations may serve active roles in the development of gene mutations. Previous studies have suggested that caspase ovarian endometriosis. recruitment domain family member (CARD)10 and CARD11 mutations may exist in endometriosis. In the present study, Introduction a collection of endometriotic lesions and paired peripheral blood from 101 patients with ovarian endometriosis were Endometriosis is a heterogeneous estrogen-dependent chronic obtained, and the entire coding sequences of the CARD10 gynecological disease in women of reproductive age (1-3). The and CARD11 genes were sequenced. Evolutionary conserva- condition is characterized by endometrial tissues ectopically tion analysis and online prediction programs were applied implanting outside the uterine cavity, and is subdivided mainly to analyze the disease-causing potential of the identified into ovarian, peritoneal and deep infiltrating endometriosis mutations. A total of 4 novel somatic mutations were according to the different implant locations (4,5). The most identified in 4 out of the 101 (4.0%) samples: 2 in-frame common clinical symptoms of endometriosis include dysmen- deletions in CARD10 (c.785_790delAGGAGA, p.K272_ orrhea, chronic pelvic pain and diminished fertility potential, E273delKE; c.785_802delAGGAGAAGGAGAAGGAGA, which greatly influence the quality of life of affected indi- p.K272_V277delKEPDNV) and 2 heterozygous missense viduals (6). Despite numerous studies being performed on this mutations in CARD11 (c.49G>T, p.D17Y; c.160G>C, research field, the molecular etiology of endometriosis is not p.E54Q). The sample with CARD10 p.K272_E273delKE yet fully understood (7,8). deletion was obtained from a 47-year-old patient who was It has long been accepted that endometriosis is actually also diagnosed with uterine leiomyoma, while the CARD10 an inflammatory disease (9,10), with cytokine levels that are p.K272_V277delKEPDNV-mutated sample was from a elevated in the peritoneal fluid, serum and endometriotic lesion 43-year-old patient exhibiting a decreased blood eosinophil tissues (11-13). Based on these observations, certain researchers granulocyte ratio (0.3%) and an elevated serum creatine kinase formulated the inflammation hypothesis that leukocytes are level (314 U/l). The patient with the CARD11 p.D17Y mutation recruited by the endometrial stromal cells within endometriotic was 38 years old and exhibited an increased level of cancer lesions, and that proinflammatory cytokines are then secreted antigen 125 (45.4 U/ml), while the patient with the CARD11 from these leukocytes, which will facilitate the progression of p.E54Q mutation was 46 years old and exhibited no other endometriosis (14,15). Furthermore, it has also been proposed gynecological conditions. Evolutionary conservation analysis that the changed progesterone responsiveness may be the main and online prediction programs suggested that these mutations reason for the elevated production of cytokines in endome- may be disease-causing. In summary, 4 novel somatic muta- triosis (16-18). However, in spite of advances (1,19), there have tions in the CARD10 and CARD11 genes were identified from not been any therapeutic strategies targeting inflammatory factors in endometriosis that have been successfully applied to samples with endometriosis, implying a great underapprecia- tion of the role of inflammation in endometriosis (20,21). Caspase recruitment domain family member 11 (CARD11) Correspondence to: Professor Ou-Ping Huang, Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi belongs to the CARD protein family; it can bind with B-cell Provincial Maternal and Child Health Hospital, 318 Bayi Avenue, CLL/lymphoma 10 and activate the inflammation‑associated Nanchang, Jiangxi 330006, P.R. China nuclear factor κB (NF-κB) signaling pathway (22). Furthermore, E-mail: [email protected] CARD11 also acts as a scaffold protein to assist the assembly of multiprotein signaling molecules in the plasma membrane (23). Key words: CARD10, CARD11, mutations, ovarian endometriosis Previous studies showed that CARD11 somatic mutations were detected frequently in multiple human cancer types, including hematological malignancies, colorectal cancer and malignant 492 ZOU et al: CARD10 AND CARD11 MUTATIONS IN OVARIAN ENDOMETRIOSIS melanoma; the mutations were distributed along the CARD11 blood in the same patients. The procedure of PCR amplifica- coding sequence while being mainly clustered within the tion and DNA sequencing was performed as described above. coiled-coil domain (24-28). Most recently, a somatic mutation in the CARD11 gene (p.R30W, c.C88T) was identified in the Evolutionary conservation analysis. The protein sequences endometriotic lesion of 1 out of 16 samples with ovarian endo- from 21 vertebrate species from GenBank (https://www.ncbi. metriosis. Considering the fact that endometriosis is a potential nlm.nih.gov/genbank/) were used to analyze the evolutionary premalignant disorder and the endometriotic lesions harbored conservation status of the identified CARD11 mutations, certain genetic alterations in tumor-associated genes (29-33), including Homo sapiens (NP_115791), Macaca mulatta and furthermore that mutations in the paralogous genes usually (XP_014988691), Rattus norvegicus (XP_017454079), Mus occurred in the same cancer types (34,35), we thus hypoth- musculus (NP_780571), Dipodomys ordii (XP_012878958), esized that mutations in the paralogous CARD10 and CARD11 Bos taurus (NP_001103266), Microcebus murinus may exist in ovarian endometriosis. (XP_012614839), Equus asinus (XP_014702187), Pan In the present study, a total of 101 patients with ovarian paniscus (XP_008971413), Cavia porcellus (XP_013008240), endometriosis were recruited and analyzed for the presence of Camelus ferus (XP_014412591), Ovis aries (XP_014959439), CARD10 and CARD11 mutations, with the aim of exploring Mustela putorius furo (XP_0129032), Canis lupus familiaris the potential involvement of mutations in these two genes in (XP_005621), Gallus gallus (NP_001006161), Calidris pugnax the pathogenesis of ovarian endometriosis. (XP_014801661), Ficedula albicollis (XP_005054487), Lipotes vexillifer (XP_007467483), Apteryx australis mantelli Materials and methods (XP_013797455), Stegastes partitus (XP_008283939) and Ictalurus punctatus (XP_017310081). Multiple sequence Samples. The endometriotic lesions of the ovaries and alignment was performed using the ‘ClustalW’ tool of the paired peripheral blood samples were obtained immediately alignment function in the Molecular Evolutionary Genetics following surgical resection from a total of 142 patients with Analysis software (MEGA, version 4.0) which was created ovarian endometriosis who were treated in the Department of and developed by Kumar et al (36). Gynecology, Jiangxi Provincial Maternal and Child Health Hospital (Nanchang, Jiangxi, China), between July 2015 and Bioinformatics programs prediction of the CARD10 and January 2018. All samples were diagnosed pathologically CARD11 mutations. PolyPhen-2 (http://genetics.bwh.harvard. by two experienced pathologists, and the 101 cases with an edu/pph2/) (37) and MutationTaster (http://mutationtaster. ectopic endometrium purity of >30% were included in the org/) (38) software were used to analyze the disease-causing present study. The study was approved by the Institutional potential for the identified missense mutations, while the Review Board of Jiangxi Provincial Maternal and Child Health SIFT (http://sift.jcvi.org/) program (39) was used to predict Hospital, and the detailed protocol was conducted according the potential pathogenicity of the in-frame deletions. All to the Declaration of Helsinki and the Jiangxi Provincial bioinformatic analysis was performed on February 6th, 2018. Maternal and Child Health Hospital. Written informed consent Together, the software automatically assessed each mutation was obtained from all patients prior to the study. as either pathogenic or benign. Mutational analysis of the CARD10 and CARD11 genes. The Statistical analysis. The frequency difference of CARD11 genomic DNA was isolated from the endometriotic lesions and mutation in the current study and the previous study (29) was paired peripheral blood samples using the DNeasy Blood and analyzed by two-tailed Fisher's exact test using SPSS software Tissue kit (catalog no. 69504; Qiagen, Inc., Valencia, CA, USA) version 18.0 (SPSS Inc., Chicago, IL, USA). P<0.05 was according to the manufacturer's protocols. The entire coding considered to indicate a statistically significant difference. region of the CARD10 and CARD11 genes in the endometriotic lesions of patients with ovarian endometriosis were ampli- Results fied by polymerase chain reaction (PCR) with sets of primer pairs (Table
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  • An Evolutionary View

    An Evolutionary View

    bioRxiv preprint doi: https://doi.org/10.1101/317719; this version posted May 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. How Much Information is Provided by Human Epigenomic Data? An Evolutionary View Brad Gulko1,2 and Adam Siepel2 1Graduate Field of Computer Science, Cornell University, Ithaca, NY, USA 2Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA ABSTRACT Here, we ask the question, “How much information do available epigenomic data sets provide about human genomic function, individually or in combination?” We measure genomic function by using signatures of natural selection as a proxy, and we measure information in terms of reductions in entropy derived from a probabilistic evolutionary model. Our analysis of the human genome considers measures of chromatin accessibility (DNase-seq), chromatin states (ChromHMM), RNA expression (RNA-seq), small RNAs, and DNA methylation across 115 cell types from the Roadmap Epigenomics project, together with gene annotations, splice sites, predicted transcription factor binding sites, and predicted DNA melting temperatures. Selective pressure is measured using patterns of genetic variation across ~50 modern humans and several nonhuman primates. We find that protein-coding gene annotations are most informative about genomic function, followed in decreasing order by RNA-seq, ChromHMM, splice sites, melting temperature, and DNase-seq. Several features exhibit clear synergy, meaning that they yield more information in combination than they do individually.