Androgen Receptor Gene Mutations Research Articles

The FKBP4 gene, encoding a regulator of the androgen receptor signaling pathway, is a novel candidate gene for androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

A Novel Mutation of the AR Androgen Receptor Gene

Abstract Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the androgen receptor (AR) gene. Loss of AR function means that, despite normal levels of androgen synthesis, the typical postreceptor events that mediate the effects of hormones on tissues do not occur. This results in the phenotype of prenatal undervirilization of external genitalia, absence of pubic and axillary hair, lack of acne, and absence of voice changes at puberty We present This baby reffered at age of 2 months from pediatric surgery as a case of bilateral inguinal hernia and chromosomes 46xy. Phenotypically female no male structures no phallus and single opening and visible labia, both test are in the inguinal canals. HCG stimulation test shows: Testosterone: the level at (0) time: 0.8 nmol/l then 3 days: 31.4 nmol/l. DHT dihydrotetostrerone: the level at (0) time: 13 NG/L then 3 days: 485 The baby was given 3 doses of Testosterone injections 150mg but no response at the genetalia. Radiological investigations shows ultrasound both tests at the inguinal canals and no uterus Also MRI of pelvis shows absence of uterus and both test at the inguinal canals Molecular genetics analysis for Androgen receptor gene: Exon 7 c.2512 G >A hem. P.Glu838lys missense, novel VUS,likely pathogenic. The segregations analysis test in the process. Her we present a novel mutation of the AR gene not reported yet in literature.

Unexpected Diagnosis of Complete Androgen Insensitivity Syndrome (CAIS) During Inguinal Hernia Repair in 11-year-old-girl

Complete Androgen Insensitivity Syndrome (CAIS) is an X-link recessive genetic mutation of androgen receptor (AR) gene leading to complete inability of cell to respond to the androgens. CAIS occurs in 1 out of 20,400 XY live-birth babies, and affects about 1–2% of prepubertal girls that present with an inguinal hernia. Although individuals with CAIS have XY, those with grades 6 and 7 on the Quigley scale are born phenotypically female, without any signs of genital masculinization. Thus, individuals affected by CAIS develop a normal external female phenotype with normal female external genitalia, well-developed breast, absent uterus, and bilateral undescended testicles. The question of CAIS diagnosis does not come forward until the absent menses at the puberty is noted or accidentally during an inguinal hernia repair in a premenarchal girl. The present study reports a case of inguinal hernia repair on 11-year-old girl, which led to unexpected intraoperative notion of CAIS. The diagnostic work-up, genetic counseling, sex assignment, and the need for preoperative CAIS screening in girls with bilateral inguinal hernia are described and discussed.
 Keywords: DSD, CAIS, bilateral inguinal hernia, gonadectomy

Clinical characteristics and molecular genetics of complete androgen insensitivity syndrome patients: a series study of 30 cases from a Chinese tertiary medical center

To study the clinical characteristics and genetic basis of complete androgen insensitivity syndrome (CAIS) in patients from the People's Republic of China. CAIS patients with 46 XY karyotype produce male levels of androgens but present with female external genitalia and secondary sex characteristics. The majority of affected individuals have androgen receptor (AR) gene mutations. This case series explored clinical and molecular characteristics of CAIS patients from the People's Republic of China. Genomic DNA from peripheral blood of clinically diagnosed CAIS patients was sequenced for mutation in the androgen receptor (AR) gene and steroid 5α-reductase type 2 gene (SRD5A2). Participants were recruited from Peking Union Medical College Hospital when they came in for consultation. Thirty patients from unrelated families were recruited. Data from medical documents recording diagnosis and treatment of these patients were retrospectively collected. Patient genotypes were determined by sequencing the AR and SRD5A2 genes. Their clinical characteristics were summarized based on symptoms, hormone profiles, operative findings, and pathological results. Twenty-one patients diagnosed with CAIS had mutations in AR exons. Analysis of AR exons revealed the presence of seven novel mutations (c.58C>T, c.645_652delGGGGGCTC, c.910G>T, c.1078C>T, c.1786T>A, c.2230G>T, and c.2522G>C); of these mutations, 47.6% (10/21) were located in the ligand-binding domain. Gonadal insufficiency was found in one case of CAIS. Among the remaining nine patients, three had SRD5A2 mutations and therefore a steroid 5α-reductase deficiency. No AR or SRD5A2 mutations were detected in the other six patients. This study broadens the spectrum of known AR gene mutations responsible for CAIS, and implies that there can be more complex underlying causes of CAIS.

In vitro functional characterization of androgen receptor gene mutations at arginine p.856 of the ligand-binding-domain associated with androgen insensitivity syndrome

Androgens are critical for male sex differentiation. Their actions are mediated by the androgen receptor (AR). Mutations disrupting AR function result in the androgen insensitivity syndrome (AIS). In this study, we identified in a patient with complete AIS, a novel AR mutation p.R856L. To investigate the functional properties of p.R856L, we performed functional studies. In comparison, we have characterized two already described mutations: p.R856H and p.R856C. We used a model composed of two different promoters fused to a reporter gene, two cell lines, and showed that all mutations were able to transactivate the (ARE)2-TATA promoter expressed in CHO cells more highly. Moreover, we confirmed the pathogenicity of the p.R856L and p.R856C mutations, and their associations with complete AIS. In contrast, the p.R856H mutation, which is associated with a spectrum of AIS phenotypes, showed less severe transcriptional constraints. Altogether, our studies allowed us to better characterize arginine residue at p.R856 position.

Molecular basis of androgen insensitivity syndromes

Individuals with complete androgen insensitivity syndrome show a female genital phenotype despite 46, XY gonosomes and the presence of androgen producing testes. This clinical observation indicates the resistance of the body and its cells to androgens like testosterone. At the molecular level, this hormone resistance is caused by hemizygous loss of function mutations in the X-chromosomal androgen receptor (AR) gene. Partial forms of androgen insensitivity syndrome (PAIS) show different degrees of virilisation largely depending on the remaining activity of the AR. Nevertheless, the phenotypic outcome can be variable even in presence of the same mutation and in the same kindred indicating the presence of further influencing factors. Importantly, the majority of clinically diagnosed PAIS individuals do not bear a mutation in their AR gene. A recent assay using the androgen regulated gene apolipoprotein D as biomarker is able to detect androgen insensitivity on the cellular level even in absence of an AR gene mutation. Using this assay a class of AIS without an AR-gene mutation was defined as AIS type II and suggests that unidentified cofactors of the AR are responsible for the PAIS phenotype. Here we outline the scientific progress made from the first clinical definition of AIS over biochemical and molecular characterizations to the concept of AIS type II. This review is based on publications in the PubMed database of the National Institutes of Health using the search terms androgen insensitivity syndrome and androgen receptor mutation.

Androgen receptor gene mutations in 258 Han Chinese patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) affects 8-13% of reproductive-age females worldwide and mutations or aberrant expression of androgen receptor (AR) may cause the onset of this disease. In the present study, 258 samples from Han Chinese patients with PCOS were analyzed for the presence of AR mutations via sequencing of all coding exons of the AR gene. A total of five heterozygous missense mutations, namely p.V3M, p.Q72R, p.S158L, p.S176R and p.G396R, were identified in five of the patients. Among these, p.S158L was a novel mutation that, to the best of our knowledge, has not been reported previously. Although the remaining four mutations have been reported previously, they existed at low frequencies or were absent in the control subjects and in the Exome Aggregation Consortium database. The results of evolutionary conservation and in silico analysis revealed that the p.V3M, p.S158L and p.S176R mutations were pathogenic, whereas the p.Q72R and p.G396R mutations were benign. Compared with the patients with PCOS without AR mutations or with benign AR mutations, markedly lower estrogen levels on the day of human chorionic gonadotropin injection were observed in the three patients with PCOS with potentially pathogenic mutations. In addition, patients with PCOS with pathogenic mutations had lower numbers of oocytes; however, the difference was not statistically significant. Of note, these observations should be interpreted with caution due to the relatively small sample size in the present study. Therefore, a larger number of samples should be collected to validate the results of the present study in future studies. In summary, the present study identified three potential pathogenic mutations in 258 Han Chinese patients with PCOS and these mutations may have an implication in the pathogenesis of PCOS.

The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome.

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

Incidence of Androgen Receptor and DNA Repair Gene Mutations in Advanced Solid Malignancies: Clinical Impact of Liquid Biopsy at Veteran Affairs Medical Center

Abstract Introduction/Objective The advent of Liquid biopsy targeting genetic mutations in solid tumors is a major milestone in field of precision oncology. This minimally invasive, novel revolutionary technique analyses circulating tumor cells (CTC) in peripheral blood and detects signature genomic alterations. DNA repair gene (DDR) mutations have been reported in 25-40% of prostatic cancers and >50% of non-small cell lung cancers (NSCLC), being more common in late-stage and hormone refractory prostate cancers. One of the DDR, especially Tp53 has been found to be associated with poor prognosis and increased germline mutations. We herein present a quality assurance study to determine feasibility of liquid biopsy for personalized management in veterans for advanced solid malignancies and its clinical impact. Methods Quality assurance documentation from Foundation One (Cambridge MA, NGS) on liquid biopsies performed for the Corporal Michael J. Crescenz Veteran Affairs Medical Center (CMCVAMC) from May 2019 to April 15, 2020 were reviewed. Statistical data for adequacy, cases with notable mutations, frequency and type of mutations of AR, DNA damage repair (DDR) gene and Tp53 were noted. Results A total of 31 liquid biopsies were performed over this time period, of which 29/31 (93.50%) were adequate for evaluation. 23/29 (79.30%) showed notable mutations, in 4/23 (17.39%) guided treatment decisions based on androgen receptor (AR) amplification, and 7/29 (24.1%) of all cases showed DDR gene mutations indicating poor outcome and resistance to the current therapy. Greater than 50% (16/29 (55.7%)) of the veterans with advanced cancers harbored Tp53 mutation, which instills hope and future insight for patient tailored oncologic therapy. Conclusion The minimally invasive liquid biopsy shows a great promise as a diagnostic and prognostic tool in the personalized clinical management of advanced prostate and NSCLC in veteran patient population with unique demographic characteristics. Difference in frequency of the genetic mutations (DDR, TP53, AR) in this cohort provides valuable information for disease progression, lack of response, mechanism of resistance to the implemented therapy and clinical decision making. Precision oncology can be further tailored for this cohort by focusing on DNA repair genes and Tp53 in future for personalized targeted therapy.

Circulating Tumour DNA as a Biomarker Source in Metastatic Prostate Cancer

Tumour molecular features are increasingly linked to treatment response and patient prognosis in advanced prostate cancer. Plasma cell-free circulating tumour DNA (ctDNA) isolated from a minimally invasive blood draw offers a convenient source of tumour material to develop clinical biomarkers. Importantly, the burden of ctDNA in the blood has strong prognostic implications at different points during the natural history of metastatic progression. In prostate cancer, the identification of somatic profiles from ctDNA requires a broad next-generation sequencing approach because of the low mutation rate and frequent structural rearrangements. Nevertheless, comparison of genomic profiles between liquid and tissue biopsies has demonstrated that ctDNA is a surrogate for tumour tissue in the metastatic setting. Our understanding of resistance to androgen receptor (AR) directed therapies has been significantly augmented by the frequent detection of AR gene amplifications, mutations, and structural rearrangements via liquid biopsy. Furthermore, early studies suggest that distinct molecular subtypes derived from ctDNA profiling can help determine the optimal therapeutic regimen for an individual patient and enable real-time monitoring for therapy response and resistance. Indeed, in clinical trials targeting the DNA damage repair pathway in prostate cancer, ctDNA-based assessment of DNA repair status is already under evaluation as a predictive biomarker. Recent advances in the study of circulating DNA fragments now make it possible to interrogate aspects of the epigenome. In this review, we describe the various applications of plasma ctDNA in metastatic prostate cancer, including its potential role as a clinically informative liquid biomarker.

Structural analysis of the impact of a novel androgen receptor gene mutation in two adult patients with mild androgen insensitivity syndrome

Structural analysis of the impact of a novel androgen receptor gene mutation in two adult patients with mild androgen insensitivity syndrome

Abstract 1960: Targeted androgen receptor (AR) protein degradation for the treatment of metastatic castration-resistant prostate cancer (mCRPC)

Abstract Androgen receptor (AR) and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer. As a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC), previous strategies that successfully target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition of AR function by AR antagonists such as enzalutamide and apalutamide (ARN-509). However, such agents become ineffective in advanced prostate cancer with AR gene amplification, mutation and alternate splicing. It is very clear however that in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent upon AR signaling. Here we describe our design, synthesis and evaluation of small-molecule AR degraders based on the proteolysis targeting chimera (PROTAC) concept and our investigation of their therapeutic potential and mechanism of action in vitro and in vivo. In vitro, our potent AR degraders effectively induce degradation of AR protein in AR+ LNCaP, VCaP and 22Rv1 prostate cancer cell lines with DC50 values as low as 1 nM. AR degraders are capable of reducing the AR protein level by >95% in these AR+ cancer cell lines and effectively reduces AR-regulated gene expression suppression. In vivo, our AR degrader showed potent AR degradation effects and anti-tumor activities in multiple murine xenograft models of prostate cancer at well-tolerated dosing schedules. Our data provides clear evidence that targeting AR for degradation by the PROTAC methodology is a novel and very exciting therapeutic approach for the treatment of mCRPC. Citation Format: Xin Han, Lijie Zhao, Weiguo Xiang, Chong Qin, Bukeyan Miao, Tianfeng Xu, Jianfeng Lu, Mi Wang, Shaomeng Wang. Targeted androgen receptor (AR) protein degradation for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1960.

Gender Dysphoria: A Review Investigating the Relationship Between Genetic Influences and Brain Development.

Gender dysphoria (GD) is a facet of modern human biology which is believed to be derived from the sexual differentiation of the brain. GD “involves a conflict between a person’s physical or assigned gender and the gender with which he/she/they identify”, as defined in the DSM-5. Individuals report feeling uncomfortable and faced with prejudice from those around them, affecting their mental health. Elucidating the relationship between genetic influences on gonadal and brain development could give an insight into understanding this clinical condition. To explore this issue, a review of the literature database was carried out. Evidence suggests that abnormal biological processes, including mutations in certain genes, can lead to abnormal gonadal development, causing some fetuses to present with indifferent gonads and to be reassigned at birth to the default female sex. This disparity in genetic influences relates to an increased likelihood of a diagnosis of GD. An investigation into complete androgen insensitivity syndrome, involving androgen receptor (AR) gene mutation, suggests that such individuals also experience GD. It is known that the brains of males and females are different. Evidence further suggests that brain anatomy and neuronal signaling pathways are more closely aligned with a person’s perceived gender identity. Individuals who present with discordant gonadal and brain developments experience psychological challenges that may contribute to a state of unease or generalized dissatisfaction with their biological sex. These point to a possible biological and genetic underpinning of GD as stemming from a discordance between gonadal and brain development. However, not enough evidence has associated these differences with GD. Further research is required to elucidate the true mechanisms and possible inheritance pattern of GD for a better education and greater understanding by clinicians and the general public on perceptions regarding GD.

Six molecular patterns leading to hemophilia A phenotype in 18 females from Poland

IntroductionFemale hemophilia is an intriguing rare disorder and few larger reports on its genetic etiology are available. While historically the diagnosis was satisfactorily reached by factor VIII activity assays, the clinical and potentially therapeutic heterogeneity of female hemophilia calls for comprehensive molecular diagnosis in each case. Currently, the genetic investigations are not a part of routine, state-funded, diagnostics in Poland, and thus molecular epidemiological data are missing. AimWe set out to perform a comprehensive genetic analysis of Polish females with hemophilia A. Patients/methodsEighteen females with hemophilia A (including 2 with severe and 5 with moderate hemophilia phenotype) consented for genetic diagnostics. To establish F8 mutations, we used next-generation sequencing of a panel of genes associated with hematological disorders, standard assays for recurrent intragenic F8 inversions and MLPA when deletions were suspected. When appropriate we also used karyotyping, genomic microarrays and X chromosome inactivation assays. ResultsWhile abnormally skewed X-chromosome inactivation combined with a F8 variant on the active allele was, as expected, the most common genetic etiology, a number of other genetic scenarios were unraveled. This included: misdiagnosis (molecular diagnosis of vWd), Turner syndrome, compound heterozygosity and androgen insensitivity syndrome (a phenotypical 46,XY female with a novel androgen receptor gene mutation). We report 3 novel F8 mutations. ConclusionEvery case of female hemophilia warrants full genomic diagnostics, as this may change the diagnosis or reveal broader morbidity than a coagulation disorder (Turner syndrome, androgen insensitivity, or cardiovascular morbidity that we described previously in a SHAM syndrome carrier).

Research Progress of the Roles of Ubiquitination/Deubiquitination in Androgen Receptor Abnormalities and Prostate Cancer

Ubiquitin is a small molecule protein consisting of 76 amino acids,widely found in eukaryotic cells. The process by which ubiquitin binding to a specific protein is called ubiquitination. Deubiquitination is the reversed process of ubiquitination. Ubiquitination stimulates downstream signal,including complex assembly,protein conformation and activity changes,proteolysis,autophagy,guilt,chromatin remodeling,and DNA repair. More than 80% of eukaryotic protein degradation is mediated by the ubiquitination system,and ubiquitin-dependent proteolysis is an extremely complex process involving many biomolecular processes. By regulating protein homeostasis,ubiquitination can also regulate a variety of biological processes including cell cycle,cell proliferation,and apoptosis,which are closely related to tumorigenesis and progression. Many abnormalities of androgen receptor (AR) including AR gene amplification,mutation,shear mutation,and AR activity enhancement are closely related to prostate cancer progression. In particular,prostate cancer progression is regulated by the ubiquitination/deubiquitination processes. This article summarizes the recent research advances in the roles of ubiquitination/deubiquitination in AR abnormalities and prostate cancer.

Clinical, hormonal and genetic characteristics of androgen insensitivity syndrome in 39 Chinese patients

BackgroundAbnormal androgen receptor (AR) genes can cause androgen insensitivity syndrome (AIS), and AIS can be classified into complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild AIS. We investigated the characteristics of clinical manifestations, serum sex hormone levels and AR gene mutations of 39 AIS patients, which provided deeper insight into this disease.MethodsWe prospectively evaluated 39 patients with 46, XY disorders of sex development (46, XY DSD) who were diagnosed with AIS at the Department of Endocrinology of Shanghai Children’s Hospital from 2014 to 2019. We analysed clinical data from the patients including hormone levels and AR gene sequences. Furthermore, we screened the AR gene sequences of the 39 AIS patients to identify probable mutations.ResultsThe 39 AIS patients came from 37 different families; 19 of the patients presented CAIS, and 20 of them presented PAIS. The CAIS patients exhibited a higher cryptorchidism rate than the PAIS (100 and 55%, P = 0.001). There were no significant difference between the CAIS and PAIS groups regarding the levels of inhibin B (INHB), sex hormone-binding globulin (SHBG), basal luteinizing hormone (LH), testosterone (T), or basal dihydrotestosterone (DHT), the T:DHT ratio, DHT levels after human chorionic gonadotropin (HCG) stimulation or T levels after HCG stimulation. However, the hormone levels of AMH (P = 0.010), peak LH (P = 0.033), basal FSH (P = 0.009) and peak FSH (P = 0.033) showed significant differences between the CAIS group and the PAIS group. Twenty-one reported pathogenic and 9 novel AR mutations were identified. Spontaneous AR mutations were found in 5 AIS patients, and 21 patients inherited mutations from their mothers, who carried heterozygous mutations.ConclusionsForty-six XY DSD patients with cryptorchidism and female phenotypes were highly suspected of having AIS. We demonstrated that CAIS patients could not be distinguished by their hormone levels alone. Compared with PAIS patients, CAIS patients exhibited higher basal FSH, peak FSH, and peak LH hormone levels but lower AMH expression. We identified 21 reported pathogenic AR mutations and 9 novel AR mutations that led to different types of AIS. Missense mutations were the major cause of AIS and mostly occurred in exon 7 of the AR gene. These findings provided deeper insight into the diagnosis and classification of AIS and will even contributed to its clinical assessment.

"Spectrum of 46 XY Disorders of Sex Development": A Hospital-based Cross-sectional Study.

Background:Disorders of sex development (DSD) are a wide range of relatively rare conditions having diverse pathophysiology. Identification of an underlying cause can help in treating any coexisting hormone deficiencies and can help with anticipating any other immediate or long-term health concerns.Objective:To study the clinical and biochemical profile of patients with 46 XY DSD along with androgen receptor (AR) gene mutation status in selected group of patients.Methods:A cross-sectional study was conducted after enrolling the eligible DSD patients. Thorough elicitation of history and detailed clinical examination was done. Assays for luteinizing hormone, follicle-stimulating hormone, testosterone, dihydrotestosterone, androstenedione, AMH & Inhibin B (where indicated), and human chorionic gonadotropin stimulation were done as per protocol.Results:In total, 48 patients were included in the study. Ambiguous genitalia (58.3%) followed by hypospadias (33.3%) were common presentation. Androgen biosynthetic defect were the most commonly encountered diagnosis followed by androgen insensitivity syndrome (AIS). Swyer syndrome was diagnosed in 4.2% of cases; partial gonadal dysgenesis, ovotesticular DSD, and vanishing testis syndrome contributed to 2% of cases each. Eight cases (16.7%) who presented with isolated proximal and midshaft hypospadias for whom no diagnosis was found were categorized in the “etiology unclear” group. AR gene mutation analysis designed against specific exons did not yield any results.Conclusion:46 XY DSD is a heterogeneous group of patients with a varying age of presentation and a diverse clinical profile. Most patients are reared as males and maintained the same gender identity except in isolated cases. Diagnosis of AIS remains a clinical challenge as a definite hormonal criterion does not exist and genetic mutations in AR gene may be negative. Flanking region sequencing, whole genome sequencing, and promoter region sequencing may reveal pathogenic variants. Variations in other genes regulating AR pathway may also be candidates to be studied.

Comprehensive Analysis of AR Alterations in Circulating Tumor DNA from Patients with Advanced Prostate Cancer.

Somatic alterations in circulating tumor DNA (ctDNA) may be associated with treatment response or prognosis in prostate cancer (PCa). The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in ctDNA from patients with PCa and to further understand the somatic genetic heterogeneity of advanced prostate cancer. This study included a heterogeneous group of 892 patients with advanced PCa (predominantly castrate-resistant prostate cancer) with AR alterations detected in ctDNA that underwent next-generation sequencing of 54 to 73 genes via Guardant360 testing (Guardant Health, Inc., Redwood City, CA). Distribution and summary of AR alterations detected, the association of AR alterations with other genes, and a pathway analysis are reported. The median absolute plasma copy number of AR amplifications was 3.3 (range, 1.2-165.2). Many patients had multiple AR mutations; a total of 112 unique mutations were identified in AR, including L702H (25%), T878A (14%), H875Y (11%), W742C (8%), W742L (4%), F877L (2%), and T878S (2%). Other ctDNA gene alterations in the Guardant assays included TP53 (50%), MYC (34%), BRAF (32%), PIK3CA (29%), MET (25%), CDK6 (26%), EGFR (24%), FGFR1 (21%), and APC (12%). Many of these non-AR alterations are not tissue verified in other studies. AR amplification cosegregated with alterations in MYC (p < .001), BRAF (p < .001), PIK3CA (p < .001), MET (p < .001), CDK6 (p < .001), EGFR (p < .001), FGFR1 (p = .391), and more. Alterations in APC were significantly associated with mutations in AR (p < .001). Several AR alterations and concomitant non-AR alterations that associate with drug resistance were detected. These findings provide additional insights into the heterogeneity of advanced prostate cancer. The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in circulating tumor DNA (ctDNA) from patients with prostate cancer in relation to non-AR gene alterations detected in the ctDNA landscape. The study included 892 patients with prostate cancer with AR alterations in ctDNA. AR alterations were significantly associated with other gene alterations detected in ctDNA. The common AR mutations found are linked to resistance to abiraterone, enzalutamide, or bicalutamide. Characterization of the circulating AR landscape and gene alterations provides potential additional insight into the somatic genetic heterogeneity of advanced prostate cancer.

Plasma Androgen Receptor in Prostate Cancer.

The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as 177Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.

Somatic mosaicism of androgen receptor gene in an androgen insensitivity syndrome patient conceived through assisted reproduction technique.

BackgroundMutations of human androgen receptor (AR) gene are responsible for androgen insensitivity syndrome (AIS). Variable phenotypes and androgen receptor binding activity have permitted the classification of AIS into complete (CAIS), partial (PAIS), and minimal or mild (MAIS) forms. Somatic mosaicism in AIS is a rare condition which happened when de novo mutations occur after the zygotic stage.MethodsClinical evaluation, hormone measurements, and molecular analysis were performed to diagnose the patient in the study.ResultsA 46, XY girl who conceived through in vitro fertilization (IVF), presented with partial virilization of external genitalia, was found to have the p.C620R in heterozygosity. The variant p.C620R of AR has been previously reported in a patient with completely feminized external genitalia, which was inherited from the heterozygote carrier mother. Mutation analysis of the mother of our patient revealed that the variant was de novo and presented as a somatic mosaicism which indicated an insufficient amount of wild‐type AR in our patient.ConclusionThis is the first case that AIS was caused by de novo mutation of AR in a 46, XY Disorder of Sexual Development (DSD) patient by the assisted reproduction technique (ART). The phenotype of partial virilization could be explained by AR mutation in somatic mosaicism.