Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, molecular pathologist, Sonic Healthcare USA, Rye Brook, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Noninvasive detection of bladder cancer: assessment of a new urine test
October 2026—Bladder cancer is diagnosed and monitored using cystoscopy, an invasive procedure in which a camera is inserted into the bladder. Because this type of cancer recurs in more than 50 percent of patients within five years, such patients require repeated cystoscopies for the rest of their lives, creating significant discomfort, cost, and clinical burden. A reliable urine-based test could reduce or even replace many of these procedures. To this end, the authors developed EpiMut-BC, a urine-based polymerase chain reaction (PCR) assay that simultaneously detects three critical mutations (two FGFR3 mutations and one TERT promoter mutation) and methylation changes in the HIST1H4F, NRN1, and POU4F2 genes. The test uses a modified real-time quantitative PCR (qPCR) method called SaqMan, which combines pyrophosphorolysis-activated polymerization with fluorescent probe-based detection. This technique achieves high sensitivity and specificity, detecting as few as 10 mutant DNA copies against a background of 100,000 wild-type copies. This level of sensitivity is critical because tumor DNA shed into urine is often present in very small quantities, especially in early-stage cancers. With EpiMut-BC, a 30-mL voided urine sample is collected before cystoscopy and DNA is extracted from the cell pellets. The sample is then aliquoted into four reaction wells—one for methylation markers and three for mutation markers—each including an internal control gene. A result is considered positive if any of the six biomarkers show a CT value below the assay-specific threshold. The process uses standard qPCR equipment and has a turnaround time of two to three working days. It has an estimated cost of $30 to $40 per test, which is much lower than cystoscopy and next-generation sequencing-based detection methods. In a prospective study of 502 participants from two Chinese hospitals (302 bladder cancer patients and 200 noncancer controls), EpiMut-BC achieved an overall sensitivity of 85.9 percent, specificity of 95.8 percent, and accuracy of 89.8 percent. Performance was strongest in high-grade tumors (93.6 percent sensitivity) and advanced stage disease (96.1 percent for T2–T4). The system maintained favorable detection in early-stage tumors, with 81.7 percent sensitivity for T1/Tis/Ta lesions and 70.3 percent for low-grade tumors. Specificity was 100 percent for healthy controls and remained above 94 percent for most noncancer subgroups, though it dipped to 87.5 percent for patients with urinary tract inflammation, a group for which positive results should be interpreted with caution. The study cohort was entirely of Chinese descent, so validation in other populations is needed before broad clinical adoption of the assay. The test was evaluated solely for initial diagnosis, not to monitor for recurrence, and the drop in specificity related to inflammation warrants further investigation. Despite these limitations, EpiMut-BC represents a promising, noninvasive, affordable screening tool that combines mutation and methylation markers on standard laboratory equipment, potentially serving as a first-line test to reduce reliance on invasive cystoscopy.
Jin D, Wang H, Jiang C, et al. Noninvasive detection of bladder cancer via urinary DNA mutation and methylation profiling using modified real-time quantitative PCR. J Mol Diagn. 2026. doi.org/10.1016/j.jmoldx.2026.07.001
Correspondence: Dr. Haige Chen at rjbladder@163.com or Dr. Ruiyun Zhang at zhangruiyun4337@163.com
Use of genetic testing to identify causes of infertility
Approximately 15 percent of couples worldwide experience infertility, and many undergo expensive, emotionally-draining treatment cycles with assisted reproductive technology, such as intracytoplasmic sperm injection, without understanding why they are experiencing infertility. In a substantial number of these cases, an undiagnosed single-gene (monogenic) defect is responsible and identifying that defect could fundamentally change whether and how to pursue treatment. Over a span of three years, the authors performed exome sequencing on 50 infertile Egyptian couples who had already undergone standard clinical evaluation, had normal karyotypes, and tested negative for Y-chromosome microdeletions to identify the monogenic cause of infertility for each couple and determine how that diagnosis could be used to direct their reproductive plans. The cohort included 26 couples with male factor infertility (abnormal semen parameters), 10 with female factor infertility, and 14 with unexplained infertility characterized by repeated intracytoplasmic sperm injection (ICSI) failure. The exome sequencing revealed 49 distinct potentially disease-causing variants in 30 infertility genes, 15 of which were novel. Seventy-eight percent of variants were pathogenic or likely pathogenic and 22 percent were variants of uncertain significance (VUS). Ninety percent of variants followed autosomal recessive inheritance, consistent with the high consanguinity rate in the study population. A striking finding was that all 14 couples with unexplained infertility turned out to have a female genetic cause, primarily in maternal-effect genes essential for the earliest stages of embryo development. These couples had been undergoing repeated failed ICSI cycles without understanding the underlying reason for their infertility. Based on the study findings, the authors divided the couples into two groups based on predictive reproductive outcome. One group comprised couples with significantly impaired reproductive potential, for whom no assisted reproductive technology (ART) procedure was expected to succeed. The other comprised couples who could have biological children with appropriate medical interventions. The single most common genetic finding in males was CFTR variants causing congenital bilateral absence of the vas deferens, which accounted for 27 percent of male infertility cases. In females, NLRP5 variants causing early embryonic arrest were the most common finding, accounting for 29 percent of female-related cases. The study demonstrated that exome sequencing can identify the genetic cause of infertility in couples who have exhausted standard evaluations and methods. This information can be used to divide couples into those who should pursue the use of ART with specific modifications and those for whom ART is unlikely to succeed. Integrating genetic testing into the standard infertility workup before initiating ART treatment cycles could spare couples unnecessary procedures, cost, and emotional burden while directing resources toward interventions that are most likely to succeed. The authors noted, however, that the study was limited by such factors as small sample size; lack of data on total couples screened, which prevented diagnostic yield calculation; need for caution when interpreting VUS findings; and use of an Egyptian-only population, which may limit generalizability.
El-Dessouky SH, Sharaf-Eldin WE, Soliman IF, et al. The importance of integrating genetic testing into reproductive medicine: a retrospective observational study investigating the monogenic causes of human infertility in couples considering ICSI. J Hum Genet. 2026;71:605–613. doi.org/10.1038/s10038-026-01485-8
Correspondence: Dr. Ebtesam Abdalla at ebtesam.nasr@alexu.edu.eg