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, associate clinical laboratory director, Omniseq/Labcorp, Buffalo, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Effect of ERCC2 mutations on the genomic landscape of somatic mutations and their role as biomarkers
February 2025—Excision repair cross-complementation group two (ERCC2) is a tumor-suppressor gene involved in DNA repair. Compound heterozygous mutations in ERCC2 are linked to rare recessive disorders, such as xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, all of which are characterized by ultraviolet light sensitivity. Somatic ERCC2 mutations in cancers, particularly bladder cancers, have emerged as significant prognostic markers. The mutations predict platinum sensitivity and correlate with favorable outcomes in patients with bladder cancer, but they have not been identified as independent prognostic indicators due to a lack of data, resulting from limited cohort sizes. The authors conducted a study in which they investigated the impact of ERCC2 hotspot mutations on genomewide mutagenesis and their implications for cancer prognosis and therapeutic stratification. The study, which used data from 113 ERCC2-mutant and 886 wild-type bladder cancer samples, revealed that ERCC2 mutations are associated with better prognosis, higher tumor mutation burden, and a distinct mutational landscape. ERCC2 mutation status was shown to independently predict improved survival outcomes, irrespective of co-mutational influences or tumor stage. The authors also investigated the impact of ERCC2 mutations on the molecular landscape of bladder cancer. They used tumor samples from the Genomics England Research Network cohort to comprehensively compare the mutations in ERCC2-mutant tumors with those in wild-type tumors. The analysis revealed significant differences in the mutational profiles between the two groups. Notably, mutations associated with the APOBEC enzyme family—characterized by cytosine-to-uracil deamination—demonstrated clear distinctions between ERCC2-mutant and wild-type cancers. These findings suggest that the normal function of ERCC2 may be to repair such lesions caused by APOBEC activity. To further explore this hypothesis, the authors conducted in vitro studies using ERCC2 knockout models. These experiments demonstrated that cells lacking functional ERCC2 exhibited increased vulnerability to uracil misincorporation during DNA replication, leading to elevated mutagenesis. Importantly, treatment with the chemotherapeutic agent pemetrexed further highlighted the role of ERCC2 in mitigating uracil-related DNA damage. Together, these results confirm that ERCC2 plays a crucial role in counteracting uracil misincorporation and maintaining genomic stability, shedding light on its contribution to bladder cancer pathogenesis. This study establishes ERCC2 mutations as independent prognostic markers in bladder cancers, linking their mutational signatures to impaired nucleotide excision repair and, more specifically, uracil repair. The identification of APOBEC-associated mutational processes underscores the interplay between transcription, replication, and repair pathways. These insights advance the medical field’s understanding of the functional role of ERCC2 in cancer biology and offer a foundation for leveraging its mutational status in precision oncology. Further exploration of the role of ERCC2 in genomic uracil repair and the development of targeted therapies for ERCC2-mutant cancers is warranted.
Barbour JA, Ou T, Yang H, et al. ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer. Cell Genom. 2024;4. doi.org/10.1016/j.xgen.2024.100627
Correspondence: Dr. Song Wu at wusong@szu.edu.cn
Use of circulating cell-free RNA in blood as a host response biomarker to identify tuberculosis
The outcomes of Mycobacterium tuberculosis infection, the causative agent of tuberculosis, can be variable and are influenced by intricate host-pathogen interactions. Methods for diagnosing tuberculosis not only have low sensitivity and specificity but also cannot distinguish between different stages of disease; differentiate between latent, incipient, and subclinical infections; or forecast progression to active tuberculosis. The authors conducted a case-control study in which they investigated plasma cell-free RNA (cfRNA) as a new category of host biomarkers for tuberculosis. The study used plasma cfRNA as a noninvasive biomarker for diagnosing active tuberculosis. The authors analyzed 251 plasma samples from people who visited outpatient clinics in Uganda, Vietnam, and the Philippines and who had persistent coughs. They performed microbiological testing to distinguish tuberculosis (TB)-positive cases from TB-negative controls. Next-generation sequencing conducted on plasma-derived cfRNA identified cell types contributing to the pool. The authors identified nearly 2,000 differentially abundant genes in the TB-positive versus TB-negative study participants, indicating heightened immune activity. Pathway analysis confirmed the upregulation of neutrophil degranulation, interferon gamma signaling, and antimicrobial peptide pathways in TB-positive patients, underscoring the potential for cfRNA to reflect active infection and host response. To test the diagnostic utility of cfRNA, the authors split the samples into training, testing, and validation sets. They applied machine learning algorithms to identify a set of genes that predict TB status. A six-gene signature that included GBP5, BNIP3L, KLF6, DYSF, LASP1, and PCBP1 emerged as a robust classifier among various models. This signature showed high sensitivity and specificity across training, testing, and validation cohorts. The six-gene panel did not fully meet all World Health Organization target product profiles for a diagnostic test, but it surpassed optimal thresholds for a triage test. Notably, GBP5 provided the strongest contribution to the panel’s performance and correlated well with semiquantitative measures of TB bacterial load. Comparisons with previously established whole blood RNA- and protein-based TB biomarkers showed that the cfRNA signature is distinct, with a larger contribution from solid organ-derived RNA fragments. Although there was some overlap, the majority of genes in the cfRNA signature did not feature prominently in whole blood RNA panels. Furthermore, the cfRNA-based approach performed better than whole blood RNA- and protein-based tests in detecting active TB. These findings indicate that plasma cfRNA presents a significant opportunity for developing reliable, nonsputum-based diagnostic tests for tuberculosis, with possible benefits related to stability, reduced sample requirements, and insights into cellular-damage mechanisms. Future study should examine the use of integrated cfRNA and whole blood RNA methodologies to improve diagnostic precision and assess the applicability of the cfRNA signature in wider clinical and epidemiological settings. This study establishes a basis for using cfRNA to manage tuberculosis and addresses significant deficiencies in current diagnostic frameworks.
Chang A, Loy CJ, Eweis-LaBolle D, et al. Circulating cell-free RNA in blood as a host response biomarker for detection of tuberculosis. Nat Commun. 2024;15. doi.org/10.1038/s41467-024-49245-6
Correspondence: Dr. Iwijn De Vlaminck at vlaminck@cornell.edu