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.
Microbiome signature of Parkinson’s disease in healthy and genetically at-risk individuals
July 2026—Parkinson’s disease, which is characterized by loss of dopamine-producing neurons in the brain’s substantia nigra and the pathologic misfolding and accumulation of alpha-synuclein, can result in a range of motor and nonmotor symptoms that may vary by individual. The cardinal motor symptoms of Parkinson’s disease (PD) are bradykinesia (slowness of movement), resting tremor, rigidity, and postural instability. A prodromal phase of the disease can generate nonmotor symptoms, such as a reduced sense of smell years prior to the onset of cardinal motor symptoms. Parkinson’s disease is believed to result from a combination of factors, including well-described genetic factors. Variants in the GBA1 gene, a lysosomal enzyme glucocerebrosidase, have been identified in approximately 15 percent of PD cases. Although GBA1 variants are widely considered the most common genetic risk factors for the disease, only an estimated 20 percent of GBA1 carriers will manifest symptoms of PD, which indicates that other factors are involved in development of the disease. The authors hypothesized that differences in the gut microbiome might identify genetically at-risk individuals who may develop PD. They conducted a study in which they generated microbiome profiles for 464 study participants: 271 with PD (109 GBA1 carriers and 162 noncarriers); 150 healthy noncarriers of GBA1, who served as controls; and 43 nondisease-manifesting GBA1 variant carriers (GBA-NMC). The authors accounted for the effects of potential lifestyle-associated variables on the gut microbiome by including the partners of patients with PD in the healthy noncarrier participant cohort. The microbiome profiles combined clinical data and shotgun fecal metagenomics. The participants were assessed using a wide range of clinical scales and questionnaires. The results indicated that a subset of GBA-NMC has a suggestion of prodromal symptoms. The microbial species Streptococcus mutans, Bifidobacterium longum, Bifidobacterium dentum, and Lactobacillus paragesseri were significantly enriched in PD patients, whereas the butyrate-producing bacteria Roseburia intestinalis, Roseburia inulinivorans, and an unclassified Faecalibacterium were significantly depleted in such patients. Depletion of these butyrate-producing bacteria is notable because butyrate has been linked to anti-inflammatory and gut barrier functions. No significant difference in microbiome composition was found between carrier and noncarrier PD groups. Those with PD and a greater amount of microbiome alterations than the control groups demonstrated more severe nonmotor symptoms. Interestingly, the GBA-NMC cohort with evidence of prodromal symptoms had an abundance of PD-enriched species. A greater number of PD-like microbiome alterations were also observed in the healthy control cohort that scored higher for symptoms of autonomic dysfunction and depression. Identifying the early signs of PD poses a diagnostic challenge due to the often subtle and nonspecific nature of the disease symptoms. Based on the results of this study, fecal microbiome analysis may prove to be a promising screening method for people genetically predisposed to PD and healthy people.
Menozzi E, Ren Y, Geiger M, et al. Microbiome signature of Parkinson’s disease in healthy and genetically at-risk individuals. Nat Med. 2026. doi.org/10.1038/s41591-026-04318-5
Correspondence: Dr. Stanislova Dusko Ehrlich at s.ehrlich@ucl.ac.uk or Dr. Victoria Meslier at victoria.meslier@gmail.com
Impact of CDKN1B inactivation on ER signaling and as a driver of resistance to endocrine therapy in breast cancer
Breast cancer, which accounts for approximately 30 percent of all newly diagnosed cancers for women in the United States, is subdivided based on hormone receptor status, with approximately 70 percent of breast cancer being hormone receptor (HR) positive and HER2 negative. Fifteen to 20 percent of patients have an innate resistance to hormone therapy, and 30 to 40 percent of patients develop resistance during the course of therapy. ESR1 mutations and loss of estrogen receptor alpha are the most common mechanisms of resistance. Other mechanisms include FGFR1 and ERBB2 amplification and mutation, activation of the MAPK signaling pathway, and loss of tumor suppressors. The authors conducted a study in which they explored additional mechanisms of resistance and proposed CDKN1B loss-of-function mutations and copy number loss as predictors of resistance in HR-positive/HER2-negative breast cancer. Whole exome sequencing or whole transcriptome sequencing, or both, were performed on tissue and blood samples from 44 hormone therapy-sensitive and 42 hormone therapy-resistant patients at Tata Memorial Centre, Mumbai, India. The 86 patients contributed 125 samples for whole exome sequencing and 81 samples for whole transcriptome sequencing, with 85 percent overlap between the two types of sequencing. The study found that hormone therapy-resistant patients tended to develop breast cancer at a younger age and presented with higher grade tumors than hormone therapy-sensitive patients. Mutations in PIK3CA, TP53, MAP3K1, and GATA3 were common in both groups. Unsurprisingly, ESR1 mutations were enriched in the resistant group, and several novel mutations were identified. Mutations in CDKN1B, ARID2, MYLK, MAP2K, INSM1, ALK, ARID1B, and SF3B1 were significantly overrepresented in the resistant cohort. In particular, CDKN1B loss-of-function mutations and copy number loss were almost exclusively present in the resistant group compared with the sensitive group and were mutually exclusive to ESR1 mutations. CDKN1B encodes for p27, a protein that regulates cell growth by inhibiting cyclin–CDK complexes, including cyclin D1–CDK4/6. For the study, the authors used the hormone therapy-sensitive breast cancer cell lines MCF7 and T47D and silenced CDKN1B expression using short hairpin RNA constructs. The knockdown cells from the two cell lines were significantly less responsive to the commonly used hormone therapies 4-hydroxy-tamoxifen and fulvestrant than were control cells. Restoring p27 expression resensitized cells to hormone therapy. Interestingly, the knockdown cells responded to CDK4/6 inhibitor treatment, as did the cells in the xenograft mouse models, with tumor growth significantly reduced after treatment. Although the exact mechanism in which CDKN1B loss induces hormone therapy resistance is unclear, the results of this study identify a potential prognostic biomarker and suggest a role for combined treatment with hormone therapy and CDK4/6-targeted therapy.
Ahmad S, Butle A, Karn A, et al. CDKN1B inactivation impacts ER signaling and drives resistance to endocrine therapy in breast cancer. Br J Cancer. 2026. doi.org/10.1038/s41416-026-03388-z
Correspondence: Dr. Sudeep Gupta at sudeep.gupta@actrec.gov.in or Dr. Amit Dutt at amitdutt@south.du.ac.in