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, OHSU; Andrés G. Madrigal, MD, PhD, assistant professor, clinical, Ohio State University Wexner Medical Center, Columbus; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; and Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center.
Genetic basis of endometriosis and its correlation with other medical conditions
June 2023—Endometriosis is defined by the presence of endometrial-like tissue outside of the uterus and can cause debilitating pelvic pain and often infertility. It has also been associated with a range of reproductive, metabolic, inflammatory, and chronic pain conditions. While it is fairly common, affecting five to 10 percent of women of reproductive age, treatment options are limited, and the precise causes of endometriosis, as well as its relationship with other conditions that cause chronic pain, remain unclear. Studies estimate that endometriosis has a heritability of approximately 50 percent. Nine genomewide association studies (GWAS) of endometriosis involving women of European and East Asian ancestry were reported prior to this study. The authors of this study conducted a meta-analysis of 24 GWAS of endometriosis that included 60,674 women with endometriosis and 701,962 control subjects of European (98 percent) and East Asian (two percent) ancestry. The meta-analysis covered 10,401,531 single-nucleotide polymorphisms and included analysis of overall endometriosis, different clinical stages of endometriosis (rASRM [revised American Society of Reproductive Medicine] 1/2 and rASRM 3/4), and endometriosis-associated infertility. The authors identified 42 genomewide significant loci with 49 distinct signals associated with overall endometriosis, including 31 loci which had not been previously reported. Most loci had larger effect sizes for stage 3/4 disease and, combined, they explained 5.01 percent of disease variance. The authors’ analysis identified genes that potentially contribute to endometriosis and that are expressed in the endometrium (SRP14, HOXB9, TRA2A, VEZT/FDG9, and GREB1) and blood (ABO, ESR1/SYNE1, GDAP1, FSHB, MLLT10, SRP14-AS1, and Wnt4). Many of these genes are also expressed in other cell types implicated in the pathogenesis of endometriosis, including neuronal, immune, and epithelial cells. Furthermore, some genes have been associated with pain perception and maintenance (SRP14/BMF, GDAP1, MLLT10, BSN, and NGF) and hormone regulation (SYNE1/ESR1 and FSHB). A genetic correlation analysis demonstrated significant correlation between endometriosis and 11 pain-inducing conditions, including migraine, headache, dorsalgia, chronic back pain, and multisite chronic pain. A significant genetic correlation was also observed between endometriosis and the inflammatory conditions asthma and osteoarthritis. This study offers further insight into potential genetic causes of endometriosis. The findings also support endometriosis and various other conditions associated with chronic pain, as well as select inflammatory conditions, sharing some genetic components. While additional targeted investigation is needed to confirm and clarify these findings, further study into the molecular biology of endometriosis may facilitate earlier intervention and new treatments for this condition.
Rahmioglu N, Mortlock S, Ghiasi M, et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat Genet. 2023;55:423–436.
Correspondence: Dr. Nilufer Rahmioglu at nilufer.rahmioglu@well.ox.ac.uk or Dr. Krina Zondervan at krina.zondervan@wrh.ox.ac.uk
Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer
PD-1/PD-L1 inhibitors have dramatically altered therapeutic strategies targeting advanced non-small cell lung cancer, with these agents approved for use in isolation or in combination with chemotherapy or CTLA4 blockade. Given that a minority of patients respond to these agents, studies have focused on identifying biomarkers of response and resistance. PD-L1 expression in tumor cell membranes and tumor mutational burden have already been identified as predictive biomarkers. However, more comprehensive analysis has been limited by the paucity of large, multi-omic, well-annotated, disease-specific cohorts. To provide further insight into the molecular features of non-small cell lung cancer (NSCLC) response and resistance to checkpoint inhibitors, the authors reported findings from integrative analysis of the Stand Up To Cancer-Mark Foundation (SU2C-MARK) NSCLC cohort. The study included whole exome sequencing and RNA sequencing from the tumors of 393 patients who had advanced NSCLC treated with checkpoint inhibitors. Consistent with prior studies, the authors found that tumor mutational burden was associated with checkpoint blockade response, while EGFR alterations and KRAS/STK11 co-mutation were negative predictors of checkpoint blockade response. In addition, further analysis into known driver mutations in NSCLC showed an association between ATM alterations and favorable response to checkpoint blockade. In contrast, TERT amplifications were associated with reduced response to immunotherapy. The authors also calculated clonal and subclonal neoantigen burden for each exome in the cohort, with total neoantigen burden and clonal neoantigen burden showing an association with checkpoint blockade response. To interrogate transcriptional predictors of response, the authors performed a genomewide analysis of genes that were differentially expressed between responders and nonresponders. The related genes PSME1, PSME2, and PSMB9 achieved cohort-wide significance. These genes play a prominent role in the function of the immunoproteasome, a noncanonical peptide-processing complex theorized to promote differential and enhanced antigen presentation in the setting of proinflammatory cytokines. Further assessment of tumor intrinsic gene expression across various NSCLC histologies yielded distinct transcriptional subtypes, including a dedifferentiated (TI-1) subtype that showed weak expression of NAPSA and TP63 (considered canonical markers of adenocarcinoma and squamous cell carcinoma, respectively). This TI-1 NSCLC subtype was the TI subtype most closely associated with response to checkpoint inhibitors. This large study shines more light on the complex mechanisms underlying immune checkpoint response in NSCLC and highlights additional potential predictive biomarkers for response or resistance. The findings provide a roadmap for additional studies into genetic pathophysiology, antitumor immunity, and therapeutic response in NSCLC that may facilitate the development of more effective, tailored therapeutic approaches to addressing the disease.
Ravi A, Hellmann MD, Arniella MB, et al. Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer. Nat Genet. 2023. https://doi.org/10.1038/s41588-023-01355-5
Correspondence: Dr. Nir Hacohen at nhacohen@broadinstitute.org, or Dr. Gad Getz at gadgetz@broadinstitute.org, or Dr. Justin F. Gainor at jgainor@mgh.harvard.edu