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.
Analysis of variants in the SERPINA1 gene in the liver of patients with A1AT deficiency
July 2025—Liver damage can result in a build up of scar tissue, or fibrosis, a hallmark of chronic liver disease (CLD). The latter has been attributed to a variety of risk factors, including viruses (primarily hepatitis B and C), obesity, and alcohol abuse. Furthermore, some patients have a genetic predisposition for the disease. Alpha-1 antitrypsin (A1AT) deficiency and hereditary hemochromatosis are two such inherited disorders that cause hepatocyte stress and damage. In A1AT deficiency, mutations in the SERPINA1 gene produce abnormal variants of the A1AT protein, which can accumulate in the liver and lead to hepatocyte damage. Mutations in the HFE gene are responsible for hereditary hemochromatosis. The mutations result in abnormal iron deposition that causes an inflammatory response, increasing the risk of liver cirrhosis. C282Y is the most common HFE gene variant. Somatic, or noninherited, variants accumulate in tissue with increasing age and cellular stress. Therefore, it is no surprise that they have been identified in patients with CLD. It is unclear how the types of variants acquired relate to the etiology of the disease. The authors conducted a study in which they analyzed somatic variants in patients with A1AT deficiency and hereditary hemochromatosis to determine whether the acquired variants were disease specific. Sequencing was performed on explanted liver tissue from five patients with homozygous A1AT deficiency (caused by the PiZZ genotype) and five patients with hereditary hemochromatosis. Whole genome sequencing was performed on tissue from one patient with A1AT deficiency and four with hereditary hemochromatosis. The remaining study participants underwent whole exome sequencing to focus on coding variation. Significant enrichment of somatic variants was not seen in patients with hereditary hemochromatosis. However, an increased number of somatic variants with a propensity for the SERPINA1 gene were identified in the A1AT cohort. These variants tended to truncate the C-terminus of the A1AT protein. A1AT deficiency affects the structure and function of the protein through a conformational change in the β-pleated sheet region, resulting in polymerization and accumulation of the abnormal protein. This sheet formation requires an interaction involving a C-terminal β-hairpin. The acquired truncation variants disrupt polymerization of the abnormal protein by reducing its ability to donate the C-terminus promoter to neighboring Z promoters. The authors theorize that reduced polymerization of the abnormal protein and the subsequent reduction in endoplasmic reticulum dysfunction may offer a selective advantage to affected hepatocytes. The evolution of somatic variants in nonsyndromic germline disease has largely been unexplored. Understanding the mechanisms that may account for a selective advantage in affected cells could be instrumental in developing treatments for conditions that have limited therapeutic options.
Brzozowska N, Wu LYD, Khodzhaeva V, et al. Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency. Nat Genet. 2025;57:875–883.
Correspondence: Dr. Joseph E. Chambers at jec202@cam.ac.uk or Dr. Peter J. Campbell at pc8@sanger.ac.uk
Effects of tumor-infiltrating clonal hematopoiesis on NSCLC tumor progression
Hematopoietic stem cells are multipotent cells that give rise to red blood cells, white blood cells, and platelets. With advancing age, somatic mutations can arise in such stem cells and lead to a competitive survival advantage and clonal expansion in the premalignant condition clonal hematopoiesis of indeterminate potential (CHIP). These mutations often occur in the epigenetic regulator genes ASXL1, DNMT3A, and TET2. They begin accumulating around middle age and can increase the risk of hematological cancers and chronic diseases, such as cardiovascular and pulmonary disease. CHIP is a relatively common finding in solid tumor tissue, affecting an estimated 20 percent of cancer patients, particularly those with non-small cell lung cancer (NSCLC), head and neck cancer, pancreatic cancer, and mesothelioma. Despite the prevalence of this condition in solid tumors, the effects of CHIP on tumor evolution is not well elucidated. The authors investigated the effect of tumor-infiltrating clonal hematopoiesis (TI-CH) on NSCLC tumor progression. They focused on a cohort of 421 early stage, untreated NSCLC patients from the Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (TraceRx) study. Blood samples obtained prior to surgery and 1,560 tumor samples from resected specimens were evaluated for CHIP mutations across 77 myeloid driver genes using a variant allele cutoff of two percent. The authors also examined a Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets pan-cancer cohort of 49,351 patients. This cohort represented 75 cancer types comprising primary and metastatic tumors with matched blood. Approximately 40 percent of NSCLC patients were found to have TI-CH compared with 26 percent of patients in the pan-solid tumor cohort. Patients with TI-CH had increased tumor progression, with TI-CH acting as an independent predictor for increased risk of death or recurrence. TET2 variants were the most common CHIP-associated mutation in patients with TI-CH. TET2-mutant CHIP mouse models and functional migration assays demonstrated preferentially increased monocyte migration toward tumor cells. The authors found that co-culture of TraceRx lung adenocarcinoma cells with human TET2-mutant or wild-type myeloid cells derived from engrafted mice suggests that TET2 mutations in myeloid cells can affect the proliferation of tumor cells. The medical community’s understanding of tumor progression with respect to the tumor microenvironment and interaction with the immune system is evolving. With this study, the authors demonstrated the relationship between a common finding in somatic tumor testing and outcome, and they proposed that TI-CH has potential prognostic and therapeutic implications.
Pich O, Bernard E, Zagorulya M, et al. Tumor-infiltrating clonal hematopoiesis. N Engl J Med. 2025;392(16):1594–1608.
Correspondence: Dr. Charles Swanton at charles.swanton@crick.ac.uk or Dr. Elsa Bernard at elsa.bernard@gustaveroussy.fr