Gastroesophageal adenocarcinoma (GEA) is a serious health concern that affects the upper digestive system, often diagnosed at an advanced stage, leading to poor prognosis. Traditional treatments have included chemotherapy and targeted drugs, but resistance to these therapies remains a challenge. Recent advancements in genetic research have highlighted the importance of understanding specific mutations that could influence treatment outcomes. One such mutation, SMARCA4, plays a crucial role in regulating gene expression and maintaining genomic stability, and its impact on GEA has been explored in a new study.
This groundbreaking observational study, conducted by Dr. Jaffer Ajani from the University of Texas at the MD Anderson Cancer Center, utilized a next-generation sequencing (NGS) panel to investigate the genetic landscape of GEA. This significant research was published in the peer-reviewed journal Cancers.
In this study, SMARCA4 mutations (SMARCA4ms) were identified in a small percentage of patients with GEA. These mutations were significantly associated with the non-signet ring cell subtype and programmed death-ligand 1 (PD-L1) positive expression. Interestingly, no significant difference in survival was observed between patients with SMARCA4ms and those with normal SMARCA4 expression. “Our study reveals that SMARCA4 mutations do not significantly impact survival outcomes in GEA patients,” said Dr. Ajani.
To identify mutations in the SMARCA4 gene, an NGS panel test was employed. This advanced method allows for the detection of various genetic alterations, including point mutations and copy number variations, which are particularly relevant for cases of metastatic and recurrent disease where systemic therapy is needed. The study included comprehensive demographic and clinical data, covering a wide range of tumor characteristics and biomarker information, which informed therapeutic strategies.
Significant associations were also found between SMARCA4ms and mutations in other genes, such as FANCA, IGF1R, KRAS, FANCL, and PTEN. Most of the SMARCA4m cases involved single nucleotide variant (SNV) missense mutations, with frequent co-occurrences with TP53, KRAS, ARID1A, and ERBB2 mutations. This highlights the complex interplay between SMARCA4 and other genetic alterations in GEA.
“Our findings emphasize the intricate genetic landscape of GEA and the necessity of understanding the molecular interactions between various gene mutations,” added Dr. Ajani. “This comprehensive examination of SMARCA4 mutations in GEA can pave the way for developing targeted therapies and personalized treatment strategies.”
Despite the significant associations discovered, the study also highlights the need for further research to fully elucidate the clinical significance of SMARCA4 mutations in GEA. Future studies should focus on the broader genetic framework of GEA, incorporating additional SWI/SNF-related genes to gain a more comprehensive understanding of their role in the disease.
In conclusion, Dr. Ajani and his colleagues have provided valuable insights into the genetic underpinnings of GEA, underscoring the importance of personalized medicine in cancer treatment. By revealing the associations between SMARCA4 mutations and other genetic alterations, their research opens new avenues for developing targeted therapies and improving patient outcomes.
Journal Reference
Yamashita, K., Sewastjanow-Silva, M., Yoshimura, K., Rogers, J. E., Rosa Vicentini, E., Pool Pizzi, M., Fan, Y., Zou, G., Li, J. J., Blum Murphy, M., Gan, Q., Waters, R. E., Wang, L., & Ajani, J. A. (2024). SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel. Cancers, 16, 1300. DOI: https://doi.org/10.3390/cancers16071300
About the Authors
Jaffer A. Ajani, MD is a tenured professor of medicine and internist at the University of Texas M.D. Anderson Cancer Center (UTMDACC). His main interest is in GI Oncology research, particularly focusing on gastric and esophageal cancers. Dr. Ajani is board certified in Family Medicine and Internal Medicine, as well as in Medical Oncology.
Dr. Ajani earned his MD degree from the Government Medical College in Nagpur, India in 1971. He remained at the college to complete a rotating internship and a residency in general surgery and orthopedics before continuing on to Pennsylvania State University for internship and residency training in Family Practice. He then completed an internship and residency in Internal Medicine at Tulane University School of Medicine and was subsequently awarded a clinical fellowship in medical oncology at the M.D. Anderson Cancer Center. He completed a two-year research fellowship in Medical Oncology. He became faculty at UTMDACC in 1982 and has remained at the institution. He has a large clinical practice and his own laboratory. He mare than 600 peer-reviewed publications. He has been awarded several DOD and NCI grants since 2007 and his funding will extend to 2027. He has been named a Giant of Gastrointestinal Cancers in 2022 (GiantofCancer.com), he is fellow of ASCO, and has been named Best Doctor of USA since 1991. He has participated in many National and International Societies. He is the Chair of Gastric Cancer and Esophageal Cancer Guidelines of the National Comprehensive Cancer Network for more than 25+ years.
Matheus Sewastjanow-Silva, M.D. has been a research investigator at the University of Texas MD Anderson Cancer Center (UTMDACC) since 2020. Dr. Sewastjanow-Silva received research grants and national awards while studying at the Federal University of Minas Gerais (UFMG) School of Medicine in Brazil, which was ranked second in his home country, for his translational and clinical cancer research projects, which he carried out from his first semester until graduation in 2018. While he made the necessary arrangements to join the world’s largest medical cancer center to continue his cancer research, Dr. Sewastjanow-Silva worked as a primary care physician for vulnerable populations, including Indigenous peoples. He also worked in hospitals and played an important role in public health management during the COVID-19 pandemic. In his recent scientific endeavors Dr. Sewastjanow-Silva has been involved in several clinical trials as well as investigating the role of multiple cancer biomarkers and new monoclonal antibody therapies.
