Gastroesophageal adenocarcinoma (GEA) is a serious health problem affecting the upper digestive system, often diagnosed at an advanced stage, leading to a poor prognosis. Traditional treatments have included chemotherapy and targeted drugs, but resistance to these therapies remains a challenge. Recent advances 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 of the University of Texas at MD Anderson Cancer Center, used a next-generation sequencing (NGS) panel to investigate the genetic landscape of AGE. This important research was published in the peer-reviewed journal Cancers.
In this study, SMARCA4 (SMARCA4ms) mutations were identified in a small percentage of patients with GEA. These mutations were significantly associated with non-signet ring cell subtype and positive expression of programmed death ligand 1 (PD-L1). 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 affect survival outcomes in patients with GEA,” said Dr. Ajani.
To identify mutations in the SMARCA4 gene, a next-generation sequencing (NGS) test panel was used. This advanced method allows the detection of a variety of genetic alterations, including point mutations and copy number variations, which are particularly relevant for cases of metastatic and recurrent disease where systemic therapy is required. The study included comprehensive demographic and clinical data, covering a wide range of tumor characteristics and biomarker information, which served as the basis for therapeutic strategies.
Significant associations were also found between SMARCA4ms and mutations in other genes, such as FANCA, IGF1R, KRAS, FANCL, and PTEN. Most SMARCA4m cases involved nonsense single nucleotide variant (SNV) 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 highlight the complex genetic landscape of AGE and the need to understand the molecular interactions between different genetic mutations,” added Dr. Ajani. “This comprehensive examination of SMARCA4 mutations in AGE may pave the way for the development of 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 AGE. Future studies should focus on the broader genetic framework of AGE, incorporating additional SWI/SNF-related genes to gain a more complete understanding of their role in the disease.
In conclusion, Dr. Ajani and colleagues have provided valuable insights into the genetic basis of AGE, highlighting the importance of personalized medicine in cancer treatment. By revealing 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 using a next-generation sequencing panel. Cancers, 16, 1300. DOI: https://doi.org/10.3390/cancers16071300
About the authors
Jaffer A. AjaniDr. Ajani is an associate professor of medicine and an internist at the University of Texas MD Anderson Cancer Center (UTMDACC). His primary research interest is in gastrointestinal oncology, with a particular focus on gastric and esophageal cancers. Dr. Ajani is board certified in family medicine and internal medicine, as well as medical oncology.
Dr. Ajani earned his medical degree from the Government Medical College in Nagpur, India, in 1971. He remained on campus to complete a rotating internship and residency in general surgery and orthopedics before continuing on to Pennsylvania State University for an internship and residency in Family Medicine. He then completed an internship and residency in Internal Medicine at Tulane University School of Medicine and subsequently received a clinical fellowship in medical oncology at MD Anderson Cancer Center. He completed a two-year research fellowship in Medical Oncology. He became a professor at UTMDACC in 1982 and has remained at the institution. He has a large clinical practice and his own laboratory. He has over 600 peer-reviewed publications. He has received several grants from the Department of Defense and the NCI since 2007 and his funding will be extended through 2027. He has been named a Giant of Gastrointestinal Cancers in 2022 (Cancer Giant.com), is a member of ASCO and has been named a Top Doctor in America since 1991. He has served on many national and international societies. He has served as chair of the National Comprehensive Cancer Network's gastric cancer and esophageal cancer guidelines for over 25 years.
Matheus Sewastjanow-SilvaDr. Sewastjanow-Silva has been an 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 ranked second in his home country, for his clinical and translational cancer research projects, which he conducted from his first semester until his graduation in 2018. While making arrangements to join the world’s largest oncology medical 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 novel monoclonal antibody therapies.
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