Identifying HR and NER Deficiencies in Gastric Cancer for Targeted Treatment Strategies

By Nilay Sethi, MD, PhD - Last Updated: March 19, 2025

Nilay Sethi, MD, PhD, discusses his latest research on mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting.

Dr. Sethi also highlights the significance of homologous recombination and nucleotide excision repair pathways in DNA repair for cancers, particularly in the context of gastric and esophageal adenocarcinoma.

Find Dr. Sethi’s continued thoughts here.

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Describe the significance of homologous recombination and nucleotide excision repair pathways in DNA repair for cancers, particularly in the context of gastric and esophageal adenocarcinoma.

Dr. Sethi: Homologous recombination and nucleotide excision repair pathways are crucial mechanisms within our cells, responsible for rectifying errors that arise. These pathways play a pivotal role in maintaining normal cellular function. However, in certain cancers—initially observed in breast and ovarian cancers—a subset exhibit a significant impairment in these repair processes. This impairment confers an advantage to cancer cells by allowing errors to accumulate, facilitating the acquisition of cancer-like characteristics. Notably, mutations in key components of these pathways, such as BRCA1 and BRCA2, are commonly associated with breast and ovarian cancers. Yet, their prevalence in gastric and esophageal cancers appears to be less pronounced.

This piqued our interest in whether these cancers harbor a subpopulation that is genuinely deficient in homologous recombination, which is often the primary repair mechanism disabled in cancer. Given that only a minority of cancers exhibit mutations in BRCA1 and BRCA2, we began to question whether there might be additional cancers or subsets thereof that are indeed deficient in homologous recombination but do not possess these known mutations. It led us to consider the possibility of alternative mechanisms disabling the pathway, perhaps even ones not yet elucidated by current understanding of these pathways.

Explain the design and methodology of your analysis. Why did your team decide to investigate the use of a validated genomic signature of HR deficiency to characterize the landscape of HR deficiency in gastrointestinal cancers?

Dr. Sethi: Expanding on the inquiry into the prevalence of mutations or impairments in homologous recombination (HR) machinery within gastric and esophageal cancers, we collaborated with Zoltan and his team, whose expertise in genomic technologies, particularly in accurately measuring genomic signatures or “genomic scars,” proved invaluable. These signatures serve as indicators of HR deficiency. By leveraging advanced genomic analyses on datasets such as TCGA and others, they meticulously scrutinized cancer genomes to identify patterns suggestive of HR deficiency.

Allow me to elaborate further. In an intact homologous recombination pathway, certain mutations are expected to be repaired, resulting in their absence from the genome. Therefore, when examining cancer genomes, the presence of uncorrected errors at frequencies higher than anticipated provides evidence of functional HR deficiency. This observation forms the basis for developing quantitative metrics, such as mutational scar scores or mutation signatures, which serve as indicators of HR deficiency.

This approach has already been successfully applied in breast and ovarian cancer, resulting in the development of a CLIA certified diagnostic test. Therefore, we sought to extend this methodology to gastric and esophageal cancer for two primary reasons. Firstly, we aimed to ascertain whether there exists a greater prevalence of HR deficiency beyond cases identified solely by BRCA1 or BRCA2 mutations. Secondly, leveraging an already approved test for another cancer type could expedite the translation of this diagnostic tool into clinical practice for gastric and esophageal cancers.

Consequently, we posed the question: Does HR deficiency exist in gastric and esophageal cancer as indicated by mutation signature scores? The answer, unequivocally, was yes. Notably, all cases harboring mutations in HR-related components such as BRCA1, BRCA2, or PALB2 exhibited elevated HR scores.

Our investigation revealed a substantial portion of gastric and esophageal adenocarcinomas lacking known mutations in HR pathway components. Specifically, approximately three to 5% of cases were associated with known mutations in these components. However, when we evaluated mutation signature scores using a threshold initially determined in ovarian cancer—although the applicability to gastric cancer remains uncertain—we identified a significant proportion of cases exhibiting scores above this threshold. In fact, approximately 28% of gastric cancers surpassed this threshold, indicating the potential presence of HR deficiency in these gastric and esophageal cancers.

Identifying HR and NER Deficiencies in Gastric Cancer for Targeted Treatment Strategies

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