Oncologists have characterised the genomic landscape of a rare and aggressive type of gastric cancer and identified several genes with tumour-promoting effects, paving the way for better-targeted therapeutics and personalised anti-cancer medicine.
Estimated to claim 738,000 lives in 2018, gastric cancer is the fifth most common neoplasm and third most deadly cancer worldwide according to the GLOBOCAN 2018 data. Among the various types of gastric cancers, there is a specific subgroup that has been reported to have a higher rate of liver metastasis and poor prognosis. This subtype is known as the alpha-fetoprotein producing gastric carcinoma, which is a rare and aggressive form of gastric cancer that accounts for 1.3 to 5.4 per cent of all gastric cancers.
As its name suggests, the alpha-fetoprotein producing gastric carcinoma is characterised by the production and secretion of alpha-fetoprotein. However, the molecular features of the disease have largely been elusive, thus hindering the development of effective therapeutic strategies.
To address this gap, a research team from the First Affiliated Hospital of Zhejiang University School of Medicine performed whole-exome sequencing analyses of alpha-fetoprotein producing gastric carcinoma and successfully identified 34 significantly mutated genes. Through bioinformatics analyses, the team also found several focal amplifications and deletions that negatively affect patient prognosis.
During their study, Dr. Teng Lisong and colleagues retrospectively analysed 105 samples of alpha-fetoprotein producing gastric carcinoma. Using this information, the scientists then characterised the genomic landscape of the cancer. Through somatic copy number alterations analysis, the team discovered the specific somatic mutation spectrum, copy number variations, and key altered pathways of the alpha-fetoprotein producing gastric carcinoma.
Importantly, they found that when genes CCNE1 at 19q12 and/or the ERBB2 at 17q12 were amplified in alpha-fetoprotein producing gastric carcinoma, worse survival rates and increased aggression of the carcinoma were observed. However, when the team amplified the two genes in common gastric cancer, they did not observe the same results, thus suggesting that alpha-fetoprotein producing gastric carcinoma is genomically distinct from common gastric cancers, unlike previously thought.
To test this hypothesis, the scientists conducted comparative analyses of different types of gastric cancers. After the investigation, they confirmed that alpha-fetoprotein producing gastric carcinoma does not share several genomic features with the gastric cancer of the Cancer Genome Atlas and four other molecular subtypes. These results suggest that treatments for common gastric cancers may not be effective to treat the alpha-fetoprotein producing subtype, thus calling the need for better and more specialised treatments.
As said by Dr Teng, “Precise treatment has been a promising area for cancer therapy. For this rare subtype of [gastric cancer], one-size-fits-all strategy has been unsatisfactory in clinical practice.”
Fortunately, having established the tumour-promoting effects of the CCNE1 and ERBB2 genes, the team saw the opportunity to turn discovery into innovation – to use the genes as potential therapeutic targets to treat alpha-fetoprotein producing gastric carcinoma. To confirm whether targeting these genes could truly help in treating the alpha-fetoprotein producing subtype, the team established a large collection of patient-derived xenograft models and performed translational research to assess the effects of inhibiting CCNE1 and ERBB2.
Based on their findings, it was revealed that the dual inhibition of the two genes demonstrated a synergistic antitumour effect. With further refinements, it is believed that targeting CCNE1 and ERBB2 could become a new avenue to overcome or reverse treatment-resistant alpha-fetoprotein producing gastric carcinoma and accelerate advancements in genome-guided personalised medicine. So far, the team has tested the efficacy of drugs that target CCNE1 and ERBB2 and reported the promising efficacy of combining trastuzumab and AZD5438 to shrink tumour tissues.
Source: Lu et al. (2021). Whole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets. Nature Communications, 12, 3946.