Short DNA fragments are released from tumors into the blood of a cancer patient. Mutated fragments in the blood, particularly when matched to somatic mutations identified in the tumor, can immediately be considered to be circulating tumor DNA (ctDNA). The mutated fragment can be traced quantitatively using ctDNA variant allele frequencies (VAFs). Our preliminary studies show that the longitudinal changes in ctDNA VAFs reflect the tumor burden of the patient earlier than conventional imaging modalities or serum markers. We are therefore attempting to establish the diagnostic pipeline of ctDNA monitoring as a new class of blood tumor markers that might lead to the early intervention for cancer relapse.
The TP53 tumor suppressor gene is the most frequently mutated in human cancers. Therefore, highly sensitive detection of the TP53 mutation may be significantly applicable to ctDNA diagnosis. The range of ctDNA VAFs is generally less than 1%, even at the peak of the tumor burden. Digital PCR (dPCR) is designed to count the absolute number of DNA fragments in the reaction mix, thereby achieving a 0.01% detection limit. This detection limit covers the majority of ctDNA VAFs. The construction of a dPCR probe library for TP53 mutations would provide an “off-the-shelf” reagent set for very sensitive tumor-burden monitoring in the majority of cancer patients.
The liver is one of the rare human organs that can regenerate. However, which cell fraction is the major source of origin for liver tissue repair and regeneration remains an unanswered question. We have identified one important cell fraction, known as the multi-lineage differentiating stress enduring (Muse) cell. Currently, we are interested in identifying useful biomarkers that may be involved in liver tissue repair and regeneration supported by Muse cells.
As a pathogen of various stomach diseases, H. pylori has been the subject of attempts at eradication by antibiotics in Japan. However, the carcinogenic involvement of H. pylori is considered to be limited to its early stage. In fact, we, along with others, have reported on advanced stage gastric cancers in which an H. pylori infection was even beneficial to the post-treatment long-term survival of the patient. We are therefore attempting to clarify the role of H. pylori infections in the treatment of gastric cancer, as well as in human health more generally, from an epidemiological viewpoint.
Although emerging clinical sequencing techniques provide information on “actionable” mutations, the actual number of patients benefiting from these exploratory treatments has been limited. It has been speculated that gene mutations alone may be insufficient to predict the gene product for a particular patient, which is most likely to be a protein. With cancer-related panel sequencing and quantitation of the mutated gene product, the matched-up gene-protein pairs can be compared in a quantitative manner. For the quantitative protein-level assessment, reverse-phase protein array (RPPA) can be used, for which a series of protocols has been established in this laboratory.
The declining population in Japan is one of the most critical, unavoidable changes expected in the near future. Indeed, a demographic change has already occurred, perhaps even 10–20 years faster than in the nation as a whole, in rural areas such as Iwate and the Tohoku district. Using the prefectural patient “big data,” we are simulating the impact of the demographic change on the regional medical research due to be conducted at Iwate Medical University in the next 20–50 years.