Biomedical subjects

Yasushi Totoki

Publications and source records attributed to Yasushi Totoki.

4 recordsLinked to original sources

PubMed2026

Prevalence and chronology of colibactin-associated mutational processes and their microbiome spectra in Japanese colorectal cancer.

The incidence of colorectal cancer (CRC) has risen in recent decades, with a disproportionate increase observed among younger individuals in Japan and other countries. The etiological contribution of the gut microbiota to CRC pathogenesis is recognized, yet the mechanisms involved remain to be fully clarified. Here we integrated whole-genome sequencing (WGS) and transcriptome profiling of CRC with whole-genome metagenomic sequencing of fecal samples to interrogate host-microbiome interactions at high resolution. Application of interpretable artificial intelligence enabled the stratification of CRC into four distinct microbiome-informed subtypes. WGS analysis identified mutational signatures SBS88 and ID18, linked to colibactin exposure, as early clonal events detected in 44.8% of non-hypermutated patients. Notably, these signatures were significantly more frequent among patients born after the 1960s. Microbiome-based subclassification revealed subtype-specific clinical and molecular features. Collectively, our findings indicate that colibactin exposure constitutes a prevalent and potentially modifiable risk factor for CRC in the Japanese population.

Humans↗

PubMed2026

Proteomic Analysis Identifies Potential Biomarkers of ELOC -Mutated Renal Cell Carcinoma.

ELOC -mutated renal cell carcinoma (RCC) is a rare tumor with only ∼40 cases reported to date; it shares a molecular background with clear cell RCC (ccRCC) in terms of hypoxia-inducible factor-alpha (HIF-α) protein accumulation. ELOC -mutated RCC is characterized by prominent leiomyomatous stromal growth and a more indolent clinical course compared with ccRCC. In our previous study, whole-genome sequencing of 102 ccRCC cases identified 5 cases of ELOC -mutated RCC. In the present study, we conducted proteomic and immunohistochemical analyses on up to 13 Japanese ELOC -mutated RCCs, including 8 previously reported cases, to elucidate its distinct molecular mechanisms and identify biomarkers that may be useful in distinguishing ELOC -mutated RCC from ccRCC. Proteomic profiling revealed that molecules, including cytokeratin 7, scinderin (SCIN), and sortilin 1 (SORT1), were significantly overexpressed in ELOC -mutated RCC compared with ccRCC. Notably, SCIN and SORT1 emerged as novel potential diagnostic biomarkers for distinguishing ELOC -mutated RCC from ccRCC. The analysis further suggested that ELOC -mutated RCC relies more on oxidative phosphorylation and less on glycolysis than ccRCC. This metabolic shift may be linked to the relative depletion of NAD+ due to the low expression of NAPRT and QPRT. In addition, we observed geographic variation in the disease frequency among different cohorts, with a higher frequency in Japan. Our findings provide novel insights into the pathogenesis of ELOC -mutated RCC and highlight SCIN and SORT1 as potential supportive biomarkers.

Humans↗

PubMed2026

Clinicopathological and genetic analysis of primary intraosseous carcinoma not otherwise specified (PIOC NOS).

BACKGROUND: Primary intraosseous carcinoma not otherwise specified (PIOC NOS) is an extremely rare jawbone cancer, accounting for approximately 1-2% of all oral cancers. Considering its rarity, no established standard treatment exists for postoperative recurrence or metastasis. This study aimed to analyse the clinical manifestations of this disease and identify novel genomic abnormalities to aid identification of potential treatment strategies. METHODS: We examined the clinical information of 14 PIOC NOS cases treated at our institution in recent years and compared it with previous reports. Genomic analysis was conducted on seven formalin-fixed paraffin-embedded surgical specimens, assessing 523 DNA and 55 RNA cancer-related genes using next-generation sequencing. RESULTS: Our findings, along with previous literature, revealed the posterior mandible as the primary site in most cases, though this was rarely identified at the time of initial diagnosis. Recurrence within two years of surgery was common. Hotspot mutations in PIK3CA were observed in 60% of cases. Additionally, one patient had high TMB status. CONCLUSIONS: Given the challenges in diagnosis and the potential for rapid recurrence or metastasis, early detection is crucial. Comprehensive genomic profiling is highly desirable, as genomic analysis may direct the development of targeted therapeutic agents to treat relapse.

Humans↗

PubMed2025

KRAS Mutations in Duodenal Lavage Fluid After Secretin Stimulation for Detection of Pancreatic Cancer.

OBJECTIVE: Although pancreatic ductal adenocarcinoma (PDAC) is still a devastating disease, the survival rate for surgically removed PDACs has significantly improved in recent years. Early detection is essential in managing PDAC. BACKGROUND: The presence of KRAS mutations in PDAC leads to the initial genetic abnormality and offers a significant timeframe for identifying resectable PDACs. A minimally invasive and highly specific PDAC screening test is necessary to prevent the need for invasive follow-up tests. METHODS: Between July 2021 and March 2023, 169 cases were enrolled in 7 institutions. By administering secretin before esophagogastroduodenoscopy (EGD), the excretion of pancreatic juice into the papillary fluid can be stimulated, creating a resource for testing. Washing fluid was collected using a specialized catheter from control individuals (n=75) and patients with resectable PDAC (n=89) at the initial diagnosis. A highly sensitive technique was employed to study KRAS gene mutations. RESULTS: This study obtained an AUC of 0.934 (95% CI: 0.904, 0.964) when using KRAS mutations in duodenal lavage fluid to differentiate between patients with resectable PDAC and healthy controls. The estimated sensitivities were calculated with specificity set at 100%, resulting in a sensitivity of 83.1% (95% CI: 71.7%, 91.2%). The McNemer test showed a significantly higher sensitivity for KRAS mutations than serum CEA and CA19-9 ( P <0.0001). CONCLUSIONS: We created a method to identify resectable PDACs by analyzing KRAS mutation levels in duodenal fluid collected during EGD with secretin stimulation of pancreatic juice secretion.

Humans↗