[Research subject]

Comprehensive cancer genome profiling of 201 colorectal cancer patients for realizing precision medicine in Japan

[Description]
The ultimate goal of cancer genome profiling utilizing next generation sequencing technology is to enable precision medicine, the tailoring of treatments based on unique genomic changes of each patient’s individual tumor. We hypothesized that sequencing a panel of cancer-associated genes would identify essentially all actionable genomic driver mutations and further determine mutational burden in colorectal cancer (CRC). In the current study, we tested this hypothesis utilizing a 415-gene panel designed for solid tumors at a high depth of coverage (500X) in Japanese patients (n = 201 tumors) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108 tumors) (J-CRC and US-CRC respectively) and from the TCGA-CRC WXS database (n = 224 tumors). We detected clinically actionable driver mutations in >99% of J-CRC and US-CRC (A). Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF (B, C). We further identified tumors with a hypermutated phenotype in both populations (D-F). Unsupervised clustering revealed that a panel of 26 genes for targeted therapies can be used to classify the patients into 8 different categories, each of which can optimally be treated with a particular combination therapy (F). Waterfall plot analysis revealed that all the three patients with progressive disease after anti-EGFR therapies belong to subgroups with actionable driver mutations (G). Moreover, Kaplan-Meier analysis demonstrated that patients in subgroup of “all wild-type” showed significantly better progression-free survival as compared to patients in subgroups of “mutated” (P = 0.009) (H). Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information can be used to determine the most optimal treatment for CRC patients.

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[Research subject]

The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications

[Description]
Sphingosine-1-phosphate (S1P) is a lipid mediator that functions as a signaling transductor inside and outside cells like a signaling protein. S1P has various functions such as proliferation and migration of cancer cells, angiogenesis and lymphangiogenesis in tumor microenvironment, and induction of inflammatory cells. Due to these important functions, S1P attracts attention as a new therapeutic target in cancer. S1P is produced by two isotypes of Sphingosine kinases (SphK1 and SphK2) in cancer cells and stromal cells such as the vascular and lymphatic endothelial cells in the tumor microenvironment, and then is secreted extracellularly and exerts its function.
We have elucidated that SphK1 has important functions in S1P secretion in breast cancer cells (J Biol Chem 2010) and lymphatic metastasis of breast cancer (Cancer Res 2012). Since S1P is a lipid, it has been difficult to measure S1P directly. However, we have successfully measured S1P concentration of a breast cancer tissue with international research collaboration. We have revealed that the S1P concentration in the cancer tissues were higher than in normal breast tissues (J Surg Res 2016) and that S1P concentration in primary breast cancer tissue is associated with the rate of axillary lymph node metastasis (J Surg Res 2016). For further investigation of the significance of S1P in the tumor microenvironment, we have developed a novel method to collect the interstitial fluid from the tumor tissue and succeeded to measure S1P concentration in the interstitial fluid (J Mammary Gland Biol Neoplasia 2016). Furthermore, we have discovered the association between S1P and chronic intestinal inflammation and colitis-associated cancer (Cancer Cell 2017).
We have been measuring S1P concentration in various gastrointestinal cancer tissues such as gastric cancer and pancreatic cancer and analyzing the clinical significance of S1P. Furthermore, we have generated the latest animal cancer models, and are analyzing the detailed mechanism how S1P produced in cancer cells or host microenvironment promotes cancer progression. Through translational research that connects basic medicine and clinical practice, we would like to challenge the development of an effective and safe therapeutic agent targeting the S1P signal in the future.

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[Research subject]

Relevance of dissection of the posterior superior pancreaticoduodenal lymph nodes in gallbladder carcinoma

[Description]
The issue of whether the posterior superior pancreaticoduodenal nodes should be regarded as regional nodes of gallbladder carcinoma remains unresolved. This study aimed to evaluate the prognostic value of positive posterior superior pancreaticoduodenal lymph nodes to clarify the need for dissection of these nodes. A total of 148 patients with gallbladder carcinoma who underwent radical resection including dissection of the posterior superior pancreaticoduodenal nodes were enrolled. The incidence of metastasis and the survival rates among patients with metastasis to each lymph node group were calculated. Of the 148 patients, 70 (47%) had nodal disease. The incidences of metastasis in the cystic duct, pericholedochal, retroportal, and hepatic artery node groups, defined as regional nodes in the UICC TNM staging system, ranged from 8.3% to 24.3% with 5-year survival rates of 12.5% to 46.4% in patients with positive nodes. The incidence of metastasis to the posterior superior pancreaticoduodenal nodes was 12.8% with a 5-year survival rate of 31.6% in patients with positive nodes. Survival after resection was significantly better in patients with distant nodal disease affecting only the posterior superior pancreaticoduodenal nodes (5-year survival, 55.6%) than in patients with distant nodal disease beyond these nodes (5-year survival, 15.0%; p = 0.046), whereas survival after resection was comparable between the former group and patients with regional nodal disease alone (5-year survival, 40.7%; p = 0.426). In gallbladder carcinoma, involvement of the posterior superior pancreaticoduodenal nodes is similar to that of regional nodes in terms of both the incidence of metastasis and the impact on survival. Inclusion of the posterior superior pancreaticoduodenal nodes among the regional nodes should be considered.

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