Association between a single nucleotide polymorphism in the R3HCC1 gene and irinotecan toxicity.

OBJECTIVE: Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A. METHODS: A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe. RESULTS: Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n = 15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G > A, rs2272761) showed a significant association with neutropenia (>grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n = 23) or modified FOLFIRINOX for pancreatic cancer (n = 40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p = 0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n = 66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n = 47). CONCLUSION: Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.

[A Case of Huge Colon Cancer Accompanied with Severe Hypoproteinemia].

We report a case of huge colon cancer accompanied with severe hypoproteinemia. A7 4-year-old woman was referred to our hospital because of abdominal fullness. Blood examinations revealed anemia(hemoglobin 8.8 g/dL)and sever hypopro- teinemia(total protein 4.5 g/dL, albumin 1.1 g/dL). Computed tomography examination of abdomen revealed ascites and large tumor(12.5×10.5 cm)at the right side colon. By further examinations ascending colon cancer without distant metastasis was diagnosed, then we performed right hemicolectomy and primary intestinal anastomosis by open surgery. Ahuge type 1 tumor(18×12 cm)was observed in the excised specimen, which invaded to terminal ileum directly. The tumor was diagnosed moderately differentiated adenocarcinoma without lymph node metastasis(pT3N0M0, fStage II ). Postoperative course was uneventful and serum protein concentration recovered gradually to normal range. Protein leakage from the tumor cannot be proved by this case, so we can't diagnose as protein-losing enteropathy, but we strongly doubt this etiology from postoperative course in this case.

[A Case of Locally Advanced Gallbladder Cancer That Developed Early Multiple Liver Metastasis after Curative Resection, and Achieved Long-TermPartial Remission Using S-1 and Gemcitabine].

A 76-year-old woman was referred to our hospital because of an abdominal tumor in September 2009. An irregularly shaped large tumor was detected in the right subcostal abdominal cavity on computed tomography, and was diagnosed as advanced gallbladder cancer without distant metastasis following further examination. We then performed a laparotomy. The tumor had invaded directly into the descending portion of the duodenum and transverse colon. We performed a curative resection of the tumor macroscopically. Pathological findings were moderately differentiated tubular adenocarcinoma derived from gallbladder cancer(T3N0M0, Stage III ). Postoperative antineoplasticc hemotherapy was not administered. At least 4 metastaticregions in the liver(segments 1, 5, 7, and 8)were detected using computed tomography 3 months after the operation, and we then initiated oral administration of S-1. After beginning treatment, we observed partial remission at 3 months and continued treatment. We changed the regimen of chemotherapy to gemcitabine 11 months later because of a drug-induced corneal disorder. One after treatment change also continues advertising, and treatment has ended 5 years after the operation. The patient has not received any treatment for the last 6 years and 7 months, and is now in the follow up period.