Seika Kuroda

High frequency of β-catenin mutations in hepatoblastoma

Abstract. Hepatoblastoma (HB) is an embryonic neoplasm representing the most frequent malignant liver tumour in childhood. Its tumourigenesis at the molecular level is still poorly understood, and candidate genes are yet to be identified. According to recent reports describing β-catenin mutations (BCM) at hot-spot regions involving exon 3 in several types of malignancies including HB, we investigated BCM in 16 HBs classified into different histological types. One tumour had been previously confirmed to harbour adenomatous polyposis coli (APC) mutations that exhibit a similar oncogenic effect to that of BCM. Mutations in both exon 3 and its flanking region of the β-catenin gene were investigated and determined. Twelve tumours (75%) revealed pathogenic BCM, including 5 with missense mutations at codons 32, 34, or 37 and 7 with interstitial deletions that partially or totally affected exon 3. All 7 deletions were in-frame deletions without frame shift. A single nucleotide change at codon 31 regarded as non-pathogenic polymorphism was detected in the tumour possessing APC mutations. Therefore, a total of 13 tumours (81%) were compromised by an enhanced β-catenin-mediated transcription pathway. Mutations were observed in every histological type of HB. The very high frequency without correlation to histological type indicates that BCM are crucial events in the tumourigenesis of HB.

p53 gene mutations in pleuropulmonary blastomas

Pleuropulmonary blastoma (PPB) is rarechildhoodtumororiginating fromeitherlung orpleura. Although several cytogenetic changes, such as trisomy 2, trisomy 8, and loss of 17p material, have been reported, evidence of gene mutations is still lacking. Pathologically, PPB shares similarities with rhabdomyosarcoma in which p53 mutations are frequently detected. Possible implication of p53 mutations in PPB was investigated. PPBs of 3 patients were analyzed for occurrence of p53 mutations by using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of mutations was confirmed by direct sequencing. Two PPBs were confirmed to harbor p53 mutations. One was a Val to Leu substitution at codon 173, and another was a ArgArg to TrpCys substitution at codons 282 and 283. In each tumor, only the mutated allele was detected, suggesting inactivation of p53. Both patients with mutations had fatal outcome, while the remaining patient in whom no mutation was detected is disease free for 3 years after completion of treatment. The results raise the possibility that p53 inactivation can occur as a nonrandom genetic change involving the pathogenesis and outcome of PPB. Further studies in a larger series are necessary to clarify these matters.

Renal cell carcinoma in a pediatric patient with an inherited mitochondrial mutation

Renal cell carcinoma (RCC) is a rare pediatric renal cancer. Recent molecular genetic studies discovered a tumor-specific mutation involving translocation of a transcription factor TFE3 in a subset of pediatric RCC with distinct histopathology. We reported a case of a 2-year-old boy with RCC associated with TFE3 translocation resulting in a PRCC-TFE3 fusion gene. Interestingly, the case carried a maternally inherited mitochondrial DNA (mtDNA) alteration at the position which is usually found in MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes) syndrome (A3243G). Although evidence of somatic alterations in mtDNA existed in various cancers, association between inherited mtDNA mutation and pediatric renal cancer has not been reported. Our case provided the first evidence of a co-occurrence between a germ line mutation in mtDNA and the somatic mutation of pediatric RCC. With this information, we speculated a role of mitochondria mutation in the pathogenesis of this cancer.

Novel germ-line deletion of SNF5/INI1/SMARCB1 gene in neonate presenting with congenital malignant rhabdoid tumor of kidney and brain primitive neuroectodermal tumor

We describe a neonate who had a rare tumor combination of a malignant rhabdoid tumor of the kidney (MRTK) and a brain primitive neuroectodermal tumor (PNET). Genetic alterations of the SNF5/INI1/SMARCB1 gene were investigated by PCR–single‐strand conformation polymorphism (SSCP), loss of heterozygosity (LOH), sequence, and karyotyping analyses, and the gene expression level was determined by real‐time quantitative RT‐PCR analysis. PCR band signals of each exon of the hSNF5/INI1 were weak or nearly undetectable in both MRTK and PNET, whereas those of the corresponding normal kidney were clearly detected. Aberrantly migrating SSCP bands led to identification of a nucleotide change in intron 8. Although this was regarded as a polymorphism, only the changed nucleotide was observed in the normal kidney of the patient. Allelic states in the parents were heterozygous for the polymorphism in the father and homozygous for the normal sequence in the mother. Thus, it was evident that a substantial genetic part of the maternal normal allele including SNF5/INI1 was deleted as a de novo germ‐line mutation. In both tumors, LOH at microsatellite loci on the long arm of chromosome 22 was evident, and expression of SNF5/INI1 mRNA was drastically decreased compared to that in control tissues (0.7–3.9 vs. 123.6–153.5). Deletion of a substantial genetic part demonstrated in our patient is the novel appearance of a germ‐line deletion of the SNF5/INI1 gene. Additional large somatic deletions resulted in total inactivation of the gene in both tumors. Our patient provides evidence for an important role of SNF5/INI1germ‐line mutation in predisposing patients to multiple rhabdoid tumors.

Laparoscopic correction of congenital portosystemic shunt in children.

Congenital portosystemic shunt is a rare clinical entity that may progress to jaundice, severe encephalopathy, and pulmonary hypertension and require surgical correction or coil embolization. We present a novel approach to the management of children with congenital portosystemic shunt by means of a minimally invasive surgical technique. Congenital portosystemic shunts were identified between the superior mesenteric vein and inferior vena cava in case 1 and between the splenic vein and left renal vein in case 2. Both of them were successfully ligated by laparoscopic approach, and catheters were subsequently replaced to monitor portal venous pressure. The patients tolerated the procedure well, and short-term results were excellent. Laparoscopic ligation of congenital portosystemic shunt is technically feasible and less invasive to the management of patients with congenital portosystemic shunts, preventing late onset, life-threatening complications.

A Case Report of Celiac Axis Compression Syndrome Combined with Gastric Cancer. Diagnosis by Doppler Ultrasonography.

胃癌の手術を契機に超音波検査で発見された腹腔動脈起始部圧迫症候群 (celiac axis compressionsyndrome: 以下, CACSと略記) の1例を報告する.症例は50歳の男性.既往歴として幼少時より月に1～2度腹部仙痛を自覚.主訴は嚥下困難で, 噴門部癌の診断のもとに当科に紹介入院-術前の超音波検査にて, 腹腔動脈起始部の狭窄と総肝動脈の遠肝性血流を認めCACSと診断した.左開胸開腹下に胃全摘術, 摘脾術を施行した.術中に内側弓状靱帯による腹腔動脈起始部の圧迫を確認し, 靱帯を切離した.電磁流量計により測定した総肝動脈血流量は靱帯切離前後で40ml/分から115ml/分に増加した.術後に腹痛の発生を認めず, また術後の超音波ドプラ検査にて総肝動脈の求肝性血流を確認した.超音波検査はCACSの診断および治療効果判定に有用と思われた.