Misako Hirai

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer

To define the involvement of p16/CDKN2 and p15/MTS2 tumor‐suppressor genes for response to chemotherapy in primary epithelial ovarian cancer, we analyzed alterations of the gene in 45 patients who were treated with primary cytoreductive surgery followed by 6 courses of cis‐diamminedichloroplatinum (II) (cisplatin)‐based combination chemotherapy. Homozygous deletion of p16/CDKN2 and p15/MTS2 genes was found in 8 (18%) and 15 (33%) cases, respectively. Response to the chemotherapy was confirmed by finding at second surgery after the chemotherapy in 26 patients, resulting in 17 responders and 9 nonresponders. The abundance of gene deletion in nonresponders (56%) was significantly higher (p = 0.0463) when compared to that in responders (18%). Moreover, the deletion of genes was a significant poor prognostic factor (p = 0.0441) in advanced ovarian cancer. These results suggest that deletion of p16/CDKN2 and/or p15/MTS2 is a potential indicator for poor chemotherapy response and adverse prognosis in ovarian cancer patients.

Inactivation of p16/CDKN2 and p15/MTS2 genes in different histological types and clinical stages of primary ovarian tumors.

To define the involvement of p16/CDKN2 and p15/MTS2 inactivation in ovarian tumorigenesis and the association of these inactivation events with histological types and clinical stages of ovarian tumors, we analyzed homozygous deletion and somatic mutation of p16/CDKN2 and p15/MTS2 genes, as well as hypermethylation of the 5′‐CpG island of the p16/CDKN2 gene, in 49 primary ovarian tumors and 6 ovarian carcinoma cell lines. We found homozygous deletions of p16/CDKN2 and p15/MTS2 in 6 (12%) and 5 (10%) primary tumors, respectively. Somatic mutation of p16/CDKN2 was found in only I primary tumor, but mutation of p15/MTS2 was not detected in any sample. None of the 28 primary tumors or 6 cell lines was hypermethylated at the 5′‐CpG island of p16/CDKN2. The incidence of inactivation of p16/CDKN2 in primary tumors was significantly higher in the advanced stages (7 of 29) than in the early stages (0 of 14). Seven of 9 alterations in p16/CDKN2 and p15/MTS2 were observed in serous (3 of 12), endometrioid (3 of 9) and clear‐cell (1 of 4) carcinomas. However, only normal sequences of these genes were detected in mucinous carcinomas. Loss of heterozygosity (LOH) at the IFNA locus was detected in 1 of 19 (5%) tumors, but no change at the D95171 locus was observed in 17 tumors. These results suggest that: (i) homozygous deletion is the main mechanism of inactivation of p16/CDKN2 and p15/MTS2 in ovarian tumorigenesis; (ii) inactivation of p16/CDKN2 and p15/MTS2 may be the histological type‐specific events involved in ovarian tumorigenesis; and (iii) inactivation of p16/CDKN2 is potentially involved in the progression of ovarian tumors in advanced stages.

Rare association of severe hypoplasia of the abdominal aorta with imperforate anus, colonic atresia, and choledochal cyst

Hypoplasia of the abdominal aorta (HAA) is a rare condition that causes marked hypertension. Although multiple etiologies have been postulated for HAA, congenital structural anomalies are rarely observed except in cases associated with some hereditary syndromes. The authors describe a neonatal case with HAA complicated by multiple anomalies including colonic atresia (CA), imperforate anus, choledochal cyst, facial cleft, and brain defects. This patient showed CA in the descending colon and caliber change in the transverse colon mimicking Hirschsprung disease, both of which were thought to be caused by vascular insult to the mesentery due to HAA. Although multiple surgical corrections were successfully performed, the hypertension was uncontrollable.

Whole-chromosome imbalance pattern of comparative genomic hybridization in neuroblastomas is associated with regressive disease from mass screening cases showing spontaneous regression

Whole-chromosome imbalance pattern of comparative genomic hybridization in neuroblastomas is associated with regressive disease from mass screening cases showing spontaneous regression