Identification of a Novel 9 cM Deletion Unit on Chromosome 6q23-24 in Papillary Serous Carcinoma of the Peritoneum LEE-WEN HUANG, MD, AUDREY P. GARREI-r, MD, MICHAEL G. MUTO, MD, CRISTIANO V. COLIFII, BsC, DEBRA A. BELL, MD, WILLIAM R. WELCH, MD, ROSS S. BERKOWITZ, MD, AND SAMUEL C. MOK, PHD To define regions of deletion on chromosome 6q in papillary serous carcinoma of the peritoneum (PSCP), we analyzed 103 tumor tissues from 53 patients by using 11 polymorphic microsatellite markers spanning loci from 6q23 to 6q27. Allelic losses on 6q were observed in 42 of 53 (79.2%) cases. We identified 3 distinct regions with a high percentage (>40%) of loss of heterozygosity. The first region is located at 6q23-24 and defined by D6S311 (15 of 35 informative cases, 42.9%). Detailed deletion mapping of chromo- some 6q23-24 in these tumor samples identified a novel 9 cM minimal deletion region flanked by D6S250 and ESR. The second one is located at 6q25.1-25.2 and defined by D6S448 (17 of 36 informative cases, 47.2%). A second minimal deletion region of 4 cM was flanked by D6S420 and D6S442. The third region is located at 6q27 and defined by D6S297 (9 of 19 informative cases, 47.4%). Comparing these results with our cases of advanced staged invasive serous epithelial ovarian carcinoma (SEOC), we observed that allelic losses at D6S311 (6q23) and D6S149 (6q27) were significantly higher for PSCP than for SEOC. The pattern of allelic loss at each tumor site within an individual patient was also studied. A total of 36 cases displayed allelic loss for at least 1 of multiple tumor sites, and 35 of these patients exhibited nonidentical patterns of allelic loss at various tumor sites of the same patient. Furthermore, an alternating pattern of allelic loss in the same patient was identified in 3 of 53 patients studied. These results show that allelic losses on 6q are very frequent in PSCP, and we show 2 discrete minimal deletion regions on 6q, suggesting the existence of at least 2 tumor suppressor genes withha 6q that may be involved in the pathogenesis of PSCP. In addition, the finding of different patterns of allelic loss at different tumor sites within the same patient indicate a mutifocal origin in some PSCP cases. These results provide strong evidence to support our previous reports that PSCP is a mnitifocal disease entity. HUM PATHOL 31:367-373. Copyright © 2000 by W.B. Saunders Company Key words: chromosome 6q, peritoneal carcinoma, loss of hetero- zygosity, ovarian cancer, multifocal origin. Abbreviations: PSCP, papillary serous carcinoma of the perito- neatm; SEOC, serous epithelial ovarian carcinoma; LOH, loss of heterozygosity; ESR, estrogen receptor; PCR, polymerase chain reaction. Papillary serous carcinoma of the peritoneum (PSCP) is an uncommon tumor of peritoneal origin that involves the peritoneal surface lining the abdomen and pelvis. The histological and ultrastructural features of PSCP are indistinguishable from serous epithelial ovarian carcinoma (SEOC). However, PSCP is character- ized by only surface ovarian involvement or minimal surface invasion of the ovarian cortex. 1,2 An autopsy study estimated an incidence of at least 1 case per 150,000 women per year s and PSCP accounts for 8% to 15% of cases with a presumed diagnosis of ovarian cancer. 4,5 Moreover, women who have undergone previ- ous prophylactic oophorectomy for a family history of ovarian cancer might have the subsequent development From the Laboratory and Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; the Department of Pathology, Massachusetts General Hospital, Boston, MA; and the Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. Accepted for publication December 1, 1999. Supported in part by Public Health Service Grants R01CA69453, R01CA69291, R01CA63381, and R01CA78523 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Address correspondence and reprint requests to Samuel C. Mok, Laboratory of Gynecologic Oncology, BLI449, 221 Longwood Ave, Boston, MA 02115. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3103-0016510.00/0 doi: 10.1053/hp.2000.5220 of PSCE 6 Although the recognition of PSCP is increas- ing, the pathogenesis and tumorigenesis of PSCP still remain obscure. Recent studies indicate that allelic loss on chromosome 6q may contribute to the development of several human malignancies including malignant mesothelioma, 7 primary breast carcinoma, s,9 gastric cancer, 1° B-cell non-Hodgkin's lymphoma, n and mela- noma. 12 Recurring deletions on 6q suggest the presence of 1 or more tumor suppressor genes within this locus. For ovarian cancer, allelotype imbalance on chromo- some 6q has also been described. 1~,14 Three main regions on 6q have been demonstrated to show a high frequency of loss of heterozygosity (LOH): 6q21-24, 6q25, and 6q27. Lee et aP 5 had the first report of allelic loss from chromosome 6q24 in ovarian cancer and demonstrated 64% of LOH at the estrogen receptor (ESR) gene locus by RFLP analysis. 15 Recently, a second region at 6q25.1 to 25.2 was identified by Colitti et al, 16 and they defined a 4 cM minimal deletion of LOH at D6S473 and D6S448.16 A third region of deletion at 6q27 has been intensively investigated by molecular studies. Based on the cosmid contig map, Saito et aP 7 defined a commonly deleted region between D6S149 and A2, which are estimated to be 300 Kb apart. Using 19 microsatellite markers from chromosome 6q, Cooke et a118 delineated a fine map of the region and demon- strated a minimal region of allelic loss between D6S264 and D6S297 (3 cM), with maximal allelic loss of 62% at D6S193 and 52% at D6S29758 367