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Human Molecular Genetics, 2001, Vol. 10, No. 13 1421-1429
© 2001 Oxford University Press

Localization of a novel susceptibility gene for familial ovarian cancer to chromosome 3p22–p25

Masayuki Sekine, Hiroshi Nagata, Shoji Tsuji1, Yasuo Hirai2, Seiichiro Fujimoto3, Masayuki Hatae4, Iwao Kobayashi5, Tsuneo Fujii6, Ichiro Nagata7, Kimio Ushijima8, Koshiro Obata9, Mitsuaki Suzuki10, Mitsuhiro Yoshinaga11, Naohiko Umesaki12, Shinji Satoh13, Takayuki Enomoto14, Satoru Motoyama15, Kenichi Tanaka+ and The Japanese Familial Ovarian Cancer Study Group§

Department of Obstetrics and Gynecology and 1Department of Neurology, Niigata University, School of Medicine, Niigata 951-8510, Japan, 2Department of Gynecology, Cancer Institute Hospital, Tokyo 170-8455, Japan, 3Department of Obstetrics and Gynecology, Hokkaido University, School of Medicine, Hokkaido 060-8638, Japan, 4Department of Obstetrics and Gynecology, Kagoshima City Hospital, Kagoshima 892-8580, Japan, 5Department of Obstetrics and Gynecology, Nagoya Daini Red Cross Hospital, Aichi 466-8650, Japan, 6Department of Obstetrics and Gynecology, National Kure Medical Center, Hiroshima 737-0023, Japan, 7Department of Obstetrics and Gynecology,National Defense Medical College, Saitama 359-8513, Japan, 8Department of Obstetrics and Gynecology, Kurume University, School of Medicine, Fukuoka 830-0011, Japan, 9Department of Obstetrics and Gynecology, Kinki University, School of Medicine, Osaka 589-8511, Japan, 10Department of Obstetrics and Gynecology, Jichi Medical School, Tochigi 329-0498, Japan, 11Department of Obstetrics and Gynecology, Kagoshima University, School of Medicine, Kagoshima 890-8520, Japan, 12Department of Obstetrics and Gynecology, Osaka City University, School of Medicine, Osaka 545-8585, Japan, 13Department of Obstetrics and Gynecology, Tohoku University, School of Medicine, Miyagi 980-8575, Japan, 14Department of Obstetrics and Gynecology, Osaka University, School of Medicine, Osaka 565-0871, Japan and 15Department of Obstetrics and Gynecology, Kobe University, School of Medicine, Hyogo 650-0017, Japan

We performed genome-wide linkage analysis in 58 patients and nine unaffected members among 28 families with no mutation in BRCA1 or BRCA2, employing a set of 410 microsatellite markers. We initially screened the whole genome, including the X chromosome, by a non-parametric method using the GENEHUNTER program. As a result, chromosome 3p22–p25 showed a suggestive score for linkage [LOD = 3.49 and non-parametric LOD (NPL) = 2.77 at D3S3611] based on a multipoint analysis. Additionally, based on a two-point analysis using dense markers, this 3p22–p25 region showed a P-value < 0.05 at 10 markers and there is suggestive evidence for linkage at two markers within ~19 cM (NPL = 2.60 and 2.49 at D3S1597 and D3S3611, respectively). To explore whether the candidate gene in this 3p22–p25 region contributed to carcinogenesis of familial ovarian cancer in a similar fashion to the tumor suppressor gene, we performed loss of heterozygosity (LOH) analysis. It was observed that the frequency of LOH at four markers in this region was >50% only in tumor tissues from patients with no mutation in BRCA1 or BRCA2, not in those with a BRCA1 mutation.

+ To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Niigata University School of Medicine, 1-757, Asahimachi-dori, Niigata City 951-8510, Japan. Tel: +81 25 227 2320; Fax: +81 25 227 0789; Email: tanaken@med.niigata-u.ac.jp

§ Collaborating groups, listed in random order: Atsushi Arakawa (Nagoya City University), Tadayuki Ishimaru (Nagasaki University), Shinji Izuma (Osaka Medical College), Hisashi Ichikawa (Sekishindo Hospital), Yuji Ito (St Mary’s Hospital), Tohru Inoue (Tokyo Kouseinenkin Hospital), Mari Iwamoto (Ehime University), Hisao Osada (Chiba University), Kazuya Oshima (Nantan General Hospital), Takaaki Oda (National Kokura Hospital), Masayuki Ohno (Kagawa Medical University), Hidetaka Katabuchi (Kumamoto University), Koji Kanazawa (University of the Ryukyus), Hiroyuki Kamata (Tochigi Cancer Center), Hirokatsu Kitai (Saitama Social Insurance Hospital), Yoshiro Kidera (Sasebo Kyosai Hospital), Takafumi Kudoh (Okayama University), Kazuo Kuzuya (Aichi Cancer Center Hospital), Hiroshi Kobayashi (Hamamatsu University), Hideki Sakamoto (Nihon University), Shigeru Sasaki (The Tama-Nagayama Hospital of Nippon Medical School), Fumitaka Saji (Osaka Medical Center for Cancer and Cardiovascular Disease), Tsuneo Jimbo (Tokyo Rosai Hospital), Toshiko Jobo (Kitasato University), Akira Suzuki (Osaka National Hospital), Kenji Suzuki (Keiyu Hospital), Masato Sudo (Yamamoto General Hospital), Michiko Takahashi (Saitama Cancer Center), Ken Takizawa (Mitsui Memorial Hospital), Tamikazu Tazaki (Social Insurance Kurume Daiichi Hospital), Hideo Tajima (Saitama Medical School), Tadao Tanaka (The Jikei University), Ichiro Taniguchi (Oita Prefectural Hospital), Teruhiko Tamaya (Gifu University), Masahiko Tsujimoto (Osaka Police Hospital), Akitsu Tsunawaki (Kumamoto City General Hospital), Yoshihiro Teramoto (Nara National Hospital), Nagayasu Toyoda (Mie University), Yasuji Nogami (Gunma Social Insurance Hospital), Tsuneo Noda(Seirei-mikatahara General Hospital), Kazuo Hasegawa (Hyogo Medical Center for Adults), Toshio Hirakawa (Kyusyu University), Hideharu Fujii (National Nagasaki Medical Center), Keiichi Fujiwara (Kawasaki Medical School), Masaki Mandai (Kyoto University), Toshihisa Mori (Kitakyusyu City Medical Center), Masazumi Yajima (Tokyo Women’s Medical University), Makoto Yasuda (The Kashiwa Hospital of Jikei University), Tatsuo Yamato (Kosei General Hospital), Kumio Yamamoto (Osaka City General Medical Center), Tsutomu Yamamoto (Koshigaya Municipal Hospital), Yasuhisa Yamamoto (Omoto Hospital), Yuichi Wada (Sendai National Hospital)


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