title: Genome-Wide Uniparental Disomy and Copy Number Variations in Renal Cell Carcinomas Associated with Birt-Hogg-Dubé Syndrome.
abstract: Birt-Hogg-Dubé syndrome is an inherited disorder caused by germline mutations of the folliculin gene (FLCN). The affected patients are prone to developing renal cell carcinomas (RCCs). Most mutant FLCN-associated RCCs (mFLCN-RCCs) are histologically chromophobe RCCs and hybrid oncocytic/chromophobe tumors. It is incompletely understood whether mFLCN-RCCs have different chromosomal abnormalities compared with their sporadic histological counterparts. Herein, we describe somatic mutations of FLCN and DNA-copy number abnormalities using a high-density, whole-genome, single-nucleotide polymorphism array. The histological types included chromophobe RCC (n = 12), hybrid oncocytic/chromophobe tumor (n = 5), and clear-cell RCC (n = 2). Of 19 tumors, 8 had pathological somatic mutations of FLCN. Among 11 mFLCN-RCCs investigated by single-nucleotide polymorphism array, 8 showed balanced genomic profiles, 2 had gains in chromosome 3q, and 1 had gains in chromosomes 1q and 7. All had copious numbers of loss of heterozygosity in a wide range of chromosomes. The common loss-of-heterozygosity regions were chromosomes 3p24, 8q11, 16q11, Xp22-21, Xp11, Xq11, Xq13, and Xq23. Most of the loss of heterozygosity was because of uniparental disomy. Common uniparental disomy patterns in chromophobe RCCs and hybrid oncocytic/chromophobe tumors indicated that these types were relatively similar in cytogenetic events. Two clear-cell RCCs also shared several uniparental disomy regions with chromophobe RCCs and hybrid oncocytic/chromophobe tumors. mFLCN-RCCs may have common therapeutic targets among different histological types.
authors.affiliation: Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Iribe
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Diagnostic Pathology, Kochi Red Cross Hospital, Kochi, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kuroda
authors.affiliation: Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.affiliation: Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: mfuruya@yokohama-cu.ac.jp.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Furuya
mesh_terms: D000328:Adult; D000368:Aged; D058249:Birt-Hogg-Dube Syndrome / Q000150:complications / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000209:etiology / Q000235:genetics*; D002877:Chromosomes, Human; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D015894:Genome, Human; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D024182:Uniparental Disomy / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins