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Histopathological analysis of aggressive renal cell carcinoma harboring a unique germline mutation in fumarate hydratase
Author(s) -
Matsumoto Kana,
Udaka Naoko,
Hasumi Hisashi,
Nakaigawa Noboru,
Nagashima Yoji,
Tanaka Reiko,
Kato Ikuma,
Yao Masahiro,
Furuya Mitsuko
Publication year - 2018
Publication title -
pathology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.73
H-Index - 74
eISSN - 1440-1827
pISSN - 1320-5463
DOI - 10.1111/pin.12684
Subject(s) - fumarase , biology , germline mutation , cancer research , exon , microbiology and biotechnology , loss of heterozygosity , mutation , pathology , genetics , gene , medicine , allele
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis with RCC. This disorder is caused by a germline mutation in the fumarate hydratase ( FH ) gene, which encodes an important enzyme of the tricarboxylic acid (TCA) cycle. This mutation distinguishes HLRCC from sporadic RCCs. Herein, we investigated a case of HLRCC in a 32‐year‐old man who underwent nephrectomy for treatment of a solid‐cystic tumor in the left kidney. Histopathology demonstrated a variegated architecture of papillary, tubulocystic and cribriform patterns composed of high‐grade tumor cells with enlarged nuclei and eosinophilic nucleoli. Immunostaining and western blotting revealed no FH expression in the tumor. Genomic DNA sequencing identified a heterozygous mutation involving deletion of the 3’ end of exon 2 and intron 2 of the FH gene (c.251_267+7delTGACAGAACGCATGCCAGTAAGTG), and RT‐PCR confirmed exon 2 skipping in FH mRNA. The somatic FH gene status of the tumor showed only the mutated allele, indicating loss of heterozygosity as the “second hit” of tumor suppressor gene inactivation. These data support that an FH mutation involving the splice site causes exon skipping, changing the conformation of the protein and accelerating carcinogenic cascades under impaired FH functioning in the TCA cycle.