Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.

Cytogenetic findings in uterine epithelioid leiomyomas.

Epithelioid leiomyomas of the uterus, unlike ordinary leiomyomas, show substantial epithelial differentiation. No chromosome abnormalities have been reported in uterine epithelioid leiomyomas before. We analyzed short-term cultures from five such tumors and detected abnormal karyotypes in four. A del(7) (q21.2q31.2) was found in two tumors, in one as the only change and in the other as a secondary aberration acquired during clonal evolution. Rearrangement of chromosomal band 12q15, another of the cytogenetic hallmarks of ordinary uterine leiomyomas, was seen in the form of a t(10;12) in one tumor. Band 17q21 was involved in structural aberrations in two cases. The data we present indicate that epithelioid leiomyomas are fundamentally similar cytogenetically, and hence presumably also pathogenetically, to the much more common smooth muscle-differentiated uterine myomas. The only differences hinted at are that epithelioid tumors may be karyotypically more complex and more often have rearrangements of 17q21.

Correlation between DNA ploidy and clinical features in smooth muscle tumors of the gastrointestinal tract.

Paraffin-embedded tissue samples from 51 surgically resected, gastrointestinal smooth muscle tumors (10 leiomyomas, 5 leiomyoblastomas and 36 leiomyosarcomas) were assayed for nuclear DNA content, and the results were examined for correlation with clinico-pathological variables (tumor size, cellularity and mitosis) and prognosis. Twenty-four (47%) of the 51 tumors, consisting of 3 (30%) of the 10 leiomyomas, 2 (40%) of the 5 leiomyoblastomas and 19 (53%) of the 36 leiomyosarcomas, were identified as aneuploid. A close correlation was found between the mitotic index and the tumor size ( = 0.528; P < 0.001). The DNA ploidy pattern of the leiomyosarcoma was closely correlated with the patient survival periods (P = 0.06). The estimated median survival period was 73 months for patients with diploid tumors, and 51 months for those with aneuploid tumors. The 10-year survival rate for aneuploid tumors was lower than that for diploid tumors (P < 0.001). The measurement of DNA content may provide an index of prognostic value in gastrointestinal leiomyosarcomas.