No germline FH mutations in familial breast cancer patients

Abstract

Fumarate hydratase (FH) was recently identified as the predisposing gene for a tumor predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC) (MIM 605839). In HLRCC, individuals with a germline heterozygous mutation in the FH gene typically develop benign leiomyomas of the skin and the uterus (fibroids, myomas). In a subset of the families, predisposition to renal cell carcinoma and uterine leiomyosarcoma occurs. Other malignancies including breast cancer have also been detected in patients with a germline FH mutation. To examine whether FH could be involved in predisposition to breast cancer, we analyzed germline FH mutations from 85 Finnish breast cancer patients. Most of the cases were selected based on positive family or personal history for malignancies associated with HLRCC. No mutations were found. These results show that FH is not a major predisposing gene for familial breast cancer. Benign tumors, leiomyomas of the skin and the uterus are the most common lesions in HLRCC families. In the Finnish families, these tumors have been detected in six out of seven families (86%). RCC has been detected more frequently in the mutation-positive families in Finland (five out of seven families, 71%) than in North America (five out of 35 families, 14%) or in the UK (one out of 35 families, 3%). The five Finnish HLRCC families include altogether 12 RCC cases. Uterine leiomyosarcoma has been detected in five patients in three Finnish HLRCC families (43%). Altogether three Finnish HLRCC patients carrying FH mutation in two families have been diagnosed with breast cancer. The first breast cancer detected in HLRCC patient displayed lobular histology, a histology which comprises 15% of unselected breast carcinomas. In addition, one case of prostate carcinoma, one case of multiple myeloma, and one case of Hodgkin's lymphoma have been detected. 1,10 In HLRCC families from other countries, in addition to RCC, only leiomyosarcoma of the skin has been reported in one North American patient. Recently, germline FH mutations were examined in prostate cancer families in two different studies. 11,12 In addition to prostate cancer being detected in one of the FH mutation carriers, positive linkage in prostate cancer families has previously been reported to 1q42 -q43, where the FH gene is localized. 13 Negative results of these studies provided evidence that mutations in FH do not confer susceptibility to familial prostate cancer.The susceptibility genes for familial breast cancer are still largely unknown. The major known high-penetrance predisposition genes BRCA1 and BRCA2 account for a large majority of families with multiple cases of early-onset breast cancer and ovarian cancer, but only a small fraction of familial breast cancer without these characteristics. 14,15 Genetic linkage studies have suggested breast cancer loci on chromosomes 2q32, 6q25, 8p21, and 13q22. 16 -19 So far, the putative susceptibility genes in these regions have not been identified.In the current study, we analyzed 85 Finnish breast...

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

“…This is currently the only such case reported, and no indication of male infertility can be seen for example in the Finnish HLRCC pedigrees (unpublished data). The role of somatic FH inactivation in the genesis of sporadic tumors has been evaluated in several tumor series including for example prostate and breast cancer and smooth-muscle tumors but only a few uterine leiomyomas and one soft-tissue sarcoma of a lower limb have emerged with a somatic FH mutation [25,49,[56][57][58][59][60][61][62]. The results indicate that FH is involved in the genesis of sporadic smooth-muscle tumors only at a low frequency.…”

Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets

“…Both factors fundamentally contributed to the growth of BC cells. However, FH may not be a major predisposing gene for familial BC [103] .…”

Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumors

“…Therefore, these disease may be a part of HLRCC syndrome [21]. However, Kiuru et al confirmed that FH gene is not a major predisposing gene for familial breast cancer [82]. Further examinations in a large scale study will be needed in order to elucidate the relationship between HLRCC and bladder/breast carcinoma or other associated lesions.…”