Wortham, N.C.; (2006) Functional genetics of hereditary and sporadic uterine leiomyomas. Doctoral thesis , University of London.

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Abstract

Uterine leiomyomas (fibroids) are common benign neoplasms arising from the smooth muscle layer of the uterus, the myometrium. Despite their prevalence in reproductive age women, little is understood of their pathobiology. The work in this thesis examined genetic and functional factors involved in the aetiology of sporadic leiomyomas, those in the hereditary leiomyomatosis and renal cell cancer syndrome, and leiomyomas from patients of African/Afro-Caribbean ethnicity, who develop more severe tumours at an earlier age. Work was carried out studying: the role of apoptosis in the tumours mutations in the FH gene and mtDNA and copy number change by microarray CGH. The findings of this work demonstrated further differences between the pathobiology of HLRCC leiomyomas, compared to sporadic lesions, particularly with regard to the mechanisms of resistance to apoptosis of each tumour type. Furthermore, germline FH mutations, which cause HLRCC, were excluded as a major cause of overall uterine leiomyoma prevalence in both sporadic cases, and in African/Afro-Caribbean women. A 1Mb resolution microarray CGH screen demonstrated a number of novel regions of copy number change, not previously reported, that may harbour novel genes involved in leiomyoma development. Furthermore, this study identified a minimal region of 7q deletion of 3.82Mb. Progressing from this, a tiling-path resolution CGH microarray specific for chromosome 7q was constructed and a number of tumours from different ethnicities were tested. This array narrowed the minimal region of deletion to 273kb on 7q22.2, a region containing 2 genes, SRPK2 and MLL5, either of which could potentially be involved in uterine leiomyoma aetiology. The results from this array also demonstrated a common overlap in the pathobiology of uterine leiomyomas from Caucasian and African/Afro-Caribbean women, who demonstrated equal frequencies of 7q deletion.

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