Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

Abstract

BRCA1 plays a pivotal role in the repair of DNA damage, especially following chemotherapy and ionising radiation. We were interested in the regulation of BRCA1 expression in acute myeloid leukaemia (AML), in particular in therapy-related forms (t-AML). Using real-time PCR and Western blot, we found that BRCA1 mRNA was expressed at barely detectable levels by normal peripheral blood granulocytes, monocytes and lymphocytes, whereas control BM-mononuclear cells and selected CD34 þ progenitor cells displayed significantly higher BRCA1 expression (P ¼ 0.0003). Acute myeloid leukaemia samples showed heterogeneous BRCA1 mRNA levels, which were lower than those of normal bone marrows (P ¼ 0.0001). We found a high frequency of hypermethylation of the BRCA1 promoter region in AML (51/133 samples, 38%), in particular in patients with karyotypic aberrations (P ¼ 0.026), and in t-AML, as compared to de novo AML (76 vs 31%, P ¼ 0.0002). Examining eight primary tumour samples from hypermethylated t-AML patients, BRCA1 was hypermethylated in three of four breast cancer samples, whereas it was unmethylated in the other four tumours. BRCA1 hypermethylation correlated to reduced BRCA1 mRNA (P ¼ 0.0004), and to increased DNA methyltransferase DNMT3A (P ¼ 0.003) expression. Our data show that reduced BRCA1 expression owing to promoter hypermethylation is frequent in t-AML and that this could contribute to secondary leukaemogenesis.

DNA Repair Deficiency Associated with Hematological Neoplasms

“…Apart from the above polymorphisms, several studies implicate BRCA1 (involved in initial recognition of a double strand break) and BRCA2 gene (involved in Homologous Recombination) deficiencies in AML pathogenesis. Scardocci et al observed that 32% of primary AML samples present with hypermethylated BRCA1 (Scardocci et al 2006). Although this finding has not been confirmed in other studies (Bianco et al 2000, Esteller et al 2001, a meta-analysis performed in 2007 which reviewed risks for hematological malignancies associated with mutations in BRCA1/2 pathway, showed that defects in this pathway increase the risk for a subset of AML that are related to gene rearrangements (Friedenson 2007).…”

Advances in the understanding of susceptibility to treatment‐related acute myeloid leukaemia

“…However, important lessons may be learnt from studying the affected genes in the above syndromes and from other highly penetrant cancer conditions because it is possible that genetic variants in these pathways would predispose to t-AML. One such recent example is a study by Scardocci et al (2006) which demonstrated reduced BRCA1 expression due to promoter hypermethylation in t-AML. The hypermethylation was not seen in the majority of the primary tumours studied suggestive of a role of the cytotoxic therapy in the induction of DNA hypermethylation in t-AML.…”

“…The hypermethylation was not seen in the majority of the primary tumours studied suggestive of a role of the cytotoxic therapy in the induction of DNA hypermethylation in t-AML. Intererestingly, AML samples with BRCA1 hypermethlation had a higher level of karyotypic abnormalities indicative of the important role of BRCA1 in DNA damage repair (Scardocci et al, 2006). Polymorphisms exist in a number of genes involved in these cancer-pathways (e.g.…”

The Role of BRCA1 and BRCA2 Genes in the Appearance of Pediatric and Adolescent Disorders

“…Fanconi anemia (FA) is transmitted as an autosomal recessive inheritance disease with direct linkage on chromosome X characterized by multiple congenital defects, failure of bone marrow and increased risk of cancer. De novo mutations of the BRCA1 gene is closely associated with the occurrence of Acute myelogenic leukemia (AML) such as 32% of primary AML tumors and 75% of secondary AML tumors characterized by reduced expression of the BRCA1 gene [38]. Alongside BRCA2 mutations detected also in cases of nonHodgkin's lymphomas (NHL) [38].…”

“…De novo mutations of the BRCA1 gene is closely associated with the occurrence of Acute myelogenic leukemia (AML) such as 32% of primary AML tumors and 75% of secondary AML tumors characterized by reduced expression of the BRCA1 gene [38]. Alongside BRCA2 mutations detected also in cases of nonHodgkin's lymphomas (NHL) [38]. The protein products of the BRCA1 and BRCA2 genes interact with the protein of Fanconi anemia forming a powerful functional complex.…”