Molecular variants of the ATM gene in Hodgkin's disease in children

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterised by telangiectasia, progressive ataxia, pulmonary infections, radiosensitivity and a combined immunodeficiency (Shiloh, 1995). Ataxia telangiectasia patients show an increased genomic instability, which results in translocations and inversions, leading to 100-fold cancer excess, particularly lymphoid malignancies (Morrell et al, 1986; Taylor et al, 1996). The most common lymphoid neoplasms are non-Hodgkin lymphomas, followed by acute lymphoblastic leukaemia and Hodgkin disease (5–10%) (Hecht and Hecht, 1990). The ATM gene is responsible for A-T, located on chromosome 11q22–23, and encodes for serine–threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3-K) family, and plays a central role in signalling pathways activated by DNA damage (Savitsky et al, 1995a, 1995b). Different studies identified a number of ATM targets including c-abl, TP53, CHK-2, NBS1 and BRCA1 (Shiloh, 2003). Ataxia telangiectasia heterozygotes have been suggested to have a reduced life expectancy owing to a higher frequency of ischaemic heart disease (Su and Swift, 2000) and an increased risk for cancer, particularly for carcinoma of the breast (Swift et al, 1991; Broeks et al, 2000; Olsen et al, 2001). Several studies have indicated that ATM may also be involved in the development of some subtypes of sporadic lymphoma and leukaemia. Missense and truncation mutations in the ATM gene have been demonstrated in adult leukaemias: T-cell prolymphocytic leukaemia (T-PLL) (Stilgenbauer et al, 1997; Vorechovsky et al, 1997; Stoppa-Lyonnet et al, 1998; Yuille et al, 1998), and B-cell chronic lymphocytic leukaemia (B-CLL) (Bullrich et al, 1999; Schaffner et al, 1999; Stankovic et al, 1999; 2002). In adult lymphomas, Vorechovsky et al (1997) first demonstrated two missense variants in 32 non-Hodgkin lymphomas. In addition, missense and loss-of-function mutations were identified in mantle cell lymphoma (MCL), mainly associated with 11q22–23 loss of heterozygosity (LOH) (Stilgenbauer et al, 1999; Schaffner et al, 2000; Camacho et al, 2002). ATM mutations have been reported in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (Gronbaek et al, 2002). Recently, Offit et al (2002) reported that ATM variants are rare in Hodgkin lymphoma and in radiation-induced breast cancer after treatment for Hodgkin disease. The aim of the study was to investigate the possible involvement of ATM gene in the pathogenesis of Hodgkin lymphoma in children.