Brain Tumors and the Lynch Syndrome

1.1 Clinical features and tumor spectrum Lynch syndrome (LS) (MIM No. 120435-6), previously known as hereditary nonpolyposis colorectal cancer (HNPCC) (Boland, 2005), is an autosomal dominant disorder caused by germline mutation in one of the DNA mismatch repair (MMR) genes. LS is among the most prevalent cancer syndromes in man and is estimated to account for 1-6% of all colorectal cancers (Lynch & de la Chapelle, 2003). Before the discovery of DNA MMR gene defects responsible for LS in the 1990s, clinical diagnostic criteria known as the Amsterdam I criteria (Vasen et al., 1991) were used to identify families likely to represent LS. The original criteria were based on colorectal cancer only and were subsequently modified to include extracolonic cancers as well (Amsterdam II criteria, Vasen et al., 1999 (Table 1). Amsterdam II criteria include colorectal cancer, cancer of the endometrium, small bowel, ureter, and renal pelvis as unequivocal manifestations of the syndrome. Later experience incorporating epidemiological, clinical, and molecular information has resulted in the expansion of the list of LS-associated tumors. The revised Bethesda criteria (Umar et al., 2004) include, among others, brain tumors as LS-related tumors (Table 1). Individuals that meet at least one of the Bethesda criteria are considered to have suspected LS, and investigating tumors for microsatellite instability (MSI) is warranted as a pre-screening method prior to germline mutation testing. Currently, the definition of LS is a molecular one and the term LS is restricted to families with an identified pathogenic germline mutation in one of the DNA MMR genes (Boland, 2005). Carriers of a pathogenic DNA MMR gene mutation have a lifetime risk of 10-53% for developing colorectal carcinoma, 15-44% for developing endometrial carcinoma, and less than 15% for other cancers (Aarnio et al., 1999; Watson & Lynch, 2001; Chen et al., 2006; Senter et al., 2008; Baglietto et al., 2010). The risk of developing cancer depends on the predisposing gene, gender and environmental factors. According to Vasen et al. (2001), the cumulative risk of developing brain tumor by 70 years is 1.2% in MSH2 mutation carriers and lower in MLH1 mutation carriers. Even if the life-time risk of brain tumor, compared to many other tumors, is low in LS families, the risk of brain tumors is unequivocally elevated compared to the general population; the calculated fold increase varies between 4 and 6 (Aarnio et al., 1999; Vasen et al., 1996). Colorectal carcinomas in LS are often diagnosed at an early age (mean, 45-50 years) and the same applies to many extracolonic tumors, at least when compared to the corresponding sporadic tumors (Vasen, 2005). In published series of LS-associated brain tumors (mainly