CussionDAPK1 is proposed to be a tumor suppressor gene in CLL.

CussionDAPK1 is proposed to be a tumor suppressor gene in CLL. In a recent study, a rare sequence variant associated with early disease onset in a large CLL family was shown to reduce DAPK1 expression on one allele to 25 of the normal level, resulting in ASE [8]. Other genetic alterations were not identified to affect DAPK1 in CLL. In the present study, we investigated the extent of germline ASE of the DAPK1 gene in CLL under the hypothesis that this might be a possible novel mechanism predisposing individuals to CLL. The association of ASE with tumor predisposition was first reported in 2001 [11]. However, 1531364 prevalence and mechanisms of ASE in tumorigenesis remain largely buy 370-86-5 unknown. Recently it was demonstrated that reduced levels of the tumor suppressor gene APC are associated with pronounced predisposition to familial adenomatous polyposis [31]. Linkage analysis in these families showed that the allele with reduced APC expression was linked to the disease; however, a genetic alteration that might explain the reduced expression of APC could not be identified. This work was followed by a study by Valle et al. [13], demonstrating ASE of TGFBR1 in 10?0 of colorectal cancer patients as opposed to 1?3 in control 16985061 populations. Reduced TGFBR1 expression affects the SMAD ediated TGF-beta signaling. The authors report that ASE is inherited in familial cases and occurs also in sporadic cases of colorectal cancer. Two major haplotypes associated with the reduced expression of TGFBR1 were reported, however no mutation that may explain this Vitamin D2 biological activity phenomenon was detected. In subsequent studies this group revised the reported frequencies of ASE in TGFBR1 to fewer cases and the authors conclude that improved quantitative techniques are required for reliable ASE detection [32,33]. We established a quantitative SNuPE/MALDITOF-based approach for ASE assessment that is sensitive and robust. Furthermore, the high-throughput capability of this assay enables investigation of larger cohorts e.g. of large epidemiological studies. Using this novel approach, we observed DAPK1 ASE in non-malignant (germline) cells in 14 of CLL cases but not in a control population evoking a novel potential mechanism for predisposition to CLL. A trend toward germline ASE positive patients being of younger age at disease onset/age at diagnosis could substantiate a predisposing role for DAPK1 ASE. We did not detect any correlation of DAPK1 ASE with familial occurrence of CLL, which has a reported prevalence of 5?0 , although the power to detect such a correlation in this cohort is low. Systematic assessment of such information in a prospective manner would be needed to draw valid conclusions. The need of heterozygosity at specific exonic SNPs and the rather low frequencies of ASE cases led to the identification of a rather small number of ASE positive patients (17 out of a collective of 303 patients who were initially included in the study). Furthermore, a prospective investigation of DAPK1 ASE in healthy individuals with monoclonal B cell lymphocytosis (MBL), a potential precursor of CLL that shows a prevalence of up to 3.5 in the entire population, would allow for a more accurate assessment of the predisposing character of DAPK1 ASE [34]. So far the mechanisms that cause allelic imbalance of mRNA expression are not clear. In our previous work, a disease haplotype and mutation could be identified which segregated with the CLL phenotype in a large family [8]. However, in the generalpopul.CussionDAPK1 is proposed to be a tumor suppressor gene in CLL. In a recent study, a rare sequence variant associated with early disease onset in a large CLL family was shown to reduce DAPK1 expression on one allele to 25 of the normal level, resulting in ASE [8]. Other genetic alterations were not identified to affect DAPK1 in CLL. In the present study, we investigated the extent of germline ASE of the DAPK1 gene in CLL under the hypothesis that this might be a possible novel mechanism predisposing individuals to CLL. The association of ASE with tumor predisposition was first reported in 2001 [11]. However, 1531364 prevalence and mechanisms of ASE in tumorigenesis remain largely unknown. Recently it was demonstrated that reduced levels of the tumor suppressor gene APC are associated with pronounced predisposition to familial adenomatous polyposis [31]. Linkage analysis in these families showed that the allele with reduced APC expression was linked to the disease; however, a genetic alteration that might explain the reduced expression of APC could not be identified. This work was followed by a study by Valle et al. [13], demonstrating ASE of TGFBR1 in 10?0 of colorectal cancer patients as opposed to 1?3 in control 16985061 populations. Reduced TGFBR1 expression affects the SMAD ediated TGF-beta signaling. The authors report that ASE is inherited in familial cases and occurs also in sporadic cases of colorectal cancer. Two major haplotypes associated with the reduced expression of TGFBR1 were reported, however no mutation that may explain this phenomenon was detected. In subsequent studies this group revised the reported frequencies of ASE in TGFBR1 to fewer cases and the authors conclude that improved quantitative techniques are required for reliable ASE detection [32,33]. We established a quantitative SNuPE/MALDITOF-based approach for ASE assessment that is sensitive and robust. Furthermore, the high-throughput capability of this assay enables investigation of larger cohorts e.g. of large epidemiological studies. Using this novel approach, we observed DAPK1 ASE in non-malignant (germline) cells in 14 of CLL cases but not in a control population evoking a novel potential mechanism for predisposition to CLL. A trend toward germline ASE positive patients being of younger age at disease onset/age at diagnosis could substantiate a predisposing role for DAPK1 ASE. We did not detect any correlation of DAPK1 ASE with familial occurrence of CLL, which has a reported prevalence of 5?0 , although the power to detect such a correlation in this cohort is low. Systematic assessment of such information in a prospective manner would be needed to draw valid conclusions. The need of heterozygosity at specific exonic SNPs and the rather low frequencies of ASE cases led to the identification of a rather small number of ASE positive patients (17 out of a collective of 303 patients who were initially included in the study). Furthermore, a prospective investigation of DAPK1 ASE in healthy individuals with monoclonal B cell lymphocytosis (MBL), a potential precursor of CLL that shows a prevalence of up to 3.5 in the entire population, would allow for a more accurate assessment of the predisposing character of DAPK1 ASE [34]. So far the mechanisms that cause allelic imbalance of mRNA expression are not clear. In our previous work, a disease haplotype and mutation could be identified which segregated with the CLL phenotype in a large family [8]. However, in the generalpopul.