Overall survival (OS; upper panels) and progression-free survival (PFS; lower panels) in all NHL patients (regardless of histology subtype) classified according to the type of <i>CHEK2</i> alterations.

<p>Panels show: <b>A.</b> the influence of all alterations affecting the CHK2 coding sequence (cds; HR_OS = 1.6; 95% CI 0.79–3.24 and HR_PFS = 2.1; 95% CI 1.12–4.05); <b>B.</b> the influence of the I157T mutation (HR_OS = 1.5; 95% CI 0.62–3.70 and HR_PFS = 3.7; 95% CI 1.42–9.43) and <b>C.</b> the influence of the c.319+43dupA variant (HR_OS = 0.8; 95% CI 0.50–1.15 and HR_PFS = 0.6; 95% CI 0.44–0.89).</p

Germline alterations of the <i>CHEK2</i> gene changing the CHK2 protein structure identified in NHL patients and controls with their frequencies and related odds ratios (OR).

<p>^a New alterations</p><p>^b Two alterations of the <i>CHEK2</i> coding sequence were identified in one patient (c.470T>C and c.1259+1G>C); <i>OR</i>–odds ratio; <i>CI</i>–confidence interval.</p><p>Note: The nomenclature of <i>CHEK2</i> alterations was based on NCBI <i>CHEK2</i> Reference Sequences NG_008150.1 (gene) and NM_007194.3 (mRNA).</p><p>Germline alterations of the <i>CHEK2</i> gene changing the CHK2 protein structure identified in NHL patients and controls with their frequencies and related odds ratios (OR).</p

Alleles in 3'-untranslated region assessed by single A-track sequencing on Alf Express™

<p><b>Copyright information:</b></p><p>Taken from "Single-track sequencing for genotyping of multiple SNPs in the N-acetyltransferase 1 (NAT1) gene"</p><p>BMC Biotechnology 2004;4():28-28.</p><p>Published online 25 Nov 2004</p><p>PMCID:PMC544357.</p><p>Copyright © 2004 Soucek et al; licensee BioMed Central Ltd.</p> Displayed area from A1038 to A1104. (A) – wild type; (B) and heterozygote; (C) and homozygote; (D) allele; (E) allele

Germline intronic and silent alterations in the <i>CHEK2</i> gene in NHL patients and controls with their frequencies and related odds ratios (OR).

<p>^a New alterations</p><p>^bThe c.319+43dupA alteration also did not show a statistically significant deviation from the Hardy-Weinberg equilibrium in any of the analyzed groups (all p > 0.05).</p><p>Germline intronic and silent alterations in the <i>CHEK2</i> gene in NHL patients and controls with their frequencies and related odds ratios (OR).</p

Association of Germline <i>CHEK2</i> Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma

<div><p>The checkpoint kinase 2 gene (<i>CHEK2</i>) codes for the CHK2 protein, an important mediator of the DNA damage response pathway. The <i>CHEK2</i> gene has been recognized as a multi-cancer susceptibility gene; however, its role in non-Hodgkin lymphoma (NHL) remains unclear. We performed mutation analysis of the entire <i>CHEK2</i> coding sequence in 340 NHL patients using denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA). Identified hereditary variants were genotyped in 445 non-cancer controls. The influence of <i>CHEK2</i> variants on disease risk was statistically evaluated. Identified <i>CHEK2</i> germline variants included four truncating mutations (found in five patients and no control; P = 0.02) and nine missense variants (found in 21 patients and 12 controls; P = 0.02). Carriers of non-synonymous variants had an increased risk of NHL development [odds ratio (OR) 2.86; 95% confidence interval (CI) 1.42–5.79] and an unfavorable prognosis [hazard ratio (HR) of progression-free survival (PFS) 2.1; 95% CI 1.12–4.05]. In contrast, the most frequent intronic variant c.319+43dupA (identified in 22% of patients and 31% of controls) was associated with a decreased NHL risk (OR = 0.62; 95% CI 0.45–0.86), but its positive prognostic effect was limited to NHL patients with diffuse large B-cell lymphoma (DLBCL) treated by conventional chemotherapy without rituximab (HR-PFS 0.4; 94% CI 0.17–0.74). Our results show that germ-line <i>CHEK2</i> mutations affecting protein coding sequence confer a moderately-increased risk of NHL, they are associated with an unfavorable NHL prognosis, and they may represent a valuable predictive biomarker for patients with DLBCL.</p></div

Genotyping of the coding region of by T-track sequencing on Alf Express™

<p><b>Copyright information:</b></p><p>Taken from "Single-track sequencing for genotyping of multiple SNPs in the N-acetyltransferase 1 (NAT1) gene"</p><p>BMC Biotechnology 2004;4():28-28.</p><p>Published online 25 Nov 2004</p><p>PMCID:PMC544357.</p><p>Copyright © 2004 Soucek et al; licensee BioMed Central Ltd.</p> (A) Displayed area from T382 to T417 (B) Displayed area from T531 to T582 (C) Displayed area from T618 to T661, with genotypes ; (D) ; (E) ; (F) – Displayed area from T735 to T797, and alleles not found

Overall survival (OS; upper panels) and progression-free survival (PFS; lower panels) in DLBCL patients.

<p>Panels show: <b>A.</b> the influence of all alterations affecting the CHK2 coding sequence (cds; HR_OS = 2.3; 95% CI 0.77–6.97 and HR_PFS = 2.6; 95% CI 0.91–7.44); <b>B.</b> the influence of the I157T mutation (HR_OS = 2.9; 95% CI 0.70–12.00 and HR_PFS = 5.2; 95% CI 1.25–22.16) and <b>C.</b> the influence of the c.319+43dupA variant (HR_OS = 0.6; 95% CI 0.32–0.97 and HR_PFS = 0.5; 95% CI 0.32–0.86).</p

A schematic diagram showing individual coding exons and flanking intronic sequences affected by the identified <i>CHEK2</i> sequence variants.

<p>The most important structural/functional domains of CHK2 kinase are depicted by color bars [SQ/TQ domain (amino acid (aa) 19–69) in blue, FHA domain (aa 112–175) in yellow, and kinase domain (aa 220–486) in violet]. The left-hand side shows synonymous and intronic <i>CHEK2</i> variants (italicized) while the right-hand side shows CHK2 protein structure-altering variants (frame-shift and missense) that were described in the NHL patients group (in red), controls (green) or in both populations (in black).</p

Steroid ligands, the forgotten triggers of nuclear receptor action; implications for acquired resistance to endocrine therapy

Purpose: There is strong epidemiological evidence which indicates that estrogens may not be the sole steroid drivers of breast cancer. We hypothesize that abundant adrenal androgenic steroid precursors, acting via the androgen receptor (AR), promote an endocrine resistant breast cancer phenotype.Experimental design: AR was evaluated in a primary breast cancer tissue-microarray (n=844). Androstenedione (4AD) levels were evaluated in serum samples (n=42) from hormone receptor positive, post-menopausal breast cancer. Levels of androgens, progesterone and estradiol were quantified using LC-MS/MS in serum from age and grade-matched recurrent and non-recurrent patients (n=6) pre- and post-aromatase inhibitor (AI) therapy (>12 months). Androgen and estrogen receptor signaling pathways activities were analyzed in two independent AI treated cohorts.Results: AR protein expression was associated with favorable progression-free survival in the total population (Wilcoxon, pConclusions: This study highlights the importance of examining the therapeutic consequences of the steroid microenvironment and demonstrable receptor activation using indicative gene expression signatures.</p

Genotype and Haplotype Analyses of <i>TP53</i> Gene in Breast Cancer Patients: Association with Risk and Clinical Outcomes

<div><p>Variations in the <i>TP53</i> gene have been suggested to play a role in many cancers, including breast. We previously observed an association between <i>TP53</i> haplotypes based on four polymorphisms (rs17878362, rs1042522, rs12947788, and rs17884306) and the risk of colorectal and pancreatic cancer. Based on these results, in the present study, we have investigated the same polymorphisms and their haplotypes in 705 breast cancer cases and 611 healthy controls in relation to the disease risk, histopathological features of the tumor and clinical outcomes. In comparison to the most common haplotype A₁-G-C-G, all the other identified haplotypes were globally associated with a significantly decreased breast cancer risk (P = 0.006). In particular, the A₂-G-C-G haplotype was associated with a marked decreased risk of breast cancer when compared with the common haplotype (P = 0.0001). Moreover, rs1042522 in patients carrying the GC genotype and receiving only the anthracycline-based chemotherapy was associated with both overall and disease-free survival (recessive model for overall survival HR = 0.30 95% CI 0.11–0.80, P = 0.02 and for disease-free survival HR = 0.42 95% CI 0.21–0.84, P = 0.01). Present results suggest common genetic features in the susceptibility to breast and gastrointestinal cancers in respect to <i>TP53</i> variations. In fact, similar haplotype distributions were observed for breast, colorectal, and pancreatic patients in associations with cancer risk. Rs1042522 polymorphism (even after applying the Dunn-Bonferroni correction for multiple testing) appears to be an independent prognostic marker in breast cancer patients.</p></div