Interaction between dietary and lifestyle risk factors and N-Acetyltransferase polymorphisms in B-Cell lymphoma etiology

Background: Gene-environment interactions are suggested to play a role in lymphomagenesis. Methods: We tested the interaction between the NAT1/NAT2 phenotype, as inferred by the respective genotypes, and exposure to dietary and lifestyle risk factors, in 199 incident lymphoma cases and 188 population controls. We used unconditional logistic regression to calculate the odds ratio (OR) and its 95% confidence interval for lymphoma (all subtypes combined) and B cell lymphoma, associated to the rapid NAT1 phenotype and to the intermediate and slow NAT2 phenotype, and to the estimated dietary intake of heterocyclic amines and folate, current smoking, coffee, and use of permanent hair dyes, as well as the respective interaction terms. We adjusted the ORs by age, gender, and education, and we used the likelihood ratio test to test the interaction between the NAT1, NAT2 phenotype and the dietary and lifestyle variables. Results: We observed an increase in risk of lymphoma (all subtypes combined) and B-cell lymphoma in particular associated with the estimated above median dietary intake of heterocyclic amines (OR = 4.2, 95%CI 1.2 – 14.8) and folate (OR = 4.1, 95%CI 0.7 – 22.4) among subjects with the NAT1 rapid acetylator phenotype, but not independent on the NAT1 phenotype. The test for interaction was significant for heterocyclic amines, but not for folate (p for interaction = 0.026 and 0.076 respectively). Ever use of permanent hair dyes was associated with an elevated risk independent on the NAT1, NAT2 phenotypes; risk decreased to null among intermediate and slow NAT1 acetylators (p for interaction = 0.010). Conclusions: Our results suggest that NAT1, NAT2 polymorphisms interact with dietary and lifestyle exposures in modulating risk of lymphoma and particularly B-cell lymphoma

Activation of the aryl hydrocarbon receptor and risk of lymphoma subtypes

The aryl hydrocarbon receptor (AhR) is a transcription factor implicated in several pathways known to be relevant in lymphomagenesis. Aim of our study was to explore the link between AhR activation and risk of lymphoma subtypes. We used a Dual-Luciferase Assay® and a luminometer to detect the activation of the luciferase gene, in HepG2 cells transfected with a specific reporter systems, by a 50 ml serum aliquot of cases of diffuse large B cell lymphoma (N = 108), follicular lymphoma (N = 85), chronic lymphocytic leukemia (N = 72), multiple myeloma (N = 80), and Hodgkin lymphoma (N = 94) and 357 controls who participated in the multicentre Italian study on gene-environment interactions in lymphoma etiology (ItGxE). Risk of each lymphoma subtype associated with AhR activation was calculated with polytomous logistic regression adjusting by age, gender, and study centre. The overall prevalence of AhR activation ranged 13.9-23.6% by subtype, and it varied by study area (8-39%). Risk associated with AhR activation was moderately elevated for follicular lymphoma (OR = 1.56, 95% CI 0.86, 2.80) and chronic lymphocytic leukemia (OR = 1.56, 95% CI 0.83, 2.96). Despite our inconclusive findings about the association with risk of lymphoma subtypes, we showed that the Dual-Luciferase Assay can be reliably and easily applied in population-based studies to detect AhR activation

A Role of <i>BRCA1</i> and <i>BRCA2</i> germline mutations in breast cancer susceptibility within Sardinian population

Background. In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Methods. Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Results and Conclusion. Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764_8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations

A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

<p>Abstract</p> <p>Background</p> <p>In recent years, numerous studies have assessed the prevalence of germline mutations in <it>BRCA1 </it>and <it>BRCA2 </it>genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of <it>BRCA1-2 </it>mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of <it>BRCA1-2 </it>germline mutations was also evaluated.</p> <p>Methods</p> <p>Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for <it>BRCA1-2 </it>mutations by DHPLC analysis and DNA sequencing. Association of <it>BRCA1 </it>and <it>BRCA2 </it>mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.</p> <p>Results and Conclusion</p> <p>Overall, 8 <it>BRCA1 </it>and 5 <it>BRCA2 </it>deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in <it>BRCA2 </it>gene. The geographical distribution of <it>BRCA1-2 </it>mutations was related to three specific large areas of Sardinia, reflecting its ancient history: <it>a</it>) the Northern area, linguistically different from the rest of the island (where a <it>BRCA2 c.8764_8765delAG </it>mutation with founder effect was predominant); <it>b</it>) the Middle area, land of the ancient Sardinian population (where <it>BRCA2 </it>mutations are still more common than <it>BRCA1 </it>mutations); and <it>c</it>) the South-Western area, with many Phoenician and Carthaginian locations (where <it>BRCA1 </it>mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of <it>BRCA1-2 </it>germline mutations.</p

Correction: Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Correction to: Leukemia https://doi.org/10.1038/s41375-022-01711-0, published online 22 October 202

Italian study on gene-environment interactions in lymphoma etiology: Translational aspects

Introduction: The objective of the "Italian Study on gene-environment interactions in lymphoma etiology", hereafter named the Italian GxE Study, is to identify individual conditions and external factors associated with lymphoma aetiology, the response to therapy and survival, as possible targets for preventive action and possible drivers of new individualized therapeutic strategies. Methods: This objective is being pursued by recruiting up to 1000 incident lymphoma cases and 1000 controls in six Italian areas: central and southern Sardinia, Florence, Bari and Taranto, Verona, Novara and Perugia. After signing the informed consent form, cases and controls will donate a blood sample and respond to a detailed questionnaire on health history, lifestyle factors, and occupational and environmental exposures of interest. The interaction between genetic polymorphisms, epigenetic conditions, and the most prevalent lifestyle and occupational exposures will be explored using the case-control epidemiological study design. Survival analysis will be conducted in relation to the therapeutic protocol, lifestyle variables, and gene polymorphisms using a modified proportional hazard model. Study design: Here are the main features of the Italian GxE study: 1. Genome Wide Scan of patients and controls DNA, which aims to evaluate several million SNPs, some functionally known, and other in strict linkage disequilibrium with genes in loci encoding for known proteins, using last generation high throughput platforms (Illumina (R) Human660W). 2. Use of the Telepathology Network to reach maximum consensus among the pathologists' panel collaborating in this project so achieving the maximum diagnostic precision, by applying the most recent lymphoma classification schemes consistently across the study areas. 3. Detailed assessment of occupational and environmental exposure, thanks to the experts in retrospective exposure assessment participating in our project and the continuous refinement of the questionnaires which have been used in international studies for the last two decades. Precision in defining external exposures is of paramount importance to effectively explore gene-environment interactions in the aetiology of the different lymphoma subtypes. 4. Analysis of response to therapy and survival of lymphoma patients in relation to their genetic features, which will allow to design future individualized therapeutic schemes, by identifying responders to specific chemotherapeutic agents based upon their polymorphisms of genes implicated in xenobiotic metabolism, DNA repair, release of inflammatory cytokines, as well as other yet to be identified. Conclusion: The Italian GxE Study contributes to the International InterLymph Consortium (http://epi.grants.cancer.gov/InterLymph/), which creates the necessary synergy to inquire into lymphoma etiology in general, and its individual subtypes in particular.</jats:p

Evaluation of Cardial Iron Deposition by T2* MRI in Transfusion Dependent Patients with Myelodysplastic Syndromes.

Abstract Cardiac T2* Magnetic Resonance Imaging (MRI) has been recently used to evaluate myocardial iron deposition in patients with transfusion dependent beta-thalassemia major. No comparable studies have been published for patients with myelodysplastic syndromes receiving chronic red blood cell transfusion. Therefore we measured cardiac-MRI T2* in 16 patients (10 male, 6 female) with myelodysplastic syndromes (aged 54 – 82 years, median age 67). All of them were transfusion dependent having received a median number of 60 (range 16–225) packed red blood cell transfusion equivalent to 3.2 – 45 (median 12) grams of iron. Nine have been irregularly and sporadically chelated by deferoxamine, seven were unchelated. Serum ferritin levels ranged from 1163 to 6241 mg/dl (median value 2086). None of the patients presented signs or symptoms of cardiac dysfunction at the time of the study. Cardiac-MRI T2*values obtained ranged from 5.6 to 80 (median value 46.5) milliseconds (ms). Correlation between serum ferritin and cardiac T2* value was weak ( r= 0.43, r2 =0.18). According to D. Pennel we considered as significant of myocardial iron deposition a relaxation time ≤ 20ms. Cardiac T2* was &lt; 20ms in 3 patients who had never used iron chelators (5.6, 12.4 and 8.5 ms, respectively). They had received 39, 101 and 200 units of red blood cell transfusion, corresponding to 7.8, 20 and 40 grams of iron, respectively. Of relevance 2 of them died within few months after the end of the study and one showed early signs of left ventricular dysfunction. None of the patients with a cardiac T2* value &gt;20 ms showed instrumental nor clinical signs of cardiac deterioration in six months follow up. No patient who had received less than 39 transfusions presented cardiac T2* value ≤20 ms. Evaluation of myocardial iron deposition by T2* cardiac MRI could be recommendable in myelodyplasia patients who had received more than 30 packed red blood cells transfusisions.</jats:p

Graft-<i>versus</i>-leukemia effects after allogeneic bone marrow transplantation are active also in the presence of clones with chromosomal anomalies in addition to the Ph chromosome

Two male patients with Philadelphia-chromosome (Ph+) chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation (ABMT) in the first chronic phase after busulfan treatment. In both cases, the donor was a sister, and engrafting was demonstrated by chromosome analyses which showed only donor cells in the BM. Cytogenetic relapse occurred 29 and 30 months after ABMT, respectively, when host cells reappeared: in both cases, the Ph and additional anomalies typical of the blastic phase of CML were evident. We then monitored the chromosome picture for 52 and 39 months, respectively: no striking evolution occurred, and cells with the Ph and additional anomalies persisted together with donor cells, which were a minority in the first patient and a great majority in the second throughout the observation period. A clinical relapse was observed in the first patient, but the disease never progressed to a blastic phase, whereas the second patient has not relapsed 7 years after ABMT. We reviewed data from the literature on cytogenetic relapse after ABMT in CML without clinical relapse, especially the 12 patients in whom cytogenetic relapse included chromosome anomalies in addition to the Ph, as in our patients. We suggest that graft-versus-leukemia (GVL) reactions in such patients are able to arrest progression of the leukemic blastic clone and prevent a possible relapse in blastic phase

Methylation analysis of the phosphates and tensin homologue on chromosome 10 gene (PTEN) in multiple myeloma

BACKGROUND: Aberrant DNA methylation of promoter region CpG islands is an alternative mechanism that leads to genetic defects in the inactivation of tumor suppressor genes during myelomagenesis. The aim of this study was to examine the promoter methylation status of the phosphates and tensin homologue on chromosome 10 (PTEN) gene in a cohort of multiple myeloma patients. FINDINGS: The PTEN gene was hypermethylated in 7 out of 58 (12%) primary myeloma samples. The correlation between functional inactivation and PTEN mRNA levels was not statistically significant. The multiple myeloma subgroup with an aberrant PTEN status had a prevalence of the component IgG, Salmon Durie stage I, lower lactate dehydrogenase levels, intermediate-standard cytogenetic risk and longer overall survival with the respect to the unmethylated subgroup. CONCLUSIONS: This is the first report demonstrating the presence of PTEN promoter hypermethylation in multiple myeloma

Genetic Association of Non Hodgkin’s Lymphoma Susceptibility to Polymorphisms in the CTLA-4 Gene on Chromosome 2q33.

Abstract The current knowledge of potential risk factors for lymphomas is limited. There is strong evidence that altered immunological function entails an increased risk of lymphoma. CTLA-4 gene encodes for a receptor that provides a negative signal to the T-cell once an immune response is initiated and complete. It is located in the 2q33 chromosomal region that harbours several genes such as CD28, ICOS, all related to immune activation playing a pivotal role in T-lymphocyte activation. Polymorphisms in these genes have been associated to a number of autoimmune diseases, including blood disorders. We have recently reported that a functional polymorphism in the CTLA-4 gene is associated with Non-Hodgkin’s lymphoma (NHL) and may have a role in genetic susceptibility to the disease. Since CD28, CTLA-4 and ICOS are closely linked and have related functions, aim of the present study was to extend the genetic analysis to the 2q33 chromosomal region harbouring these genes. Three polymorphisms of CTLA-4 gene (at positions -308C*T, +49A*G, +642 3′UTR (AT)n), the CD28 (CAA)n, ICOS c1564T*C and D2S72 markers within a 1.3cM region were analyzed in 100 unrelated NHL patients and in 128 healthy controls both originating from the central part of Sardinia. Statistical analysis was performed to test association of each marker with NHL using Chi-squared test and Odds Ratio (OR). Haplotypes were inferred and analyzed using the PHASE 2.1 software. Exact test of Linkage Disequilibrium (LD) was calculated between all pairs of seven markers separately in cases and controls using the Arlequin program. We found a strong association of the CTLA-4 +49*A and the 3′UTR (AT)82 alleles with NHL with ORs of 2 (CI95% 1.2–3.2) and 1.6 (CI95% 1.1–2.4), respectively. The −308*C−+49*A− (AT)82 was the most represented haplotype in the studied population and resulted associated with NHL (p value = 0.0029; OR = 1.7 [CI95% 1.2–2.5]). No independent association between CD28, ICOS and D2S72 markers was observed. Genetic analysis of the entire haplotype CD28–CTLA-4-D2S72-ICOS resulted in 196 and 234 different best haplotypes in patients and controls, respectively. The most common haplotype was CD28*163-308*C-+49*A-(AT)82-D2S72*156-ICOS*T and it was found to be significantly over-represented in NHLs than in controls (p value = 0.012, OR=1.86 CI95% 1.1–3). Strong LD was observed between the three CTLA-4 gene markers and the two adjacent markers CD28 and D2S72, and less significant LD was found between ICOS and some of the CTLA-4 gene markers. We found genetic linkage between a specific haplotype in the 2q33 region and NHL, but allelic association was detected for CTLA-4 markers and for none of the adjacent functionally related gene markers. Thus, it seems possible to dissect the CTLA-4 as the true “causative” risk gene for NHL susceptibility at least in Sardinian patients.The functional characterization of disease-associated CTLA4 gene variants will be worthy of future investigation to elucidate their role in the pathogenesis of NHL.</jats:p