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IntroductionThe Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups in endometrial cancer (EC), among which two are correlated with an intermediate prognosis: the MisMatch Repair-deficient (MMRd) and the No Specific Molecular Profile (NSMP) groups. The two groups represent a heterogeneous subset of patients frequently harboring CTNNB1 alterations with distinctive clinicopathologic features. The study aimed to evaluate the miRNA expression in ECs to identify potential biomarkers of prognosis.MethodsWe analyzed miRNA expression in 72 ECs classified as MMRd or NSMP including 15 ECs with CTNNB1 mutations. In the discovery step, miRNA expression was evaluated in 30 cases through TaqMan miRNA arrays. Subsequently, four miRNAs were validated in the total cohort of ECs. The data were further tested in the TCGA cohort, and correlations with overall survival (OS) and progression-free interval (PFI) were evaluated.ResultsmiR-499a-3p and miR-499a-5p resulted to be overexpressed in CTNNB1 mutant EC patients at intermediate risk. Similarly, in the TCGA cohort, miR-499a-3p and miR-499a-5p were differentially expressed between CTNNB1 mutant and wild-type patients (p < 0.0001). NSMP patients with low miR-499a-5p expression showed longer OS (p = 0.03, log-rank test). By combining miR-499a-3p or -5p expression levels with the CTNNB1 status, ECs with CTNNB1 mutation and lower miR-499a-5p expression showed better OS compared with the other subgroups (p = 0.03, log-rank test), among the NSMP patients. Moreover, in a multivariate analysis, combination of wild type CTNNB1 status and high miR-499a-5p expression was indipendently associated with high risk of death [HR (95%CI): 3.53 (1.1-10.5), p = 0.02].ConclusionOur results suggest that the combination of CTNNB1 status and miR-499a-5p allows a better stratification of NSMP patients and could promote a personalization of the treatment in intermediate-risk patients.

Endometrial cancer (EC) is the most common gynecological cancer, with annual incidence rates in Western countries ranging between 15 and 25 per 100.000 women. About 15-20% of patients with EC have high-risk disease and follow an aggressive clinical course. Unfortunately, the assessment of histologic parameters is poorly reproducible and conventional clinicopathological and molecular features do not reliably predict either the patient's response to the available treatments or the definition of personalized therapeutic approaches. In this context, the identification of novel diagnostic and prognostic biomarkers, which can be integrated in the current classification schemes, represents an unmet clinical need and an important challenge. MiRNAs are key players in cancer by regulating the expression of specific target genes. Their role in EC, in association with clinical and prognostic tumor biomarkers, has been investigated but, so far, with little consensus among the studies. The present review aims to describe the recent advances in miRNAs research in EC taking into consideration the current classification schemes and to highlight the most promising miRNAs. Finally, a perspective point of view sheds light on the challenges ahead in the landscape of endometrial cancer. This article is protected by copyright. All rights reserved.

Epithelial ovarian cancer (EOC) is one of the most lethal cancers worldwide, mostly due to nonspecific symptoms and a lack of screening tests, which, taken together, contribute to delayed diagnosis and treatment. The current clinical biomarker is serum CA-125, which allows the identification of most advanced primary and relapsed disease and correlates with disease burden; however, as well highlighted in the literature, CA-125 often lacks sensitivity and specificity, and is not helpful in monitoring chemotherapeutic response or in predicting the risk of relapse. Given that, the identification of novel biomarkers able to foster more precise medical approaches and the personalization of patient management represents an unmet clinical requirement. In this context, circulating miRNAs may represent an interesting opportunity as they can be easily detected in all biological fluids. This is particularly relevant when looking for non-invasive approaches that can be repeated over time, with no pain and stress for the oncological patient. Given that, the present review aims to describe the circulating miRNAs currently identified as associated with therapeutic treatments in OC and presents a complete overview of the available evidence.

Background: Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply changed the prognosis of GIST patients, however, the majority of them acquire secondary mutations and progress. Unfortunately, besides tyrosine-kinase inhibitors, no other therapeutic options are available. Therefore, it is mandatory to identify novel molecules and/or strategies to overcome the inevitable resistance. In this context, after promising preclinical data on the novel PI3K inhibitor BYL719, the NCT01735968 trial in GIST patients who had previously failed treatment with imatinib and sunitinib started. BYL719 has attracted our attention, and we comprehensively characterized genomic and transcriptomic changes taking place during resistance. Methods: For this purpose, we generated two in vitro GIST models of acquired resistance to BYL719 and performed an omic-based analysis by integrating RNA-sequencing, miRNA, and methylation profiles in sensitive and resistant cells. Results: We identified novel epigenomic mechanisms of pharmacological resistance in GISTs suggesting the existence of pathways involved in drug resistance and alternatively acquired mutations. Therefore, epigenomics should be taken into account as an alternative adaptive mechanism. Conclusion: Despite the fact that currently we do not have patients in treatment with BYL719 to verify this hypothesis, the most intriguing result is the involvement of H19 and PSTA1 in GIST resistance, which might represent druggable targets.

Background Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O6-methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors. Results Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9–67%–, vs. 6/39–15%– of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24–46%–, vs. 1/24–4%– of KIT/PDGFRA-mutant cases, p = 0.002). Conclusions A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors. Electronic supplementary material The online version of this article (10.1186/s13148-018-0594-9) contains supplementary material, which is available to authorized users.

Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell proliferation, differentiation, apoptosis and angiogenesis. A recent chapter in epigenetics is represented by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) which regulate gene expression. Dysregulated miRNAs and lncRNAs have been associated with several diseases including cancer. Herein we report the most recent findings concerning miRNAs and lncRNAs regulating GH and the IGF system in the context of pituitary adenomas, osteosarcoma and colorectal cancer, shedding light on new possible therapeutic targets. Pituitary adenomas are increasingly common intracranial tumors and somatotroph adenomas determine supra-physiological GH secretion and cause acromegaly. Osteosarcoma is the most frequent bone tumor in children and adolescents and was reported in adults who were treated with GH in childhood. Colorectal cancer is the third cancer in the world and has a higher prevalence in acromegalic patients.

Introduction: Gastrointestinal stromal tumors (GIST) are the best example of a targeted therapy in solid tumors. The introduction of tyrosine kinase inhibitors (TKIs) deeply improved the prognosis of this tumor. However, a degree of inter-patient variability is still reported in response rates and pharmacogenetics may play an important role in the final clinical outcome. Areas covered: In this review, the authors provide an updated overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST treatment efficacy and toxicity. Expert opinion: Besides the primary role of somatic DNA in dictating the clinical response to TKIs, several polymorphisms influencing their pharmacokinetics and pharmacodynamics have been identified as being potentially involved. In the last 10years, many potential biomarkers have been proposed to predict clinical response and toxicity after TKI administration. However, the evidence is still too limited to promote a clinical translation. To date, the somatic mutational status represents the main player in clinical response to TKIs in GIST treatment; however, pharmacogenetics could still explain the degree of inter-patient variability observed in GIST patients. A combination of different theoretical approaches, experimental model systems, and statistical methods is clearly needed, in order to translate pharmacogenetics to clinical practice in the near future.

Contrasting results have been reported on the role of rs628031 and rs683369 polymorphisms of SLC22A1 and rs776746 of CYP3A5 on imatinib treatment response in patients with chronic myeloid leukemia (CML). In the present study, we conducted a systematic review and meta-analysis of published studies to estimate the impact of the above-mentioned gene variants on major molecular response (MMR) or complete cytogenetic response (CCyR) in imatinib-treated CML patients. We performed a comprehensive search through PubMed, Web of Knowledge, and Cochrane databases up to September 2017. The pooled analyses showed association between carriers of SLC22A1 rs628031A allele (GA + AA vs GG, OR: 0.58, 95% CI: 0.38–0.88, P = 0.011) or rs683369G allele (CG + GG vs CC, OR: 0.64, 95% CI: 0.42–0.96, P = 0.032) and a lower MMR rate. The combined analyses also revealed a correlation between the dominant (GG + AG vs AA, OR: 2.43, 95%CI: 1.12–5.27, P = 0.024) or the allelic model (G vs A, OR: 1.72, 95% CI: 1.09–2.72, P = 0.020) of CYP3A5 rs776746 with higher CCyR rates. The subsequent sensitivity analysis confirmed the statistical significance of CYP3A5 rs776746 among Asian CML patients (dominant model OR: 3.90; 95%CI: 2.47–6.14, P < 0.001; allelic model OR: 2.08; 95% CI: 1.47–2.95, P < 0.001). In conclusion, the present meta-analysis supports the association of SLC22A1 and CYP3A5 genotypes with clinical imatinib response rates of CML patients, nevertheless further large studies, particularly in Caucasians, are still warranted to provide conclusive evidences.

none 11 no Several antipsychotics and antidepressants have been associated with QTc prolongation or other electrocardiogram (ECG) alterations, but their impact is still debated and other risk factors are known to affect QTc. We investigated the effect of antidepressants and antipsychotics on QTc and other ECG intervals/waves in three samples. Two discovery samples (cross-sectional sample n = 145 and prospective sample n = 68, naturalistic treatment) and a replication prospective sample (Clinical Antipsychotic Trials of Intervention Effectiveness, n = 515, randomized treatment) were analysed. In both prospective samples, baseline/follow-up changes in ECG parameters were analysed in relation to the number of psychotropic drugs stratified according to their known cardiovascular risk. In the cross-sectional sample, ECG parameters were compared among drugs with different risk profile. The possible effect of single nucleotide polymorphisms (SNPs) in the CACNA1C gene on QTc was also investigated. There was no evidence of mean QTc prolongation or increased risk of clinically relevant QTc prolongation (≥20 msec.) in association with psychotropic drugs stratified according to their known cardiovascular risk. The prescription of drugs with cardiovascular risk was less common in older individuals or individuals with cardiovascular comorbidities. Other factors (gender, baseline QTc, renal function) affected QTc. rs1006737 and SNPs in linkage disequilibrium with it modulated QTc duration/changes in all samples. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not observed. A number of factors other than psychotropic drugs may influence QTc. CACNA1C rs1006737 may modulate QTc in patients treated with psychotropic drugs. none Fabbri, Chiara; Boriani, Giuseppe; Diemberger, Igor; Filippi, Maria Giulia; Ravegnini, Gloria; Hrelia, Patrizia; Minarini, Alessandro; Albani, Diego; Forloni, Gianluigi; Angelini, Sabrina; Serretti, Alessandro Fabbri, Chiara; Boriani, Giuseppe; Diemberger, Igor; Filippi, Maria Giulia; Ravegnini, Gloria; Hrelia, Patrizia; Minarini, Alessandro; Albani, Diego; Forloni, Gianluigi; Angelini, Sabrina; Serretti, Alessandro

Aim: The present study aimed to conduct a series of meta-analyses to investigate the influence of imatinib trough concentration (C0), as well as ABCB1 and ABCG2 polymorphisms, on the clinical response in patients with chronic myeloid leukemia (CML). Methods: A literature search was conducted using the PubMed and Cochrane electronic databases to locate relevant papers from 2003 onward. Then, an initial meta-analysis of 14 studies involving 2184 patients was conducted to understand the effect of imatinib mesylate (IM) C0 on clinical outcome in CML patients. Subsequently, a series of meta-analyses were performed, including up to 23 studies with 2577 patients, on the effect of genetic polymorphisms of ABCB1 and ABCG2 on the clinical response to IM. Results: Meta-analysis revealed that patients who achieved a major molecular response (MMR) have a significantly higher IM C0 than those who failed to achieve an MMR. We also found that the patients who achieved a complete cytogenic response (CCyR) have a significantly higher IM C0 than those who did not achieve a CCyR. However, no significant difference in IM C0 was found between the complete molecular response and non-complete molecular response groups. Additional analysis showed that ABCG2 421 variant A allele was significantly associated with a higher rate of MMR and overall response, especially in Asian patients. Meta-analysis did not reveal a correlation between ABCB1 C3435T and C1236T polymorphisms with any clinical response to IM. However, the G2677T/A polymorphism could play a role in IM response in the recessive model. Conclusion: This meta-analysis demonstrates that there was a significant correlation between the IM trough concentration and clinical responses, especially MMR and CCyR, in CML patients. Furthermore, we found that the probability of successful treatment was correlated with the ABCG2 C421A polymorphism, at least within the Asian population. We failed to determine an association between ABCB1 polymorphisms and IM response, although the G2677T/A polymorphism might be involved. However, further large-scale investigations using more sensitive genotyping methods would be required to confirm this.

The angiogenic pathway plays a pivotal role in tumor growth, invasiveness and metastasis. The most important actors in the angiogenic pathway are VEGFA and its receptors VEGFR1, 2 and 3. These genes are polymorphic, and the presence of single nucleotide polymorphisms may result in angiogenic deregulation. Herein, we hypothesized that germline variants may affect sunitinib efficacy (TTP and OS) and/or toxicity. Therefore, we investigated 19 polymorphisms, in four genes, in 54 GIST patients, treated with second-line sunitinib and 147 healthy controls. Through a multiple candidate gene approach, we also investigated, for the first time, any possible significant associations with GIST susceptibility and clinical pathological features. The most important result shows two associations between polymorphisms in VEGFR3 rs6877011 (CC vs. CG, OR 9.7, 95% CI 3.31-28.4; P < 0.001) and rs7709359 (AA+AG vs. GG, OR 5.01, 95% CI 1.33-18.8; P = 0.017) and TTP. Interestingly, the association between VEGFR3 rs6877011 and TTP maintained the significance after applying the Bonferroni correction for multiple testing (P = 0.017). We also highlighted the association with sunitinib-related toxicity; in particular, VEGFA polymorphism rs3025039 (CT+TT vs. CC, OR 15.3, 95% CI 2.2-102.1; P = 0.005) is associated with severe toxicity, with the presence of the variant T allele associated with a grade a 3 AE. Because of the small sample size and large number of tests performed, we cannot ignore the possibility that some associations have been retrieved by chance. However, the influence of VEGF polymorphisms in angiogenesis is a hypothesis worthy of exploration in cellular models and confirmation in a sizeable cohort of patients.

Background: A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression. miR-221 and miR-222 have been frequently identified as deregulated across different cancer types; however, their prognostic significance in cancer remains controversial. In view of these considerations, we performed an updated systematic review and meta-analysis of published data investigating the effects of miR-221/222 on overall survival (OS) and other secondary outcomes among cancer patients. A systematic search of PubMed, Web of Knowledge, and Cochrane Library databases was performed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Results: Fifty studies, analyzing 6086 patients, were included in the systematic review. Twenty-five studies for miR-221 and 17 studies for miR-222 which assessed OS were included in the meta-analysis. High expression of miR-221 and miR-222 significantly predicted poor OS (HR: 1.48, 95% CI: 1.14−1.93, p = 0.003 and HR: 1.90, 95% CI: 1.43−2.54, p < 0.001, respectively). Subgroup analysis revealed that the finding on miR-221 was not as robust as the one on miR-222. Furthermore, high miR-222 expression was also associated with worse progression-free survival and disease-free survival pooled with recurrence-free survival. Conclusions: The meta-analysis demonstrated that high expression of miR-222 is associated with poor prognosis in cancer patients, whereas the significance of miR-221 remains unclear. More work is required to fully elucidate the role of miR-221 and miR-222 in cancer prognosis, particularly in view of the limitations of existing results, including the significant heterogeneity and limited number of studies for some cancers.

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Gastrointestinal stromal tumors (GISTs) are rare entities, which, however, represent the most common mesenchymal tumor of the gastrointestinal tract. The discovery of gain of function mutations onKIT andPDGFRA receptor genes led to a deep revolution in the knowledge of this tumor. This paved the way to the introduction of imatinib and other tyrosine-kinase inhibitors (TKIs), which terrifically revolutionized the prognosis of GIST patients. Currently, it is well established that tumor mutational status is the main player in clinical outcome; however, with the research advances, it has been slowly understood that GIST landscape is more complex than expected and the TKIs available are not effective for all the GIST subtypes. For this reason, in the era of tailored/personalized medicine, each GIST patient should be considered individually and genetic consult should be the first step to take in consideration in the therapeutic decision making process.

Individuals chronically exposed to low-level ionising radiation (IR) run the risk of harmful and long-term adverse health effects, including gene mutations and cancer development. The search for reliable biomarkers of IR exposure in human population is still of great interest, as they may have a great implementation potential for the surveillance of occupationally exposed individuals. In this context, and considering previous literature, this study aimed to identify mutations in the human interferon alpha-2b (hIFNα-2b) as a potential biomarker of occupational chronic low-dose IR exposure linking low-IR exposure to the effects on haematopoiesis and reduced immunity. The analysis was performed in the genomic DNA of 51 uranium miners and 38 controls from Kazakhstan, and in 21 medical radiology workers and 21 controls from Italy. hIFNα-2b gene mutations were analysed with the real-time polymerase chain reaction (PCR) or Sanger sequencing. However, none of the investigated workers had the hIFNα-2b mutation. This finding highlights the need for further research to identify biomarkers for early detection of health effects associated with chronic low-dose IR exposure., Kronična izloženost niskim razinama ionizirajućega zračenja povezana je s rizikom od dugoročnih štetnih posljedica za zdravlje, što obuhvaća i mutacije gena te nastanak raka. U tijeku je potraga za pouzdanim biopokazateljima izloženosti ionizirajućem zračenju u ljudi, budući da njihova primjena može značajno unaprijediti praćenje profesionalno izloženih osoba. U tom smislu, a s obzirom na ranija saznanja, cilj je ovoga istraživanja bio utvrditi mutacije gena za proizvodnju humanoga interferona alfa-2b (hIFNα-2b gena) kao mogućega biopokazatelja profesionalne kronične izloženosti niskim dozama ionizirajućega zračenja, koje je usto povezano s djelovanjem na hematopoezu i pad imuniteta. Analiziran je genomski DNA 51 rudara u rudnicima uranija te 38 kontrolnih ispitanika iz Kazahstana, odnosno genomski DNA 21 zdravstvenoga radnika na radiologiji i 21 kontrolnoga ispitanika iz Italije. Mutacije hIFNα-2b gena utvrđivane su metodom lančane reakcije polimerazom u stvarnom vremenu (engl. real-time PCR) odnosno sekvenciranjem prema Sangeru, ali se pokazalo da niti jedan radnik nije imao niti jednu od deset traženih mutacija toga gena. Stoga ne preostaje drugo nego i dalje tražiti pouzdane biopokazatelje za rano otkrivanje štetnih zdravstvenih učinaka povezanih s kroničnom izloženosti niskim dozama ionizirajućega zračenja.

Gastrointestinal “juvenile-like (inflammatory/hyperplastic) mucosal polyps” (JLIHMPs) have been proposed as a neurofibromatosis type 1 (NF1)-specific gastrointestinal manifestation. Juvenile polyposis syndrome (JPS) has also been reported in a NF1 patient, harboring concurrent NF1 and SMAD4 germline mutations. Additionally, NF1-like cafe-au-lait spots have been described in biallelic mismatch repair deficiency, another condition featuring gastrointestinal polyps. The SMAD4 and BMPR1A genes that are involved in 50–60% of JPS cases have not been investigated in the ~ 20 published cases of NF1-associated JLIHMPs with the exception of the abovementioned patient with concomitant JPS and NF1. NF1 defects have been found in the only two cases exhaustively tested. Therefore, JLIHMP has been questioned as an independent, NF1-specific entity. Incidental associations between NF1 and gastrointestinal polyposes at risk for gastrointestinal carcinoma should not be overlooked, given their implications in terms of clinical surveillance. We describe two patients featuring JLIHMPs in clinically/genetically proven NF1, in the absence of SMAD4 and BMPR1A mutations. In one case, the intervening mucosa was markedly inflamed, unlike JPS. We suggest that JLIHMP probably represents a gastrointestinal lesion specific to NF1.

Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.

The existence of genetic traits might explain the susceptibility to develop hypercholesterolemia and the inter-individual differences in statin response. This study was performed to evaluate whether individuals’ polymorphisms in HMG-CoA and KIF6 genes are independently associated with hypercholesterolemia, other lipid-associated traits, and statin response in unselected individuals enrolled in the Brisighella heart study (Survey 2012). A total of 1622 individuals, of which 183 under statin medication, were genotyped for a total of five polymorphisms (KIF6 rs20455, rs9471077, rs9462535; HMG-CoA rs3761740, rs3846662). The relationships between the five loci and clinical characteristics were analyzed. The principal basic parameters calculated on 12 h fasting blood included total cholesterol (TC), High Density Lipoprotein Cholesterol (HDL-C), Low-Density Lipoprotein Cholesterol (LDL-C), and triglycerides (TG). Hypercholesterolemia was defined as a TC >200 mg/dL or use of lipid-lowering medication. 965 individuals were characterized by hypercholesterolemia; these subjects were significantly older (p < 0.001), with body mass index (BMI) and waist circumference significantly higher (p < 0.001) compared to the others. HMG-CoA rs3846662 GG genotype was significantly over-represented in the hypercholesterolemic group (p = 0.030). HMG-CoA rs3846662 genotype was associated with the level of TC and LDL-C. Furthermore, in the same subset of untreated subjects, we observed a significant correlation between the KIF6 rs20455 and HDL-C. KIF6 variants were associated with a significantly lower (rs20455) or higher (rs9471077 and rs9462535) risk of obesity, in males only. No association between responsiveness to statins and the polymorphisms under investigation were observed. Our results showed associations between HMG-CoA rs3846662 and KIF6 rs20455 and lipid phenotypes, which may have an influence on dyslipidemia-related events. Moreover, this represents the first study implicating KIF6 variants with obesity in men, and point to the possible involvement of this genetic locus in the known gender-related differences in coronary artery disease.

Individual sensitivity to ionising radiation (IR) is the result of interaction between exposure, DNA damage, and its repair, which is why polymorphisms in DNA repair genes could play an important role. We examined the association between DNA damage, expressed as micronuclei (MNi), nuclear buds (NBs), and nucleoplasmic bridges (NPBs) and single nucleotide polymorphisms in selected DNA repair genes (APE1, hOGG1, XRCC1, XRCC3, XPD, PARP1, MGMT genes; representative of the different DNA repair pathways operating in mammals) in 77 hospital workers chronically exposed to low doses of IR, and 70 matched controls. A significantly higher MNi frequency was found in the exposed group (16.2±10.4 vs. 11.5±9.4; P=0.003) and the effect appeared to be independent from the principal confounding factor. Exposed individuals with hOGG1, XRCC1, PARP1, and MGMT wild-type alleles or APEX1, as well as XPD (rs13181) heterozygous showed a significantly higher MNi frequency than controls with the same genotypes. Genetic polymorphism analysis and cytogenetic dosimetry have proven to be a powerful tool complementary to physical dosimetry in regular health surveillance programmes.

Colorectal cancer (CRC) is currently the third most common malignancy in the world. The prognosis of CRC is directly related to the stage of the cancer at the time of diagnosis, and survival is significantly better when CRC is diagnosed at an early stage. Consequently, there is an urgent need for the discovery of non-invasive diagnostic markers that can reflect the early events linked to colorectal carcinogenesis. Clinical and experimental data indicate that chronic inflammation and oxidative stress are involved in the development of CRC. In this review, we evaluate risk prediction, the diagnostic and prognostic value of biomarkers related to oxidative stress, antioxidant status, oxidative DNA damage, and the inflammation process in CRC.

Imatinib mesylate, a competitive tyrosine kinase inhibitor, is considered the first-line therapy drug for Ph+ chronic myeloid leukemia (CML). Three single-nucleotide polymorphisms (SNPs) in the ATP-binding cassette, subfamily B (MDR/TAP), member 1 gene (ABCB1/MDR1), c.1236C>T, c.2677G>T/A and c.3435C>T, have been shown to affect cellular transport/metabolism of imatinib. The associations between these SNPs and imatinib response in CML patients have been widely evaluated, but the results were inconsistent. To derive a conclusive assessment of the associations, we performed a meta-analysis by combining data from a total of 12 reports including 1826 patients. The results showed that the 2677G allele or 3435T allele predicted a worse response to imatinib in CML patients, whereas 1236CC genotype was associated with better response in CML patients from Asian region. In conclusion, this meta-analysis suggests that c.1236C>T, c.2677G>T/A and c.3435C>T can be served as predictive markers for the therapeutical use of imatinib in CML patients.

The early detection of colorectal cancer (CRC) can significantly improve the prognosis of affected patients. The loss of genomic stability and the resulting gene alteration play an important role in the molecular pathological steps that occur early in tumorigenesis of CRC. Thus, the identification of non-invasive biomarkers, whose function may provide useful insights into critical early events in the CRC process, is of great interest. In this regard, micronucleus (MN) frequency in peripheral blood lymphocytes (PBL) has become one of the most established biomarkers for studying DNA damage in the human population. This study investigated the MN frequency in the PBL of 82 subjects (30 females and 52 males; aged 50-70 years) who were participating in a screening programme for CRC prevention. All 82 patients were positive in fecal occult blood tests and they were subsequently classified, according to colonoscopy and histological findings, as patients with CRC, patients with colon polyps or subjects without intestinal lesion, referred to as study controls. This study also examined the relationship between the plasma clastogenic activity and the frequency of micronuclei of the study population. The MN frequency was significantly higher in CRC patients than in both colon polyp patients (16.82 ± 6.56 versus 12.23 ± 1.88; P = 0.002) and controls (16.82 ± 6.56 versus 8.00 ± 1.77; P < 0.001). An increased MN frequency was detected in the lymphocytes of the polyp group in comparison to the control group, although this was lower than that observed in CRC patients (12.23 ± 1.88 versus 8.00 ± 1.77; P < 0.001). In the overall study population, the increase of MN frequency, which was observed in the lymphocytes of the subjects involved, was significantly associated with the clastogenic activity detected in their plasma (r = 0.594, P < 0.001). Overall, the results suggest that the MN test can become a promising biomarker for the early detection of CRC.

The aim of the study was to investigate any possible influence of polymorphisms of transmembrane transporters human organic cation transporter 1 (hOCT1), ABCB1, ABCG2 on imatinib pharmacokinetics in 33 men and 27 women (median age and range, 56 and 27-79 years, respectively) affected by chronic myeloid leukemia. A population pharmacokinetic analysis was performed to investigate imatinib disposition in every patient and the role of transporter polymorphisms. Results showed that the α1-acid glycoprotein and the c.480C>G genotype of hOCT1 had a significant effect on apparent drug clearance (CL/F) being responsible, respectively, for a 20% and 10% decrease in interindividual variability (IIV) of CL/F (from 50.1 up to 19.6%). Interestingly, 25 patients carrying at least one polymorphic c.480 G allele had a significant lower CL/F value with respect to the 35 c.480CC individuals (mean±s.d., 9.6±1.6 vs 12.1±2.3 l h-1, respectively; PG SNP may significantly influence imatinib pharmacokinetics, supporting further analyses in larger groups of patients.

In recent years, growing research interest has focused on the so-called liquid biopsy. A simple blood test offers access to a plethora of information, which might be extremely helpful in understanding or characterizing specific diseases. Blood contains different molecules, of which circulating free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and extracellular vesicles (EVs) are the most relevant. Conceivably, these molecules have the potential for tumor diagnosis, monitoring tumor evolution, and evaluating treatment response and pharmacological resistance. This review aims to present a state-of-the-art of recent advances in circulating DNA and circulating RNA in gastrointestinal stromal tumors (GISTs). To date, progress in liquid biopsy has been scarce in GISTs due to several issues correlated with the nature of the pathology. Namely, heterogeneity in primary and secondary mutations in key driver genes has greatly slowed the development and application in GISTs, unlike in other tumor types in which liquid biopsy has already been translated into clinical practice. However, meaningful novel data have shown in recent years a significant clinical potential of ctDNA, CTCs, EVs and circulating RNA in GISTs.

Gastrointestinal stromal tumor (GIST) is a well-recognized and now relatively well-understood mesenchymal tumor. Before the imatinib era, the treatment of metastatic GIST was frustrating owing to its refractoriness to conventional chemotherapy and radiotherapy. After a metastatic GIST patient was granted compassionate use of imatinib in 2000, the treatment of this disease has emerged as a model for the development of other molecularly targeted therapies. In this article the authors review how tumor genotypes, in particular KIT and PDGFRA mutational analysis, have been integrated in the optimal clinical management of GIST patients. The authors also discuss the potential practical relevance of pharmacogenetics, which, integrated with therapeutic drug monitoring, should receive greater consideration, with the aim of personalized therapy.

Introduction: Gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML) are two tumor types deeply different from each other. Despite the differences, these disorders share treatment with tyrosine kinase inhibitor imatinib. Despite the success of imatinib, the response rates vary among different individuals and pharmacogenetics may play an important role in the final clinical outcome. Areas covered: In this review, the authors provide an overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST and CML treatment efficacy and toxicity. Expert opinion: So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, the data are not yet conclusive enough to translate pharmacogenetic tests in clinical practice. In this context, the major obstacles to pharmacogenetic test validation are represented by the small sample size of most studies, ethnicity and population admixture as confounding source, and uncertainty related to genetic variants analyzed. In conclusion, a combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.

Background QTc prolongation is a potentially life-threatening side effect of some antidepressants and antipsychotics, and a number of other electrocardiogram (ECG) alterations were associated with psychotropic drugs. Poor knowledge is available about the genetic risk factors of QTc prolongation during treatment with these drugs. Polymorphisms in the α1-subunit of cardiac L-type calcium channel (CACNA1C) were associated with several types of arrhythmic diseases (including Long QT syndrome), but no data are available in regard to their possible effect on QTc duration during psychotropic drugs use. The present study primarily aimed to investigate QTc variation in relation to the prescription of psychotropic drugs stratified according to their cardiovascular risk [3]. The possible modulating effect of polymorphisms in the α1-subunit of cardiac L-type calcium channel (CACNA1C) gene was considered. As secondary aim, we investigated other ECG alterations possibly associated with psychotropic drugs. Methods 213 patients with a diagnosis of mood, anxiety or psychotic disorder who required a pharmacological treatment with antidepressant and/or antipsychotic drugs were included. A cross-sectional sample (n=145) had one standard ECG at baseline while a prospective sample (n=68) had a baseline and follow-up ECG. 13 SNPs in the CACNA1C gene were genotyped in both samples. An independent prospective sample was available from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Patients having a baseline and follow-up ECG were selected (n=515) and CACNA1C polymorphisms were extracted from imputed genome-wide data. In the prospective samples changes in ECG intervals (QTc, PR, QRS, RR, and QR) between baseline and follow-up were analyzed in relation to the number of psychotropic drugs stratified according to their cardiovascular risk (from moderate-high to none). In the cross-sectional sample ECG parameters were compared among groups taking psychotropic drugs with different cardiovascular risk. The effect of genotypes on these associations was tested. Results There was no evidence of mean QTc prolongation or increased risk of QTc prolongation ≥ 20 ms in association with risk drugs. The prescription of drugs with cardiovascular risk was less common in older subjects (p=0.04) or with cardiovascular comorbidities (p=0.02). Other factors (gender, ethnicity, baseline QTc, kidney function) affected QTc. rs1006737 modulated QTc duration/changes in the original prospective sample (p=0.04) and in cross-sectional sample (p=0.002) and four polymorphisms in linkage disequilibrium with it modulated QTc changes in the CATIE. An association between risk drugs and shorter RR interval or higher heart rate was found in all samples. Discussion A relevant effect of psychotropic drugs with cardiovascular risk on QTc duration was not found. A number of other factors may influence QTc. CACNA1C rs1006737 may modulate the risk of QTc prolongation in patients treated with risk drugs. Finally, high resting heart rate, even within the accepted normal range, should not be overlooked in patients treated with psychotropic drugs since it was independently associated with increased risk of all-causes mortality.

The Italian fishing industry, especially the part operating in the Adriatic, has long requested a change to the period of the fishing ban, normally effective in August, when Italy sees the greatest number of tourists. This study aims to contribute to knowledge of the reproductive periods of the main species fished in Italian waters, with the aim of protecting both the biodiversity of seafood and the income of fishermen using the technical ban. The tool chosen was consultation of the available bibliographic and documentary sources, in order to reliably and scientifically define the breeding periods of individual species. The results enabled the development of a reproductive calendar for every species taken into consideration. This calendar provides the technical basis to initiate a discussion on the scientific schedule for the biological bans.

OBJECTIVE:Cardiovascular disease (CVD) represents the most common and lethal chronic disease worldwide. Lipids levels are the strongest risk factors for CVD and this is demonstrated by the fact that lipid-lowering statin therapy is largely used to prevent CVD. The role of the KIF6 gene in response to the statin therapy is controversial, and the biological mechanism through which it may act is still unknown.We investigated the role of KIF6 locus variants alone and their interaction with the well-established lipid locus at HMGCR in the variability of metabolic traits and in response to statin therapy in an Italian sample. DESIGN AND METHOD:We genotyped two intronic rs20455, rs9462535 and a coding rs9471077 within the KIF6 gene, as well as two non-coding rs3761740 and rs3846662 at HMGCR. We tested the association of these SNPs with 19 cardiometabolic phenotypes and lipid-lowering therapy response in a sample of 1645 individuals from the Brisighella cohort (BC). RESULTS: Established rs3846662 (Willer et al, Nat Gen 2013) at HMGCR is associated (P = 8.5x10-4) with LDL cholesterol (LDL-C) in BC. We did not find any significant association of KIF6 variants with response to statin therapy. We observe a locus-wide significant association at KIF6 between rs9471077 and APOB levels and rs20455 and HDL-C (P less than 0.001). rs3761740 at HMGCR showed an effect on systolic and diastolic blood pressure (SBP/DBP, P less than 0.007), which however wasn't significant after multiple testing correction. CONCLUSIONS: This is the first genetic study reported for Brisighella cohort, which confirms association with LDL-C at HMGCR locus. We noticed an effect of KIF6 variants on APOB and HDL-C, while we don't observe any effect on statin therapy. The study sample is relatively small to discover a common variant effect and might still be due to chance; therefore, we are seeking for replication in additional cohorts. These findings, if confirmed, might contribute to development of approaches for stratified patient care.

Background Socio-economic, cultural and environmental factors are becoming increasingly important determinants of chronic obstructive pulmonary disease (COPD). We conducted a study to investigate socio-demographic, lifestyle and clinical factors, and to assess their role as predictors of acute events (mortality or hospitalization for respiratory causes) in a group of COPD patients. Methods Subjects were recruited among outpatients who were undertaking respiratory function tests at the Pneumology Unit of the Sant’Orsola-Malpighi Hospital, Bologna. Patients were classified according to the GOLD Guidelines. Results 229 patients with COPD were included in the study, 44 with Mild, 68 Moderate, 52 Severe and 65 Very Severe COPD (GOLD stage). Significant differences among COPD stage, in terms of smoking status and fragility index, were detected. COPD stage significantly affected the values of all clinical tests (spirometry and ABG analysis). Kaplan-Meier estimates showed a significant difference between survival curves by COPD stage with lower event-free probability in very severe COPD stage. Significant risk factors for acute events were: underweight (HR = 4.08; 95% CI 1.01–16.54), having two or more comorbidities (HR = 4.71; 95% CI 2.52–8.83), belonging to moderate (HR = 3.50; 95% CI 1.01–12.18) or very severe COPD stage (HR = 8.23; 95% CI 2.35–28.85). Conclusions Our findings indicate that fragility is associated with COPD stage and that comorbidities and the low body mass index are predictors of mortality or hospitalization. Besides spirometric analyses, FeNO measure and comorbidities, body mass index could also be considered in the management and monitoring of COPD patients.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a good and stable response for approximately 18–36 months. However, resistance is very common and it is vital to identify new biomarkers. Up until now, there have been two main approaches with focus to characterize novel targets. On the one hand, the focus is on the tumor genome, as the final clinical outcome depends mainly from the cancer specific mutations/alterations patterns. However, the germline DNA is important as well, and it is inconceivable to think the patients response to the drug is not related to it. Therefore the aim of this review is to outline the state of the art of the personalized medicine in GIST taking into account both the tumor DNA (somatic) and the patient DNA (germline).

The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST. Response to imatinib mainly depends from KIT and PDGFRα mutational status. Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations. This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available. We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400 mg daily as first line therapy. Included in this analysis were polymorphisms in the transporters’ family SLC22 , SLCO , ABC , and in the metabolizing genes CYP - 3A4 and - 3A5 . Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372). Importantly, multivariate analysis, adjusting for age, gender, KIT / PDGFRα mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance. In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy. Further investigations are required in an attempt to further personalize GIST therapy.

The accomplishment of the Human Genome Project, followed by the availability of high-throughput technologies, has led to an impressive change in biomedical research.[...]

During their working and living activities, humans are constantly exposed to different environmental genotoxic agents. Biological consequences of the exposure are accumulation of different mutations and DNA damage that can lead to disruption of genetic material. Numerous endogenous genotoxic agents can also cause DNA damage. Loss of normal cell function can cause cell death or can result in different health disorders, including teratogenic and cancerogenic effects (Jeggo & Lavin, 2009). There is an increasing concern about mutagenic and cancerogenic effects of genotoxic agents and their influence on individuals who are exposed to them by accident, or by living/working lifestyle (Au, 1991; Carrano & Natarajan, 1988; Kassie et al., 2000). Exposure to ionising radiation, as a well known genotoxic agents (Balasem & Ali, 1991; Erexon et al., 1991; Fenech et al., 1990; He et al., 2000; Jeggo & Lavin, 2009), can leed to different DNA damage, such as oxidative damage, base and sugar modification in DNA, apurinic/apirimidinic places, single/double strand chromosomal breaks, adduct creation, inter/intra DNA cross linking and other types of damage (Hall & Giaccia, 2006). Numerous studies deal with ionising radiation exposure of individuals who are chronically professionally exposed to low doses (Andreassi, 2009; Au, 1991; Carrano & Natarajan, 1988; Kassie et al., 2000). The results showed the increase in chromosomal damage during chronically low dose exposure (Barquinero et al., 1993; Boutcher, 1985; Cardoso et al., 2001; Jha, 1991; Nowak & Jankowski, 1991), but without confirmed relationship between the received dose and the intensity of DNA damage (Bolus, 2001; Coates et al., 2004; Morgan, 2003; Mothersill et al., 2000, 2001; Seymour & Mothersill, 2000). The influence of chronically low dose exposure has been considered mutagenic and cancerogenic (Fachini et al., 2009). Although it is possible to estimate the influence of absorbed dose and the effect on the

In the context of a medical surveillance program aimed at preventing cancer risk from exposure to ionizing radiation, we investigated chromosomal damage in peripheral lymphocytes from 37 hospital workers exposed to low levels of ionizing radiation and 37 controls. The micronuleus (MN) assay was used as a biomarker of genetic damage. The influence of confounding factors like smoking status, age and gender was investigated by multiple regression analysis. The results indicated that, overall, MN frequency was higher in exposed workers than in controls, although the difference was not statistically significant. Interestingly, smoking status significantly raised MN frequency among the exposed workers but not among controls. This suggests that smoking can influence chromosomal damage induced in humans by ionizing radiation. Among both exposed workers and controls, MN frequency was found to increase with age. Female gender influenced the increase in MN frequency in the exposed group. Our results suggest that the effect of cigarette smoking should be carefully factored into genetic monitoring studies assessing the risks associated with low level radiation exposure.

The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). We thus investigated a panel of 20 SNPs in ABCB1, ABCG2, SLC22A1, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Median age was 46 yrs; male to female ratio was 103:86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the entire population enrolled. Treatment outcomes (major molecular response [MMR]; complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). Additive models, with SNPs represented as number of major alleles, were used. Significant results are summarized in the Table below and will be presented in detail. Cumulative incidence plots were also analysed, with similar results. Our data suggest that in CML pts, genotyping should be taken into account in an attempt to further individualize treatment, with the aim of enhancing efficacy in terms of MMR and CMR achievement. On the basis of our findings, stratification of pts according to genotypes may be proposed for selection between IM and second generation TKIs, and represents an attractive opportunity for new clinical trials. Supported by Novartis, TOPS Correlative Studies Network Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5448. doi:10.1158/1538-7445.AM2011-5448

Abstract 670 The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). Pharmacogenetics has proven a potential source of biomarkers given the known influence of polymorphisms in key genes encoding drug transporters and metabolizing enzymes on drug delivery – hence effectiveness. In CML, only two studies had so far explored this field, but both were conducted in heterogeneous populations including pts at different stages of disease, not all receiving IM first-line. We thus aimed to investigate a panel of 20 single nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLC22A1, OATP1A2, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Pts selection was exclusively based on availability of written informed consent and sufficient amount of archived material. Median age was 46 years; male to female ratio was 103 to 86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the overall population. Treatment outcomes (complete cytogenetic response [CCyR]; major molecular response [MMR] and complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). CC genotype in OCTN1 had a favorable impact on the achievement of MMR at 12 months (MMR@12m; P = 0.03). With respect to the summary measures, combination of SNPs in the SLC22A1 gene was significantly correlated with MMR@12m (P = 0.03). When considering summary measures of uptake and efflux, the former was found to be associated with both MMR@12m and CMR@12m (P = 0.003 and P = 0.01, respectively). A separate analysis limited to Caucasian pts (n=156) yielded similar results (Table 1). In addition, the analysis in the Caucasian subgroup evidenced a significant association between the CC genotype in ABCB1 rs60023214 and MMR@12m (P = 0.005) (Table 1). Cumulative incidence plots based on the Kaplan-Meier method were also analyzed in the overall population and in Caucasians, with comparable results. Representative plots are shown in Figure 1. There was evidence for difference among MMR cumulative incidence curves for 2 single SNPs and 2 score measures. Presence of the major allele in OCTN1 (CC) and of the minor allele in CYP3A4 rs2740574 (GG) were associated with increased MMR rate (P = 0.028 and P = 0.042, respectively, in the overall population and P = 0.027 and P = 0.038, respectively, in Caucasians). Similarly, an increase in the number of favorable alleles in the SLC22A1 gene was associated with increased MMR rate (P = 0.030 and P = 0.043 in the overall population and in Caucasians, respectively). In addition, the combination of favorable alleles in the genes involved in IM uptake was associated with increased rates of both MMR and CMR (P = 0.004 and P = 0.015, respectively, in the overall population and P = 0.005 and P = 0.009, respectively, in Caucasians). Our results suggest that SNP genotyping might be helpful in selecting pts who are more likely to benefit from first-line use of more potent inhibitors. Further assessment of the SNPs here identified in larger series of pts is warranted. Table 1 . Summary of significant associations Overall population (n=189) Caucasians (n=156) Gene, rs Outcome P Hazard ratio[95% CI] P Hazard ratio[95% CI] OCTN1 - rs1050152 MMR@12m 0.03 0.78 (0.63, 0.98) 0.03 0.77 (0.60, 0.97) ABCB1 (MDR1) - rs60023214 CMR@12m 0.06 0.71 (0.49, 1.02) 0.005 0.56 (0.37, 0.84) SLC22A1 (hOCT1) - SNP combination MMR@12m 0.03 1.24 (1.02, 1.50) 0.04 1.24 (1.00, 1.54) Uptake - SNP combination MMR@12m 0.003 1.21 (1.06, 1.37) 0.005 1.24 (1.06, 1.44) Uptake - SNP combination CMR@12m 0.01 1.30 (1.05, 1.61) 0.01 1.37 (1.08, 1.74) Download : Download high-res image (197KB) Download : Download full-size image Figure 1: . Cumulative incidence of pts achieving MMR and CMR according to the # of major alleles in uptake-related gene (SLC22A1, OATP1A2, OCTN1) SNPs Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. White: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Rosti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hatfield: Novartis: Employment. Martinelli: Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

6554 Background: Imatinib mesylate (IM) is the first-choice treatment in CML, with excellent response rates. Major and complete molecular responses are the current goals of therapy, but not all pat...