The Effect of Gene Mutations on Metastasis and Overall Survival in Metastatic and Nonmetastatic Colon Cancers

Abstract A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1mut patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2mut patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2mut patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2mut patients. U2AF35mut patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2mut/TET2wt (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.

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Frequency and Prognostic Relevance of Gene Mutations in Pediatric AML Patients At First Relapse.

Blood ◽

10.1182/blood.v120.21.2480.2480 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2480-2480

Author(s):

Costa Bachas ◽

Gerrit Jan Schuurhuis ◽

Dirk Reinhardt ◽

Ursula Creutzig ◽

Zinia J. Kwidama ◽

...

Keyword(s):

Overall Survival ◽

Receptor Tyrosine Kinase ◽

Risk Group ◽

Gene Mutations ◽

Single Nucleotide ◽

Mutational Status ◽

Variate Analysis ◽

First Relapse ◽

Pediatric Aml ◽

Group Stratification

Abstract Abstract 2480 Relapsed pediatric AML patients respond poorly to conventional re-induction therapy and as a consequence long term survival rates of these patients are low (up to 36%). Accurate characterization and risk group stratification at first relapse may facilitate personalized, targeted re-induction therapies for these patients and ultimately improve outcome. Gene mutations provide putative targets in personalized treatment (e.g. FLT3/ITD, KIT or RAS mutations) and their incidence and prognostic relevance in pediatric AML at first relapse remains to be elucidated. Changes in mutational status occur during therapy; hence, assessment of mutations at first relapse is warranted to establish the accurate mutation status of the leukemic cells before the start of salvage treatment. Mutational status at first relapse as well as clinical and karyotypic data were retrospectively analyzed in a large set (n = 240) of relapsed non-FAB M3, non-Down syndrome AML patients younger than 19 years. The majority of patients (88%) were uniformly treated at first relapse according to the ‘Relapsed AML 2001/01’ protocol of the International Berlin-Frankfurt-Münster (BFM) study group that involved two re-induction courses of chemotherapy with FLAG as standard treatment with or without liposomal daunorubicin (randomization), followed by allogeneic stem cell transplantation in most cases. Other patients received FLAG based (5%) or other high dose cytarabin based therapy (6%). We screened the relapse samples for hotspot mutations in a selected panel of genes (FLT3, WT1, KIT, N-RAS, K-RAS, NPM1) relevant for AML and found one or more mutations in 139 out of 240 patients (57.9%). Gene mutations were mutually exclusive in 73 out of 139 patients carrying mutations (52.5%), while in 66 out of 139 patients (47.5%) two or more gene mutations were observed. FLT3/ITD mutations coincided with 50% of NPM1 and 53% of WT1 exon 7 mutated cases (p=.003 and p<.0001 respectively). The frequencies of mutations at first relapse are summarized in the Table below including their impact on event free and overall survival, according to uni-variate analysis. In multivariate analyses, we included mutations and other variables (e.g. FAB type, WBC) with a uni-variate P value below 0.2 to exclude confounding factors. From these analyses, three independent factors significantly increased the risk of a second relapse (RFS after first relapse diagnosis); WT1 mutations (HR=11.2, P<.0001), WT1 single nucleotide variants (HR 3.4, P=.003) and FAB type M7 (HR= 2.2, P=.027). Different independent factors were associated with dismal overall survival after first relapse including FLT3/ITD mutations (HR=2.2, P=.028) and high WBC (HR=3.2, P=.004) at first relapse. In conclusion, mutations in the studied panel of genes in this large cohort of pediatric relapsed AML patients were frequent. Overall, we detected receptor tyrosine kinase mutations in more than 25% of the patients, indicating the large proportion of relapsed patients that is eligible for targeted receptor tyrosine kinase inhibitor treatment. The gene mutations studied here provide strong prognostic factors for dismal outcome after first relapse. The relevance of these markers in predicting outcome should be validated in a prospective setting. Accurate risk group stratification of relapsed AML patients should be based on clinical and molecular characterization performed at first relapse. In addition, mutations in drugable genes can identify patients that are eligible for personalized, targeted re-induction strategies. Table Uni-variate analysis of the association of relevant gene mutations in pediatric AML at first relapse with outcome after 1st relapse, ranked according to frequency. Frequency RFS after 1st relapse OS after 1st relapse Hazard ratio CI P Hazard ratio CI P FLT3/ITD 17.8% 1.2 0.6–2.3 0.586 1.4 0.9–2.4 0.153 WT1 mutations 10.2% 5.0 2.0–12.4 0.001 2.0 0.9–4.1 0.077 WT1 SNV 10.2% 2.0 1.1–3.8 0.025 1.0 0.6–1.7 0.989 KIT 9.0% 0.5 0.2–1.3 0.137 0.6 0.3–1.1 0.114 KRAS 7.5% 1.6 0.8–3.3 0.176 0.8 0.4–1.5 0.422 NRAS c12/13 6.4% 0.6 0.2–1.9 0.376 1.2 0.6–2.2 0.658 NPM1 5.7% 0.2 0.1–1.7 0.156 0.7 0.3–1.8 0.519 NRAS c61 1.9% 0.1 0.0–397 0.511 2.5 0.9–6.8 0.072 ITD = internal tandem duplication, SNV = single nucleotide variant, c = codon, CI = 95% confidence interval Disclosures: No relevant conflicts of interest to declare.

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Hematopoietic Stem Cell Transplantation (HSCT) Benefits the Survival of Acute Myeloid Leukemia (AML) Patients with IDH1, NRAS and DNMT3A Mutations

Blood ◽

10.1182/blood.v120.21.1981.1981 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1981-1981

Author(s):

Yang Xu ◽

Zhen Yang ◽

Hong Tian ◽

Huiying Qiu ◽

Aining Sun ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Gene Mutations ◽

Newly Diagnosed ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Abstract 1981 Background: Gene mutations may serve as potential markers to extend the prognostic parameters in acute myeloid leukemia (AML) patients. In this study, we detected distribution of mutations in the nucleophosmin gene (NPM1), C-KIT, the fms-related tyrosine kinase 3 gene (FLT3), Isocitrate dehydrogenase gene 1 and 2 (IDH1, IDH2), the neuroblastoma RAS viral oncogene homolog (NRAS) and DNA methyltransferase 3A gene (DNMT3A) in 442 newly diagnosed AML patients (none-APL). Associations of gene mutations with clinical outcomes in these patients followed HSCT treatment or chemotherapy were further evaluated. Methods: Between February 2005 and December 2011, 442 newly diagnosed AML (none-APL) patients in our centre were retrospectively analyzed. There are 248 males and 194 females, and the median ages were 40 (16–60) years. 393 patients (88.9%) of patients were with single or normal karyotype and 49 patients (11.1%) were with complex abnormal karyotype. In addition to MICM examination, direct sequencing was employed to access the distribution of mutations in of FLT3-ITD (exon14), FLT3-TKD (exon 20), NPM1 (exon12), C-KIT (exon8, 17), IDH2 (exon 4), NRAS (exon1, 2), DNMT3A (exon23) of 445 AML patients. Complete remission (CR) was achieved in 258 patients (58.4%) followed the standard induction therapy, 128 patients received HSCT (Allo-HSCT: 121 vs. Auto-HSCT: 7) therapy after first remission or second remission while 258 patients received consolidation chemotherapy contained 4–6 cycles high dose Ara-C (HD-Ara-C). Overall survival (OS) and Event-free survival (EFS) were measured at last follow-up (censored), and Kaplan-Meier analysis was used to calculate the distribution of OS and EFS. Results: In 442 AML (None-APL) patients, 44 patients (9.7%) had C-KIT mutations, 97 patients (21.9%) had NPM1 mutations, 95 patients (21.5%) had FLT3-ITD mutations, 26 patients (5.9%) had FLT3-TKD mutations, 23 patients (5.2%) had IDH1 mutations, 48 patients (10.9%) had IDH2 mutations, 31 patients (7.0%) had DNMT3A mutations, and 40 patients (9.0%) had NRAS mutations. Using COX regression, we found that mutations in FLT3-ITD (HR:2.113; 95%CI: 1.1420 to 3.144),IDH1 (HR:3.023; 95%CI: 1.055 to 3.879), NRAS (HR:1.881; 95%CI: 1.021 to 2.945), and DNMT3A (HR: 2.394; 95%CI: 1.328 to 4.315) were independent unfavorable prognostic indicators of overall survival of AML patients. We further compared the outcomes of AML patients with such gene mutations followed different therapy (HSCT vs. HD Ara-C), and results shown that patients with mutations in IDH1, NRAS and DNMT3A received HSCT therapy had better survival. The median OS and EFS of patients with FLT3-ITD, IDH1, NRAS and DNMT3A in the two groups (HSCT vs. HD Ara-C) were as follows: IDH1 (OS: 35 months vs. 11 months, p=0.016; EFS: 34 months vs. 8 months, p=0.012), NRAS (OS: 27months vs. 8 months, p=0.008; EFS: 23 months vs. 4 months, p=0.049), DNMT3A (OS: 66 months vs. 19 months, p=0.008; EFS: 54 months vs. 13 months, p=0.002). Conclusions: Taken together, our data proved that mutant FLT3-ITD, IDH1, NRAS, and DNMT3A might serve as poor prognostic markers and hematopoietic stem cell transplantation as first-line treatment could favor the outcome of AML patients carrying IDH1, NRAS, and DNMT3A mutations. Disclosures: No relevant conflicts of interest to declare.

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Analysis of 12 Genes in 268 Cases with CMML Identifies ASXL1 Mutations As the Most Important Genetic Alteration Associated with Adverse Outcome

Blood ◽

10.1182/blood.v120.21.3491.3491 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3491-3491

Author(s):

Susanne Schnittger ◽

Manja Meggendorfer ◽

Vera Grossmann ◽

Tamara Alpermann ◽

Christiane Eder ◽

...

Keyword(s):

Overall Survival ◽

Adverse Outcome ◽

Multivariable Analysis ◽

Melting Curve ◽

Gene Mutations ◽

Prognostic Impact ◽

Mutant Genotype ◽

Cox Regression Analysis ◽

Significant Difference ◽

Equity Ownership

Abstract Abstract 3491 Introduction: Chronic myeloid monocytic leukemia (CMML) has been associated with a high number of somatic mutations in diverse genes and various mutant genotype combinations were observed. The patterns of marker combinations and prognostic impact of single markers are poorly understood. Aims: Comprehensive analysis of the genetic marker profile in a large CMML cohort and evaluation of potential prognostic implications. Patients and Methods: In total, 268 cases with CMML (CMML-1 n=191, CMML-2 n=77) were included. The cohort comprised 186 males and 82 females with a median age of 73.0 yrs (range: 21.9 – 93.3 yrs). In 262 cases cytogenetic data was available: 185 cases (70.6%) had a normal karyotype and 77 (29.4%) showed aberrant karyotypes. Data on mutations were available in all patients for SRSF2, U2AF1, JAK2 V617F, and in subcohorts for: ASXL1 (n=255), CBL (n=267), EZH2 (n=205), KIT D816 (n=263), KRAS (n=260), NRAS (n=266), RUNX1 (n=267), SF3B1 (n=240), and TET2 (n=157). Mutations were analyzed by a combination of amplicon deep-sequencing (Roche 454, Branford, CT), direct Sanger sequencing, real time PCR or melting curve analyses. Analysis for overall survival was restricted to 185 cases with evaluable clinical data (median follow-up: 427 days, median OS: 51%). Results: In total 633 mutations were detected in 268 patients (median: 2 per patient, range 0–7). In CMML-1 the mean number of mutations was equal to CMML-2 (2.38 vs. 2.55, p=n.s.). In detail, the most frequent mutations were detected in TET2 (61.1%; 96/157), followed by SRSF2 (47.8%; 128/268), ASXL1 (44.7%; 144/255), RUNX1 (22.8%; 61/267), CBL (19.1%; 51/267), NRAS (15.4%; 41/266), KRAS (10.8%; 28/260), EZH2 (9.3%; 19/205), JAK2 (6.7%; 18/268), U2AF1 (5.2%; 14/268), SF3B1 (5.0%; 12/240), and KIT (4.2%; 11/263). Impact on survival was tested for all 12 gene mutations. A significant difference in overall survival (OS) was observed only for ASXL1 mut vs ASXL1 wt patients (median OS: 19.4 months vs not reached; p=0.003). None of the other gene mutations showed a significant impact on OS. In a next step mutations from the RAS pathway (NRAS, KRAS, CBL) were combined into one group (n=85) and were analyzed in comparison to all others (n=90). However, no impact on OS was detected. Next, patients with at least one mutation in a gene from the splicing machinery (U2AF1, SRSF2, SF3B1) (n=109) were combined and tested vs all other patients (n=57), however, no prognostic relevance was found. In addition, no difference in outcome was observed between CMML-1 and CMML-2 patients. Of note, the adverse impact of ASXL1 mut was restricted to the CMML-2 subcohort (25 mut, 31 wt, median OS: 17.3 months vs n.r.; p=0.001), whereas there was no effect in CMML-1 pts (59 mut and 54 wt). We also evaluated the cytogenetic risk score introduced by Such et al. (Haematologica 2011) and were not able to find differences in survival (neither pairwise between the respective subgroups, nor overall). However, we were able to show prognostic impact of ASXL1 mut within the cytogenetic risk groups suggested by Such: within the favorable subgroup ASXL1 mut patients (n=56) had worse outcome than ASXL1 wt (n=65) (median 19.4 months vs n.r.; p=0.027). This was true also for the adverse subgroup showing a trend to worse outcome for ASXL1 mut vs ASXL1 wt (n=16 vs n=9; median 17.3 months vs n.r.; p=0.057). No difference was seen between the 9 ASXL1 mut and 8 ASXL1 wt patients within the intermediate risk group. In the univariable cox regression analysis taking age, gender, type dysplastic vs proliferative, CMML-1 vs CMML-2, WBC, hemoglobin (Hb), Such score and ASXL1 mut into account, the following parameters were found to be relevant for outcome: age (p=0.001, HR 1.74 per decade), WBC (p=0.044, HR 1.08 per 10×109/L), Hb (p<0.001, HR 0.70, ASXL1 mut (p=0.004, HR 2.38). These parameters entered the multivariable analysis and age (p=0.005, HR: 1.61 per 10 yrs of increase), Hb (p<0.001 HR 0.704) and mutated ASXL1 status (p=0.009, HR 2.30) were independent prognostic parameters for OS. Conclusion: 1) CMML-1 as well as CMML-2 are genetically complex diseases each showing a high number of mutations. 2) One of the most frequently mutated genes in both subgroups is ASXL1. 3) ASXL1 is the only one out of 12 genes which is independently associated with adverse outcome. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

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Mutations Of Genes Regulating DNA Methylation Are Common In MLL Partial Tandem Duplication AML and DNMT3A Mutations Are Associated With Adverse Outcome

Blood ◽

10.1182/blood.v122.21.1407.1407 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1407-1407

Author(s):

Hsiao-Wen Kao ◽

Lee-Yung Shih ◽

Ming-Chung Kuo ◽

Tung-Liang Lin ◽

Sung-Tzu Liang ◽

...

Keyword(s):

Dna Methylation ◽

Overall Survival ◽

Tandem Duplication ◽

Conflicts Of Interest ◽

Direct Sequencing ◽

Gene Mutations ◽

Genetic Alterations ◽

Older Age ◽

Partial Tandem Duplication ◽

Pcr Assays

Abstract Background and purpose Abnormalities of genes regulating DNA methylation have been described in acute myeloid leukemia (AML). MLL protein is a transcriptional regulator and governs proper hematopoiesis through its histone methyltransferase activity. AML with partial tandem duplication of MLL (MLL-PTD) was associated with an unfavorable prognosis. The cooperating roles of MLL-PTD with other mutated genes regulating DNA methylation have not been comprehensively studied in AML. We aimed to determine the prevalence and clinical impact of mutations of DNA methylation regulators in AML with MLL-PTD. Materials and methods Bone marrow samples from 98 AML patients with MLL-PTD were analyzed for gene mutations of TET2, DNMT3A, IDH1 and IDH2. MLL-PTD was screened by RT-PCR and confirmed by real-time quantitative PCR assays. The mutational analysis was performed with PCR assays followed by direct sequencing for TET2 (whole coding exons 3–11) and IDH1/2 (hotspots exon 4). For the detection of DNMT3A mutations, the PCR products amplified for entire coding exons 2 to 23 were first screened with denaturing high-performance liquid chromatography followed by direct sequencing for the abnormal profiles. Results The frequency of TET2, IDH1, IDH2 and DNMT3A mutations in AML patients with MLL-PTD was 17.0% (16/94), 10.2% (10/98), 18.4% (18/98), and 31.6% (31/98), respectively. Taken together, 61.1% of patients with MLL-PTD had at least one mutated gene of DNA methylation regulators. TET2, IDH1 and IDH2 mutations were mutually exclusive with each other whereas DNMT3A mutations frequently co-existed with other DNA methylation modifiers:TET2 (n=8), IDH1 (n=5) and IDH2 (n=4). No differences were observed between the mutation status of the DNA methylation modifiers and clinico-hematologic features of patients with MLL-PTD except that TET2 (P=0.012) and DNMT3A (P=0.024) mutations were associated with older age. Of the 55 MLL-PTD patients who received standard chemotherapy, IDH2 mutation was associated with a lower complete remission rate (25.0% vs 67.8%, P=0.018), while DNMT3A mutations conferred an inferior event-free survival (0.0 vs 6.8 months, P=0.027) and overall survival (6.0 vs 11.5 months, P=0.032). In multivariate analysis, older age (P=0.008) and DNMT3A mutations (P=0.049) were independent adverse factors for overall survival. The crosstalk between MLL-PTD and genes involving DNA methylation in the leukemogenesis of AML warrants further investigation. Conclusions Gene mutations involving DNA methylation frequently co-existed in AML patients with MLL-PTD, especially DNMT3A mutations which conferred a poor outcome. Our study demonstrated the importance of genetic alterations involving DNA methylation in the pathogenesis of MLL-PTD AML and provided potential epigenetic-targeted therapy. Grant support The work was supported by NHRI-EX93-9011SL, NSC95-2314-B-195-001, NSC96-2314-B-195-006-MY3, NSC97-2314-B-182-011-MY3 and MMH-E-101-09. Disclosures: No relevant conflicts of interest to declare.

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ΝFΚΒΙΕ Deletions: A Novel Marker of Clinical Aggressiveness in Primary Mediastinal B-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.609.609 ◽

2016 ◽

Vol 128 (22) ◽

pp. 609-609

Author(s):

Daniel Noerenberg* ◽

Larry Mansouri* ◽

Emma Young ◽

Frick Mareike ◽

Maysaa Abdulla ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

High Frequency ◽

Research Funding ◽

Cell Lymphoma ◽

Gene Mutations ◽

B Cell Lymphoma ◽

Mutation Status ◽

Lymphoid Malignancies ◽

Ann Arbor

Abstract Deregulated NF-κB signaling is a hallmark of most, if not all, lymphoid malignancies, and recurrent gene mutations in both the canonical and non-canonical NF-κB pathway are known to lead to NF-κB activation. However, the full compendium of NF-κB gene mutations in lymphoid malignancies remains to be elucidated. Recently, we reported a 4-bp truncating mutation in the NFKBIE gene, which encodes IκBε, a negative regulator of NF-κB, in patients with chronic lymphocytic leukemia (CLL). The NFKBIE deletion was enriched in clinically aggressive CLL patients (7-8%) and associated with a worse clinical outcome. At the functional level, NFKBIE-deleted CLL showed reduced IκBε levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65, compared to wildtype patients. Preliminary data has indicated an increased frequency of NFKBIE aberrations in other lymphoid malignancies as well. To explore this further, we screened for NFKBIE deletions in a large cohort of patients diagnosed with a range of different lymphoid neoplasms. Overall, NFKBIE deletions were identified in 76 of 1414 patients (5.4%). While NFKBIE deletions were relatively infrequent in patients diagnosed with follicular lymphoma (3/225, 1.3%), splenic marginal zone lymphoma (3/175, 1.7%), and T-cell acute lymphoblastic leukemia (1/94, 1.1%), moderate frequencies were observed among diffuse large B-cell lymphoma (18/521, 3.5%), mantle cell lymphoma (8/189, 4.2%), and primary CNS lymphoma (1/34, 2.9%) patients. In contrast, a remarkably high frequency of NFKBIE deletions (41/176 cases, 23%) was observed among primary mediastinal B-cell lymphoma (PMBL) patients. Noteworthy, the prevalence of NFKBIE-deleted PMBL cases was similar in the different contributing centers. All PMBL patients in the present series received a CHOP based treatment regime; in ~75% of cases rituximab was added and ~25% were treated with dose intensified schemes. For the latter, the vast majority of patients received CHOEP, while individual cases were treated with MegaCHOEP, DA-EPOCH or ACVBP. Regarding clinicobiological associations, there were no significant differences between NFKBIE-deleted and wildtype PMBL patients with respect to age, sex, Ann Arbor stage, IPI risk-groups, extranodal or bone marrow involvement, bulky disease, and LDH elevation. However, NFKBIE-deleted patients were more likely to be refractory to primary chemotherapy (31% vs. 3%, P=.001) and had a shorter overall survival compared to wildtype patients (5-year overall survival: 63% vs 84%, P=.013). In multivariate analysis (including age, gender, Ann Arbor stage, IPI, and NFKBIE mutation status), NFKBIE mutation status (95% CI: 1.23-10.61; HR: 3.61; P=0.020) remained an independent factor for poor prognosis. In summary, we document NFKBIE deletions as a common genetic event across B-cell malignancies, albeit at varying frequencies. The high frequency of NFKBIE deletions in PMBL alludes to the critical role of this aberration in the pathophysiology of the disease. NFKBIE deletions were associated witha worse clinical outcome, hence potentially representing a novel poor-prognostic marker in PMBL. *Contributed equally as first authors. **Contributed equally as senior authors. Disclosures Stamatopoulos: Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding.

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Searching for CDH1 gene mutations in early-onset diffuse gastric cancer in Chinese patients.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.23 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 23-23

Author(s):

Xu Yanjun ◽

Cao Wenming ◽

Xu Qi ◽

Guo Jianmin ◽

Wang Xinbao ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Lymph Node ◽

Gene Mutations ◽

Germline Mutations ◽

Chinese Patients ◽

Diffuse Gastric Cancer ◽

Cdh1 Gene ◽

Node Metastasis ◽

Cdh1 Mutation

23 Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T>C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G>C, p.Glu218Asp; Two in exon 12: c.2012C>G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P < 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P < 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P < 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.

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Association of CDH1 mutation with prognosis in gastric adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15514 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15514-e15514

Author(s):

Xiangyang Yu ◽

Shimin Yang ◽

Rong Du ◽

Jingbo Zhang ◽

Nan Fang ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Stomach Cancer ◽

Gastric Adenocarcinoma ◽

Tumor Metastasis ◽

Gene Mutations ◽

Predictive Marker ◽

Synonymous Mutations ◽

Cdh1 Mutation ◽

Gastric Cancer Patients

e15514 Background: Stomach cancer is a major cause of cancer death in East Asia. The purpose of this study was to find a predictive marker to estimate the prognosis of stomach cancer. Methods: In this study, a total of 34 gastric cancer patients receiving therapy in Tianjin Nankai Hospital were enrolled. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue sections, including carcinoma and pericarcinous tissues. Targeted regions of 549 cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina Next-Seq 500 platform. Results: 25/34 patients had tumor metastasis. 135 non-silent mutations in 62 genes were detected in 27 tumor samples, while 7 patients’ samples had no mutation detected. CDH1, BRCA2 and SMAD4 gene mutations only occurred among metastasis patients. CDH1, BRCA2 and KRAS gene mutations are associated with a lower overall survival rate. Among them, 5 patients had a CDH1 mutation, including one splicing mutation, three frameshift mutations, one non-frameshift mutation and two non-synonymous mutations. All five patients had tumor metastasis, with the survival time less than 17 months, compared with all patients’ average overall survival of 22 month. Conclusions: Previous studies showed that mutation in CDH1 is linked to gastric cancer (GC) susceptibility and tumor invasion. Our results indicated that the mutation of CDH1 was also associated with the prognosis of gastric adenocarcinoma (P < .01) and was an independent factor (P < .05).

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