10 research outputs found
Caractérisation des sables et morphologie du fond du lac du barrage hydroélectrique de Taabo (Côte d\'Ivoire)
Une analyse sédimentologique et minéralogique réalisée sur un cycle hydrologique entre octobre 2004 et août 2005 a permis d\'évaluer les charges solides en suspension et de caractériser les sédiments du lac du barrage de Taabo.
La concentration moyenne en matières en suspension (12 mg.L-1) et la turbidité moyenne (20 NTU) montrent que les eaux du lac sont relativement peu chargées. Ces charges en suspension sont composées d\'une fraction inorganique et d\'une fraction organique.
Les sables qui composent les sédiments de ce lac sont majoritairement moyens à grossiers et médiocrement classés avec une moyenne granulométrique de 451,48 μm et un indice de classement moyen de 1,13. Les vases et les sables fins occupent les zones profondes du lac et les zones envahies par les végétaux aquatiques. Les sables moyens sont localisés aux voisinages des berges tandis que les sables grossiers sont situés aux voisinages des îles et de la digue. Le cortège minéralogique des sédiments est caractérisé de minéraux lourds (l\'amphibole, la tourmaline, le diopside et l\'épidote) et de minéraux légers (le quartz et les feldspaths). Par ailleurs, cette étude a permis de réaliser la première carte bathymétrique du lac de Taabo 26 ans après sa mise en eau.A sedimentological and mineralogical study carried out on a hydrological cycle from October 2004 to August 2005 has permitted to assess the solid suspended matters and to characterize the sediments of the Taabo dam lake. The average of suspended matters concentration (12 mg.L -1) and the average of turbidity (20 NTU) reveal that the lake is relatively little loaded with suspended matters. These suspended matters are compound of an inorganic fraction and an organic fraction. Sands size in the sediments of this lake are from middle to coarse and badly classified. The grain size average is 451,48 μm; the standard deviation average is 1,13. Muds and fine sands are found in the deeper zones of the lake and also in
the zones invaded by the aquatic plants. Middle sands are located near banks while coarse sands are located aside the islands and the dam. The minerals found in the sediments are characterized by heavy minerals (the amphibole, tourmaline, diopside and epidote) and light minerals (quartz and feldspars). Elsewhere, this study has permitted to carry out the first bathymetric Map of this lake 26 years after its setting in water. Keywords: keywordBarrage, lac, granulométrie, minéralogie, bathymétrie, Taabo./Dam, lake, grain size, mineralogy, bathymetry, Taabo.Sciences & Nature Vol. 4 (1) 2007: pp. 93-10
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Phenotype/Genotype Associations in TET2-Driven Myeloid Neoplasms
Abstract
TET2 is one of the most commonly mutated genes in myeloid neoplasia. The frequency of TET2 mutations (TET2MUT) increases with age and they have been found in aging healthy controls, in whom their presence was associated with a subsequent risk of developing a myeloid neoplasm. The TET2 gene product is an enzyme that uses alpha-ketoglutarate (αKG) and vitamin C to hydroxylate 5-methylcytosine (5MC), leading to both passive demethylation during cell replication and active demethylation via base excision DNA repair enzymes.
Despite large studies, there is no consensus opinion as to the clinical impact of TET2 mutations and their mechanistic role in the pathogenesis of MDS. It is likely that the heterogeneity of TET2MUT, their configuration, sub-clonal context and co-associated variables result in biological heterogeneity that precludes proper assessment of clinical impact. To address these issues we analyzed a cohort of 4974 patients with myeloid neoplasms using targeted deep sequencing of a panel of 60 genes found to be most frequently affected by somatic mutations in myeloid neoplasms. A total of 1861 TET2 alterations were identified as somatic in 1238 cases using various bioanalytic algorithms and sequencing of germline DNA where possible. Of these mutations, 80% were frame shift/stop codons (fs/sc) likely leading to various truncations, while 20% were missense (ms) mutations. While no hotspots for mutations were found, 53% were located in the proximity of the catalytic domain. The most recurrent ms alteration was p.Ile1873Thr, found in 2% of all TET2MUT cases. Biallelic TE2MUT were present in 45% of mutant cases; of which fs/sc alteration combinations were the most common (333/557; 60%), and an additional 9% were homozygous fs/sc variants. Biallelic ms mutations were present in 5% of biallelic cases (3% of homozygous ms configurations). Clinically, TET2MUT were found in 17% of MDS patients, 65% of MDS/MPN, 12% of MPN, 21% of non-core binding factor pAML, and 26% of sAML, and were most frequently associated with normal cytogenetics (p<.001) and correlated with increased age (p=.001). Biallelic fs/sc TET2MUT were most common in MDS/MPN (34%).
TET2MUT tend to display a higher number of additional mutations than TETWT (p<.001) cases, a trend that was also present comparing ancestral to secondary TET2MUT carriers. In general, TET2MUT were more associated with ASXL1 (p<.001), NPM1 (p<.001), and SRSF2 (p<.001) than were WT cases, whereas ETV6 (p<.001), IDH2 (p<.001), and TP53 (p<.001) were more common in TET2WT cases. A TET2MUT was most commonly associated with another TET2 alteration in 37% of MDS cases, followed by ASXL1 (17%), SF3B1 (13%) and SRSF2 (13%) mutations; in 54% of MDS/MPN cases, followed by SRSF2 (33%), ASXL1 (27%), and RUNX1 (13%) mutations); and in 40% of sAML, followed by ASXL1 (35%), RUNX1 (27%), and SRSF2 (22%) mutations. In contrast, in MPN, JAK2 (39%), TET2 (21%), and ASXL1 (16%) were the most common co-occurring mutations, and in pAML, NPM1 (71%), DNMT3A (48%), and TET2 (44%) co-occurred most commonly.
Analysis of clonal architecture including co-associated events revealed that 40% of TET2MUT were dominant/possibly ancestral within the clonal hierarchy. In cases with a dominant TET2MUT, the most commonly associated somatic events involved TET2 (18%), followed by SRSF2 (8%), ASXL1 (7%) and DNMT3A (6%). In those cases (26%) in which TET2 was not the dominant clone, SRSF2 (11%), ASXL1 (10%), DNMT3A (9%), and EZH2 (9%) were the most common early events. In 33% of TET2MUTcases, the TET2MUTclones were co-dominant with another TET2 (29%), SRSF2 (15%), DNMT3A (11%), or ASXL1 (9%).
TET2MUT confers worse survival than WT cases (p<.001) in the population studied. No survival difference was seen between dominant and secondary TET2 mutations in total and within sub entities. Patients with multiple/homozygous TET2 mutations tend to have a worse prognosis than those with monoallelic TET2MUT (p=.056). In MDS, MPN and MPN/MDS, patients with fs/sc mutations had worse survival than those with ms mutations (p=.05).
Our analyses demonstrate that TET2 lesions are strongly selected for in myeloid neoplasia and a gene dose effect may dictate biological and molecular features. While ancestral TET2 ancestral events do not determine the subsequent phenotype, subtypes of myeloid neoplasms appear to be associated with specific sets of secondary or tertiary sub-clonal events.
Disclosures
Nadarajah: MLL Munich Leukemia Laboratory: Employment. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment
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Pathogenic Relevance of Germ Line TET2 Alterations
Abstract
Several familial mutations predisposing to the development of leukemia have been identified, mostly in association with childhood or adolescent presentations of myeloid neoplasms or bone marrow failure states. However, many of these genetic syndromes have variable penetrance and latency. Thus, late presentations of familial diseases are possible as with DDX41 mutations associated with adult myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growing evidence exists to support the notion that germ line (GL) alterations may play a greater than previously known role in otherwise typical spontaneous adult myeloid neoplasms. These alterations may include known predisposition leukemia genes (i.e.,. ETV6, RUNX1, CEBPa, and DDX41), heterozygous alterations known to generate recessive disorders, or new unidentified genes. The search for such predisposition genes is difficult but we hypothesized that genes frequently damaged by somatic mutations may also be affected by GL alterations, a similar principle as seen for CEBPa or TP53. Further, that a collection of rare variants (MAF<1%) within a gene could be associated with risk of MDS according to the allelic burden (AB) theory. To develop proof-of-principle of this theory we focused on the gene TET2. In comparisons of the AB of rare TET2 GL variants of patients vs. ethnically-matched controls (selected according to ethnic indicator SNPs), MDS patients examined by whole exome sequencing (WES, N=368) had more rare coding-sequence variants than controls (p<.001). On average, patients had 3 TET2 rare variants, while controls had only 1.5 variants. This suggests that the burden of TET2 rare variants could increase risks of myeloid neoplasms. This finding is in agreement with several other observations; 1.) TET2 is frequently mutated and extremely polymorphic; 2.) it is often associated with biallelic mutations, of which some may be a combination of GL and somatic lesions; and 3.) GL alterations in TET2 may predispose to acquisition of additional lesions.
We analyzed a cohort of 4159 patients with myeloid neoplasms using WES and targeted deep next generation sequencing (NGS). Extensive scoring algorithms, along with mutational databases were used to detect GL variants. Serial tumor samples were examined to discriminate GL from somatic defects. We identified 2518 TET2 SNPs in 1475 patients. Multiple SNPs were seen in the same patient, 28% of patients had 2 SNPs, 11% had 3 and 6% had 4 or more SNPs. Of those 52% were found in proximity to the catalytic domain, and 10% were homozygous. TET2 SNPs irrespective of their population frequency were found in 21% of MDS, 27% of MDS/MPN, 31% of MPN, and 33% of AML patients.
We focused our analysis on the top 10 canonical SNPs with the highest odds ratio (OR) when comparing frequencies in our population to that of healthy controls derived from the ExAC base of 60,000 individuals. The SNPs with the highest OR was present in 2% of patients (p.Val1718Leu) vs. 0.5% of controls. Combinations of SNPs (biallelic configuration) were then investigated; SNPs p.Leu1721Trp and p.Pro363Leu co-occurred in 8% of patients, and p.Val218Met, p.Leu34Phe and p.His1778Arg co-occurred in 3%. We also queried whether GL TET2 SNPs create a haplotype (i.e., increased the risk for acquisition of somatic TET2 mutations) or are mutually exclusive. Overall, 32% of cases with any TET2 SNP also acquired a TET2 somatic mutation vs the WT form for these (68%). Conversely, among the somatic mutant carriers, for example SNP p.Met1701Ile, SNP p.Tyr864His and SNP p.Gly355Asp had an OR vs. controls of 1.1. In particular, 55% of all TET2 mutants had SNP p.Leu1721Trp in a biallelic fashion vs. 46% of somatic WT cases. This suggests a predisposition haplotype. We also examined the relationship between unrelated somatic mutations and "top OR" TET2 SNPs. No correlation was seen between SNPs and other somatic mutations.
In sum, several GL TET2 variants or their combination may constitute complex, likely low penetrance predisposing factors for myeloid neoplasm that also interact with somatic lesions and lead to cancer decades later.
Disclosures
Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Maciejewski:Celgene: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau
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TET 2 Alterations in Myeloid Malignancies, Impact on Clinical Characteristics, Outcome, and Disease Predisposition
Abstract
TET2 mutations are the most common somatic genetic lesions in myeloid neoplasms. TET2 mutant clones have been found also in healthy individuals, increase with age, and convey an increased risk for myeloid clonal diseases. The TET2 gene is very polymorphic, with hundreds of single nucleotide polymorphisms (SNPs) of unknown clinical impact, but with some variants that may be pathogenically important. Similarly, somatic mutations affect all portions of the gene, and can be missense or truncating, homo-, hemi- and heterozygous. While the majority of TET2 mutations are ancestral, they can also be subclonal, implicating the clonal architecture in the consequences of TET2 lesions. This diversity may be hampering establishment of the clear prognostic impact of TET2 mutations.
Taking advantage of a large cohort of patients (pts, N=4985 including 1616 MDS, 871 MDS/MPN, 1782 pAML, 304 sAML, 333 MPN, and 79 therapy-related MDS/AML/MDS-MPN) analyzed by targeted deep sequencing for TET2 and other common myeloid lesions, we examined the distribution and impact of TET2 mutations. DNA sequencing of all coding exons of TET2 and 61 other genes representing the most common somatic mutations in myeloid neoplasms. Nonsynonymous alterations not present in SNP database (dbSNP) were annotated as somatic mutations or SNPs if present in myeloid and T cells whenever available. Nonsynonymous alterations not in dbSNP or ExAC databases and not confirmed to be somatic were excluded. Overall, TET2 somatic mutations (TET2mut) were present in 920 pts (18%); 38% of MDS/MPN, 19% pAML, 16% MPN, 16% sAML, 12% MDS, and 13% of therapy related MDS/AML/MDS-MPN. Mutations included 16% missense, 33% frameshift deletions, 18% frameshift insertions, and 33% nonsense. TET2mut pts were older than those with TET2 wild type (TET2wt, 72 vs. 67 yrs, p<.001), had a higher presenting WBC (6 vs. 4 x103 /uL, p <.001), and lower blast % (3 vs. 7%, p =.03). Similar findings were observed in each myeloid subtype. Overall, median OS for TET2mut pts was similar to TET2wt (12 vs. 17 mo, p =.20). Median OS was similar in TET2mut pts compared to TET2wt in pts with MDS (23 vs. 23 mo, p =.77), MDS/MPN (15 vs. 21 mo, p=.1), pAML (9 vs. 14 mo, p =.77), sAML (6 vs. 9 mo, p =.07), and MPN (30 vs. 35 mo, p =.66). Neither the type of mutation (mis-, nonsense vs. truncating) nor location (catalytic domain vs. other) impacted the OS. Using variant allelic frequencies (VAF), we established a clonal hierarchy in individual cases; 24% of TET2 mutations were ancestral, 17% subclonal, and 59% codominant. TET2 mutations were ancestral in 23% of MDS samples, 29% of MDS/MPN, 25% of pAML, and 19% of sAML. Whether the mutation was ancestral or subclonal did not impact OS. The presence of TET2mut was associated with different mutations in each myeloid subtype. In MDS, TET2mut were associated with APC (p<.001), ASXL1 (p<.001), BCOR (p<.001), BCORL1 (p<.001), ETV6 (p<.04), SUZ12 (p<.001), RAD21 (p<.02), NF1 (p<.001), KDM6A (p<.001), ZRSR2 (p<.001), and U2AF1 (p=.02), in MDS/MPD correlated with ASXL1 (p<.04), NRAS (p<.02), and SRSF2 (p<.05), in pAML with JAK2 (p<.001), RUNX1 (p =.05), and CBL (p=.05), and in sAML with RUNX1 (p<.001), ASXL1 (p<.001), BCORL1 (p=.01), SUZ12 (p=.02), STAG2 (p=.05), and JAK2 (p<.001).
When we next focused on germ line variants, we identified 2518 SNPs of TET2. All recurring SNPs were ranked according to the difference in their frequencies between pts and healthy controls. A large number of these SNPs were more common in our pts compared to controls, among them we identified 2 SNPs (both located in the dioxygenase domain) with a significantly higher frequency: SNP1 (OR 10.6, p<.0001), and SNP2 (OR 6.7, p=.02). We further investigated whether these SNPs were mutually exclusive or increased the risk for acquisition of somatic TET2 mutations; 91% of cases with SNP1 and 67% with SNP2 also acquired somatic mutations in TET2. In silico and crystallographic analyses showed that SNP1 is adjacent to the iron binding site (7th beta stand in the jelly roll motif) and is predicted to change the orientation of a-KG binding and thereby to be hypomorphic. SNP2 is located in a hot spot area known to be targeted by 3 recurrent somatic mutations.
In conclusion, both somatic mutations as well as germ line variants affect TET2 in myeloid neoplasia. The interaction between clonal mutations and germ line lesions may lead to gain of function and thus a growth advantage. These mechanisms are currently being explored.
Disclosures
Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees
The Impact of Different TP53 Mutations on Outcome in Patients with Myelodysplastic Syndromes (MDS)
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The Complexity of Interpreting Genomic Data in Patients with Primary and Secondary Acute Myeloid Leukemia (AML)
Abstract
Background
Acute myeloid leukemia (AML) is a complex, heterogeneous neoplasm characterized by the accumulation of complex genetic alterations that are responsible for the initiation and progression of the disease. Secondary AML (sAML) represents a progression from antecedent hematologic disorders such as myelodysplastic syndromes (MDS) or myeloprolifrative neoplasms (MPN). Certain acquired mutations have been reported to be specific for sAML when compared to primary AML (pAML), but many limitations exist when cytogenetic grouping or other parameters are taken into account. In addition, some mutations have been shown to impact survival in some studies, but not others.
Methods
We performed targeted deep sequencing on samples from bone marrow and peripheral blood of pts diagnosed with sAML and pAML and treated at our institution between 1/2003-1/2013. Additional data on pAML was added from The Cancer Genome Atlas (TCGA). A panel of 62 gene mutations described as frequently recurrent mutations in myeloid malignancies were assessed. Cytogenetic grouping was defined by CALGB/Alliance criteria. Differences were compared using Fisher's exact test and the Mann-Whitney U test for categorical and continuous variables, respectively. Overall survival (OS) was calculated from the time of diagnosis to last follow up or death.
Results:
A total of 496 pts included: 273 with pAML and 223 with sAML. Comparing pAML to sAML, pts were younger (median age 59 vs. 68 years, p 3 abnormalities) compared to 11% and 16% for pAML (p< .001, .009), respectively. Mutations in ASXL1 (p<.001), JAK2 (p=.014), CBL (p=.05), BCOR (p=.02), STAG2 (p =.003), SF3B1 (p=.04), SRSF2 (p=.001 ), and U2AF1 (p=.03) were highly specific for the sAML phenotype, whereas mutations in NPM1 (p<.001 ), FLT3 (p< .001), DNMT3A (p<.001), and IDH2 (p=.02) were more specific for pAML. When the analysis was restricted to pts with NK cytogenetics, only ASXL1 (p<.001) remained specific for sAML and DNMT3A (p<.001) for pAML.Further, when the analysis was restricted to pts with unfavorable risk cytogenetics, only ASXL1 (p=.01) remained specific for sAML. No other mutations were specific for pAML.
We then evaluated whether the mutations that were specific to each AML phenotype had an impact on OS. We observed different mutations that impacted OS in each phenotype: DNMT3A (HR 1.81, 95% CI 1.28-2.57, p<.001), TP53 (HR 3.1, 95% 1.74-5.53, p< .001), and SUZ12 (HR 3.18, 95% CI 1.01-10, p=.05) led to worse OS in pAML, whereas mutations in EZH2 (HR 2.12, 95% CI 1.07-4.21, p =.03), PRPF8 (HR 2.32, 95% CI 1.20-4.46, p=.01), and TP53 ( HR 2.92, 95% CI 1.69-5.04, p<.001) lead to worse OS in sAML. Different mutations had a different impact on OS when cytogenetic analysis was taken into account. Mutations in FLT3 (HR 2.15, 95% CI 1.37- 3.35, p<.001) and DNMT3A (HR 2.41, 95% CI 1.57-3.70, p<.001) led to worse OS in NK pAML, whereas none of the mutations impacted OS in NK sAML. Further, in pAML with unfavorable cytogenetics, BCOR (HR 2.41, 95% CI 1.57-3.70, p<.001) and TP53 (HR 2.41, 95% CI 1.57-3.70, p<.001) had led to worse OS, whereas BOCR (HR 2.95, 95% CI 1.03-8.50, p<.001), SF3B1 (HR .19, 95% CI .05-.82, p<.001), SUZ12 (HR .12, 95% CI .01-.99, p<.001),and TP53 (HR 1.9, 95% CI 1.09-3.46, p<.001) only impacted OS in sAML.
Conclusion
Clear genomic variations exist between sAML and pAML. Although some of these genomic changes are more specific to each phenotype in general, this specificity and the impact on OS differed for each cytogenetic subgroup, highlighting the complexity of interpreting genomic information in pts with AML and the need to incorporate both cytogenetic and molecular data in prognosis-driven treatment decisions.
Disclosures
Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees
TET 2 Alterations in Myeloid Malignancies, Impact on Clinical Characteristics, Outcome, and Disease Predisposition
The Complexity of Interpreting Genomic Data in Patients with Primary and Secondary Acute Myeloid Leukemia (AML)
Consequences of mutant TET2 on clonality and subclonal hierarchy
Somatic mutations in TET2 are common in myelodysplastic syndromes (MDS), myeloproliferative, and overlap syndromes. TET2 mutant (TET2
) clones are also found in asymptomatic elderly individuals, a condition referred to as clonal hematopoiesis of indeterminate potential (CHIP). In various entities of TET2
neoplasia, we examined the phenotype in relation to the strata of TET2 hits within the clonal hierarchy. Using deep sequencing, 1781 mutations were found in 1205 of 4930 patients; 40% of mutant cases were biallelic. Hierarchical analysis revealed that of TET2
cases >40% were ancestral, e.g., representing 8% of MDS. Higher (earlier) TET2 lesion rank within the clonal hierarchy (greater clonal burden) was associated with impaired survival. Moreover, MDS driven by ancestral TET2
is likely derived from TET2
CHIP with a penetrance of ~1%. Following ancestral TET2 mutations, individual disease course is determined by secondary hits. Using multidimensional analyses, we demonstrate how hits following the TET2 founder defect induces phenotypic shifts toward dysplasia, myeloproliferation, or progression to AML. In summary, TET2
CHIP-derived MDS is a subclass of MDS that is distinct from de novo disease