Jack Baty

Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome

BACKGROUND The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known. METHODS We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome. RESULTS We identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis. CONCLUSIONS By comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.

DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient’s skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.

Recurrent DNMT3A mutations in patients with myelodysplastic syndromes

Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.

Incidence and Cost of New Onset Diabetes Mellitus Among U.S. Wait-Listed and Transplanted Renal Allograft Recipients

This study sought to determine 1) the incidence and costs of new onset diabetes mellitus (NODM) associated with maintenance immunosuppression regimens following renal transplantation and 2) whether the mode of dialysis pretransplant or the type of calcineurin inhibition used for maintenance immunosuppression affected either the incidence or cost of NODM. The study examined the United States Renal Data Systems clinical and financial records from 1994 to 1998 of all adult, first, single‐organ, renal transplantations in either 1996 or 1997 with adequate financial records. It used the second diagnosis of diabetes in previously nondiabetic patients to identify NODM. While NODM had an incidence of approximately 6% per year among wait‐listed dialysis patients, NODM over the first 2 years post‐transplant had an incidence of almost 18% and 30% among patients receiving cyclosporine and tacrolimus, respectively. By 2 years post‐transplant, Medicare paid an extra

Early Predictors of 15-Year End-Stage Renal Disease in Hypertensive Patients

21 500 per newly diabetic patient. We estimated the cost of diabetes attributable to maintenance immunosuppression regimens to be

RECURRENT MUTATIONS IN THE U2AF1 SPLICING FACTOR IN MYELODYSPLASTIC SYNDROMES

2025 and

Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia

3308 for each tacrolimus patient and

Acquired copy number alterations in adult acute myeloid leukemia genomes

1137 and

The value of informant versus individual’s complaints of memory impairment in early dementia

1611 for each cyclosporine patient at 1 and 2 years post‐transplant, respectively.

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

There has been a continuing increase in the incidence of end-stage renal disease (ESRD) in the United States, including the fraction that has been attributed to hypertension. This study was done to seek relationships between ESRD and pretreatment clinical data and between ESRD and early treated blood pressure data in a population of hypertensive veterans. We identified a total of 5730 black and 6182 nonblack male veterans as hypertensive from 1974 through 1976 in 32 Veterans Administration Hypertension Screening and Treatment Program clinics. Their mean age was 52.5 +/- 10.2 years, and their mean pretreatment blood pressure was 154.3 +/- 19.0/100.8 +/- 9.8 mm Hg. During a minimum of 13.9 years of follow-up, 5337 (44.8%) of these patients died and 245 developed ESRD. For 1055 of these subjects, pretreatment systolic blood pressure (SBP) was greater than 180 mm Hg; 901 were diabetic; 1471 had a history of urinary tract problems; and 2358 of the 9644 who were treated had an early fall in SBP of more than 20 mm Hg. We used proportional hazards modeling to fit multivariate survival models to determine the effect of the available pretreatment data and early treated blood pressure levels on ESRD. This model demonstrated the independent increased risk of ESRD associated with being black or diabetic (risk ratio, 2.2 or 1.8), having a history of urinary tract problems (risk ratio, 2.2), or having high pretreatment SBP (for SBP 165 to 180 mm Hg, risk ratio was 2.8; for SBP > 180 mm Hg, risk ratio was 7.6).(ABSTRACT TRUNCATED AT 250 WORDS)