Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by a deregulation of blood cell formation with cytopenia in varying degrees and frequently ...develop into acute myeloid leukemia (AML). Next generation sequencing (NGS) has significantly contributed to diagnosis and prognostication in patients with MDS. To explore the role of acquired mutations in MDS biology and clinical features, we performed mutational profiling of 111 genes in 125 patients with MDS based on target-sequencing. The results showed that 89% of patients had one or more carcinogenic mutations. Mutation frequencies of several genes, including ASXL1 (16.8%), RUNX1 (14.4%) and TET2 (12%), were above 10% in MDS patients. According to univariate analysis in 108 patients with survival data, mutations of GATA1/2, TP53 and DNMT3A were identified as adverse prognostic factors for overall survival (OS), while RUNX1, KRAS/NRAS, SRSF2 and TET2 mutations were determined as unfavorable factors for progression free survival (PFS). By multivariate COX regression analysis, mutations of KRAS/NRAS, GATA1/2 and DNMT3A were independent risk factors for OS, whereas IDH1/2 gene mutations were favorable factors for PFS. By evaluation of the clinical benefit of hypomethylating agents (HMAs), it showed that for patients harboring mutations associated DNA methylation or not and receiving HMAs treatment or not, the order of the outcome from good to bad was geneWT with non-HMAs, geneWT with HMAs, genemut with HMAs and genemut with non-HMAs. Therefore, target-sequencing of mutational spectrum is a feasible and highly promising prediction method for prognostic evaluation in patients with MDS, which would contribute to personalized therapeutic decisions.
No relevant conflicts of interest to declare.
Of the 1.1 million Alu retroposons in the human genome, about 10,000 are inserted in the 3′ untranslated regions (UTR) of protein-coding genes and 1% of these (107 events) are active as ...polyadenylation sites (PASs). Strikingly, although Alu's in 3′ UTR are indifferently inserted in the forward or reverse direction, 99% of polyadenylation-active Alu sequences are forward oriented. Consensus Alu+ sequences contain sites that can give rise to polyadenylation signals and enhancers through a few point mutations. We found that the strand bias of polyadenylation-active Alu's reflects a radical difference in the fitness of sense and antisense Alu's toward cleavage/polyadenylation activity. In contrast to previous beliefs, Alu inserts do not necessarily represent weak or cryptic PASs; instead, they often constitute the major or the unique PAS in a gene, adding to the growing list of Alu exaptations. Finally, some Alu-borne PASs are intronic and produce truncated transcripts that may impact gene function and/or contribute to gene remodeling.
Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency ...of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next‐generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non‐BRCA1/2 gene. Major mutant non‐BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non‐BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER‐2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non‐BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non‐BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.
What's new?
The prevalence of mutations in breast cancer predisposition genesare not well investigated in Asia. We assessed germline mutations of 40 cancer susceptibility genes in 937 consecutive selected breast cancer patients from 26 centers of China, and discovered 23.8% of participates carried the pathogenic mutation, including 6.8% with mutations in non‐BRCA1/2 genes, while TP53 and PALB2 had a relatively high mutation rates (1.9% and 1.2%).There was no factors predicted for detrimental mutations in non‐BRCA1/2 genes when treated as a whole.
Myelodysplastic syndromes (MDS) are a group of myeloid hematological malignancies, with a high risk of progression to acute myeloid leukemia (AML). To explore the role of acquired mutations in MDS, ...111 MDS-associated genes were screened using next-generation sequencing (NGS), in 125 patients. One or more mutations were detected in 84% of the patients. Some gene mutations are specific for MDS and were associated with disease subtypes, and the patterns of mutational pathways could be associated with progressive MDS. The patterns, frequencies and functional pathways of gene mutations are different, but somehow related, between MDS and AML. Multivariate analysis suggested that patients with ≥ 2 mutations had poor progression-free survival, while
,
and
mutations were associated with poor overall survival. Based on a novel system combining IPSS-R and molecular markers, these MDS patients were further divided into 3 more accurate prognostic subgroups. A panel of 11 target genes was proposed for genetic profiling of MDS. The study offers new insights into the molecular signatures of MDS and the genetic consistency between MDS and AML. Furthermore, results indicate that MDS could be classified by mutation combinations to guide the administration of individualized therapeutic interventions.
Clinical and genetic features incompletely predict outcome in acute myeloid leukemia (AML). The value of clinical methylation assays for prognostic markers has not been extensively explored. We ...assess the prognostic implications of methylC-capture sequencing (MCC-Seq) in patients with de novo AML by integrating DNA methylation and genetic risk stratification. MCC-Seq assessed DNA methylation level in 44 samples. The differentially methylated regions associated with prognostic genetic information were identified. The selected prognostic DNA methylation markers were independently validated in two sets. MCC-Seq exhibited good performance in AML patients. A panel of 12 differentially methylated genes was identified with promoter hyper-differentially methylated regions associated with the outcome. Compared with a low M-value, a high M-value was associated with failure to achieve complete remission (
= 0.024), increased hazard for disease-free survival in the study set (
= 0.039) and poor overall survival in The Cancer Genome Atlas set (
= 0.038). Hematopoietic stem cell transplantation and survival outcomes were not adversely affected by a high M-value (
= 0.271). Our study establishes that MCC-Seq is a stable, reproducible, and cost-effective methylation assay in AML. A 12-gene M-value encompassing epigenetic and genetic prognostic information represented a valid prognostic marker for patients with AML.
Intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML cases, is highly heterogeneous. Although several mutations have been identified, the heterogeneity of ...AML is uncertain because novel mutations have yet to be discovered. Here we applied next generation sequencing (NGS) platform to screen mutational hotspots in 410 genes relevant to hematological malignancy. IR-AML samples (N=95) were sequenced by Illumina Hiseq and mutations in 101 genes were identified. Only seven genes (CEBPA, NPM1, DNMT3A, FLT3-ITD, NRAS, IDH2 and WT1) were mutated in more than 10% of patients. Genetic interaction analysis identified several cooperative and exclusive patterns of overlapping mutations. Mutational analysis indicated some correlation between genotype and phenotype. FLT3-ITD mutations were identified as independent factors of poor prognosis, while CEBPA mutations were independent favorable factors. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was identified with associated with specific clinical AML features and poor outcomes. Furthermore, by integrating multiple mutations in the survival analysis, 95 IR-AML patients could be stratified into three distinct risk groups allowing reductions in IR-AML by one-third. Our study offers deep insights into the molecular pathogenesis and biology of AML and indicated that the prognosis of IR-AML could be further stratified by different mutation combinations which may direct future treatment intervention.
Anaplastic lymphoma kinase (
ALK
) fusion is present in approximately 2–7% of patients with lung adenocarcinoma.
ALK
fusion-positive patients can benefit from targeted therapy. We herein report a ...53-year-old Chinese male patient diagnosed as lung adenocarcinoma with a smoking history. Next-generation sequencing was performed to detect somatic mutations of oncogenic drivers and tumor suppressor genes in plasma-derived circulating tumor DNA using an ultra-deep 160-gene panel. A novel
HPCAL1-ALK
fusion variant was identified in the patient responding to
ALK
inhibitor treatments, and the fusion variant was also confirmed by fluorescence in situ hybridization and immunohistochemical. Our study expands the mutational spectrum of
ALK
fusion variants and provides options for the precise treatment of such patients.
Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency ...of germline mutations in 40 cancer predisposition genes, including
BRCA1
and
BRCA2
, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next‐generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in
BRCA1/2
, 61 in 15 other BC susceptibility genes and 3 in both
BRCA1/2
and non‐
BRCA1/2
gene. Major mutant non‐
BRCA1/2
genes were
TP53
(n = 18),
PALB2
(n = 11),
CHEK2
(n = 6),
ATM
(n = 6) and
BARD1
(n = 5). No factors predicted pathologic mutations in non‐
BRCA1/2
genes when treated as a whole.
TP53
mutations were associated with HER‐2 positive BC and younger age at diagnosis; and
CHEK2
and
PALB2
mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non‐
BRCA1/2
genes.
TP53
and
PALB2
had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non‐
BRCA1/2
genes, some clinical features were associated with mutations of several particular genes.
What's new?
The prevalence of mutations in breast cancer predisposition genesare not well investigated in Asia. We assessed germline mutations of 40 cancer susceptibility genes in 937 consecutive selected breast cancer patients from 26 centers of China, and discovered 23.8% of participates carried the pathogenic mutation, including 6.8% with mutations in non‐
BRCA1/2
genes, while
TP53
and
PALB2
had a relatively high mutation rates (1.9% and 1.2%).There was no factors predicted for detrimental mutations in non‐
BRCA1/2
genes when treated as a whole.
Due to lack of systematic reviews, BRCA, DNA Repair Associated (
) mutations in the Chinese population are not completely understood. The following study investigates the prevalence and type of
...mutations in Chinese patients with high hereditary risk of breast cancer (BC). Patients Drwere recruited from 14 cities between October 2015 and February 2016, and were selected based on family and personal medical history.
mutations were analyzed by collecting blood samples from all participants. 437 BC patients were included. A total of seventy-six (17.4%) mutation carriers were identified with no geographic difference. The mutation rate in the early-onset BC patients was lower compared to family history of breast/ovarian cancer (OC), bilateral BC, male BC, BC&OC or meeting ≥2 criteria (9.2 vs. 21.7, 24.0, 22.2, 16.7 and 24.3%, respectively, P=0.007). A total of 61 mutation sites were identified (
32,
29) including 47.5% novel sites and extra 10 variants of uncertain significance. A total of five sites were repeated in more than one unrelated patient. A total of 11 sites were associated with hereditary breast and ovarian cancer syndrome, two of which were confirmed by family pedigrees. Compared with
patients, patients with
mutation tended to be triple-negative BC (P<0.001), whereas patients with
mutation were more likely to be hormone receptor positive BC (P=0.02). The present study provides a general
mutation profile in the Chinese population. The prevalence of
mutation in BC patients with high hereditary risk is lower compared with Western populations. Chinese mutation type is different with Western people, without obvious founder mutation.
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