PTPN11 and RAS Gene Mutation Pattern Identifies an Unique Feature of Upregulated RAS Function in Infant ALL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 996-996
Author(s):  
Giovanni Cazzaniga ◽  
Simone Martinelli ◽  
Monique L. den Boer ◽  
Lilia Corral ◽  
Monica Spinelli ◽  
...  
Keyword(s):  
Cell Population ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Ras Signaling ◽  
Ras Gene ◽  
Ras Pathway ◽  
Exon 1 ◽  
Pediatric All ◽  
The Common ◽  
Genetic Events

Abstract Point mutations affecting RAS GTPase activity promote upregulation of RAS signaling, and are among the most common genetic alterations in human cancers. Oncogenic mutations in NRAS and KRAS2 genes are found with variable prevalence in hematological malignancies, including ALL. Upregulation of RAS signaling can also results from molecular lesions in genes coding transducers controlling RAS function. We recently provided evidence that PTPN11 is mutated in approximately one-third of pediatric ALL cases. Significantly, while PTPN11 mutations appeared to be preferentially associated with the common immunophenotype, mutations in NRAS or KRAS2 were uniformly distributed among the B-cell precursor ALL subtypes. Very few are the data on RAS pathway status in pediatric ALL patients aged <1 year (Infant). Infant ALL is a rare subgroup of leukemia peculiar for several characteristics, mainly related to a possible origin from a not-fully committed stem cell. In order to explore whether alterations of RAS signaling may identify specific subgroups within this heterogeneous patient population, we analyzed 87 Infant cases prospectively enrolled in the Interfant-99 International ALL protocol. This is the largest series of Infant ALL analyzed for alteration of the RAS pathway. PTPN11 (exon 3 and 13), NRAS (exon 1 and 2), and KRAS2 (exon 1 and 2) mutation analysis was performed by DHPLC analysis and direct sequencing. None of the 87 Infant cases carried a PTPN11 somatic mutation. By contrast, a high prevalence of mutations affecting NRAS and KRAS2 was observed (approximately 30%). Thirteen cases (14.9%) were positive for a mutation in exon 1 (codons 12 and 13, 10 cases, 11.5%) or exon 2 (codon 61, 3 cases, 3.4%) of the NRAS gene. Seventeen cases (19.5%) carried a variety of exon 1 KRAS2 mutations: codons 12 and 13, n=13 (14.9% of total); insAGC(30–32), n=1; G(40)C, n=1; C(53)A, n=1; G(57)C, n=1. Interestingly, in 9/27 cases (33.3% of RAS mutated cases, 10.3% of total) DHPLC and sequencing consistently showed the presence of the RAS mutation only in a fraction (10 to 40%) of the blast cells population. In one additional case a KRAS2 mutation was observed in a subset of cells along with a full NRAS mutation. In two more cases mutations affecting NRAS and KRAS2 coexisted on the same patient; in both cases the mutations were representative of a subgroup of the total cell population. In conclusion: differently from older children, PTPN11 gene mutations are a rare event in infant ALL. This could be related to the low incidence of the “common” immunophenotype in Infants. By contrast, the overall incidence of RAS gene mutations is high, accounting for about 30% of cases. Interestingly, in 10% of cases a mutation (or even more than one) was found in a fraction of the blast cell population. This could reflect the fact that RAS mutations were secondary to other genetic events, and in any case related to the oligoclonal characteristic of this age-specific ALL subgroup. The prognostic effect of these genetic events must be evaluated in a longer follow up time of prospective series of patient, as in the Interfant Consortium.

scholarly journals Genomic Heterogeneity Contributed to the Different Prognosis of Adult and Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Yanxin Chen ◽  
Yongzhi Zheng ◽  
Yan Huang ◽  
Jiazheng Li ◽  
Jingjing Wen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Ras Signaling ◽  
Gene Rearrangements ◽  
Genomic Profiling ◽  
Pediatric All ◽  
Two Populations ◽  
Biological Differences

Prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior than children. Hence, ALL is still a challenging disease to be cured in adults population. Aberrant genetic alterations has been observed previously in acute lymphoblastic leukemia (ALL), while the patterns of differential gene alteration have not much been comprehensively determined in the adult and pediatric ALL on a genome-wide scale. This study attempted to investigate the biological differences in genomic profiling between the adults and children with ALL, and the correlation between the genomic heterogeneity and prognosis. We collected the survival informations and surveyed the gene mutations profile using whole-exome sequencing (WES) in samples from 39 adults and 54 children of de novo ALL in our institution.The sequencing revealed 663 high-confidence somatic single-nucleotide variants (SNVs), 25 stopgain and 17 frameshift insertion in 690 genes in the 39 adult ALL samples. While in the 54 pediatric ALL samples, 232 SNVs, 12 stopgain and 10 frameshift insertion in 284 genes were identified. The results showed the similar common mutation types in adult and pediatric ALL. However, the median number of detected gene mutations was 19 (range: 1-53) per sample in adult ALL and 4.5(range: 1-19) in pediatric ALL(P&lt;0.001), indicating the reduced prevalence of genetic alterations in pediatric ALL. A significant correlation between the increased of number of gene mutations and age was found (R2 = 0.3096, P&lt;0.001,FigureC). The most frequently mutated genes were NOTCH1 in 6 samples (15.38%), TTN in 5 samples(12.8%), IKZF1 in 4 samples(10.2%) and NRAS in 4 samples(10.2%) in adult ALL. In pediatric ALL, the most frequently mutated genes were KRAS in 15 samples(27.7%), NOTCH1 in 13 samples (24.1%), NRAS in 9 samples(16.7%) and CREBBP in 6 samples(11.1%). The SETD2 and TTN mutations were significantly enriched in adult ALL. While the KRAS, ARID1A and CREBBP mutations were significantly enriched in pediatric ALL. (P&lt;0.05,FigureA, B). Moreover, TP53 mutation was found in 1(0.03%) adult and 2(0.03%) pediatric ALL samples. 67 and 53 driver genes were identified in adult and pediatric ALL samples, respectively. Analysis of transcriptome sequencing data identified transcripts derived from 41 gene rearrangements in 25 (60.9%) adult ALL samples and 20 gene rearrangements in 15 (27.7%) pediatric ALL samples. The most frequent gene rearrangements were BCR/ABL1 fusions (13 samples), fusions of PAX5/ZCCH7 (4 samples) in adult ALL. The most common gene rearrangements in pediatric ALL were MLL fusions(7 samples), TEL-AML1 fusions (6 samples). Using integrated genomic analysis, we identified 3 functional pathways recurrently mutated in adult ALL: transcriptional regulation, NOTCH1 signaling, Ras signaling, and 5 in pediatric ALL: PI3K-AKT-mTOR signaling, JAK-STAT signaling, NOTCH1 signaling, Ras signaling, microRNA processing. The incidence of relapse was 33.3% and 7.7% in the adult and pediatric ALL, respectively(P=0.003). The overall survival(OS) and relapse free survival (RFS) of adult ALL were poorer than pediatric ALL(P=0.003, P&lt;0.001, respectively,FigureD, E), indicating an unfavorable prognosis. Moreover, the number of gene mutations seems to be related with the decreased of times to relapse(R2 = 0.0571, P=0.39). Patients with different genetic subtypes were assigned to the different subgroups. The signatures may related to the inferior outcome of adults compared to children were identified. Adult ALL patients had more enrichment for alterations of amino acid degradation and transcription misregulation, which may explain in part the disparity in the different responses to treatment of the two populations. The study in genomic profiling across the age spectrum elucidated the genomic heterogeneity between adult and pediatric ALL, including the different in the counts of gene mutation, the frequently mutated genes and the fusion genes, which may be the contributing factors that influence prognosis. This genomic landscape enhanced the understanding of the biological differences of disease between the two populations and provided a clue for novel therapeutic approaches. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bcor Mutations Cooperate with Tet2 Deficiency to Promote RAS Transformation of Mouse Hematopoietic Progenitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 888-888
Author(s):  
Iman Fares ◽  
Rahul S. Vedula ◽  
Shabbir M. Vahanvaty ◽  
Christopher S Waters ◽  
Marlise R. Luskin ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Somatic Mutations ◽  
Genetic Alterations ◽  
Ras Signaling ◽  
Wild Type ◽  
Ras Pathway ◽  
Tp53 Mutations ◽  
Oncogenic Ras ◽  
Mdm2 Overexpression

Abstract Somatic mutations can have highly stereotyped positions in the myeloid clonal hierarchy and distinct patterns of co-occurring mutations. Gene mutations that cause aberrant activation of RAS/MAPK signaling are typically late events in myeloid disease progression and are closely associated with leukemic transformation. We hypothesized that the phenotypic output of oncogenic RAS signaling is dynamically reprogrammed during leukemogenesis based on evolving genetic and epigenetic context. To identify genetic alterations that may modulate RAS-mediated transformation, we evaluated 1273 adults with myelodysplastic syndrome, including 150 with mutations in NRAS, KRAS, PTPN11, CBL, RIT1, NF1, or FLT3. Somatic mutations in ASXL1 (q<0.0001), RUNX1 (q<0.0001), EZH2 (q<0.0001), BCOR (q=0.0002), and STAG2 (q=0.001) were most significantly associated with co-occurring RAS pathway mutations, compared to those without RAS pathway mutations, while TP53 mutations were less frequent (q=0.059). We validated these observations in an independent cohort of 6343 unselected patients, including 1081 patients harboring either RAS pathway mutations (n=651),TP53 mutations (n=494), or both (n=57). To define the effects of sequential acquisition of driver mutations, we developed a mouse serial transplantation model of somatic myeloid transformation. First, we used in vivo pI:pC treatment to induce biallelic inactivation of Tet2 in adult Mx1-Cre/Tet2flox/floxmice. After 12 weeks, we purified Tet2-/-or control hematopoietic stem and progenitor cells (HSPCs) and used CRISPR/Cas9 to separately introduce inactivating mutations in Ezh2, Asxl1-exon12, Stag2, or Bcor, then evaluated their functional effects using ex vivo serial replating or in vivo competitive transplantation. Tet2-/-HSPCs with control sgRNA showed a modest enhancement of serial replating compared to Tet2-wild type HSPCs, while Tet2-/-HSPCs Asxl1, Stag2, and Bcor, but not Ezh2 sgRNA had markedly enhanced serial replating capacity (>6 platings in all replicates). In primary transplantation, secondary mutations caused in vivo clonal advantage after 16 weeks, but never resulted in histologic transformation to acute leukemia. We next evaluated the impact of tertiary NRASG12Dmutations in each pairwise Tet2-/-CRISPR combination (Asxl1, Bcor, Ezh2, Stag2, control). We purified HSPCs from recipient mice 16 weeks after primary transplantation, transduced with a lentiviral NRASG12Dexpression vector and transplanted into secondary recipients. Recipients of Tet2/Bcor/NRAS, Tet2/Asxl1/NRAS, or Tet2/Ezh2/NRAS cells succumbed to CD11b+myeloid disease with variable latency in Bcor (14 days), Ezh2 (50 days), and Asxl1 (120 days) cells, suggesting that combined Tet2 and PRC1/2 alterations may modify the effects of oncogenic RAS signaling. To determine whether pre-existing epigenetic mutations cooperate to alter the transcriptional response to acute oncogenic stress compared to wild type cells, weperformed RNA-seq 12 and 24 hours after induced expression of NRASG12D in isogenic immortalized mouse progenitor cells deficient for Tet2, Bcor, or both Tet2 and Bcor. We observed rapid activation of inflammatory and cellular senescence programs in all conditions, suggesting a genotype-independent immediate early response to oncogenic signaling. However, we also identified genotype-specific regulation of tumor suppressor and cell cycle checkpoint pathways. While Cdnk1a expression was strongly induced in all conditions, Cdnk2a expression (and p16Ink4a and p19ARF protein levels) was preferentially upregulated in the context of Bcor deficiency. Moreover, expression of the p53 negative regulator Mdm2 was increased 11-fold in Tet2/Bcor-deficient cells, but only 4 to 5-fold in wild type, Tet2-, or Bcor-deficient cells. Tet2/Bcor-deficient cells were significantly more sensitive to treatment with the Mdm2 antogonist, Nutlin, upon induction of NRAS expression than were wild-type cells, suggesting that Mdm2 overexpression directly mediates acquired tolerance of oncogene stress. These human genetic data and mouse models suggest that epigenetic alterations occurring during early myeloid leukemogenesis may enable evasion of oncogene protection mechanism. Bcor mutations can pair with initiating Tet2 mutations to facilitate RAS mediated transformation while incurring a dependency on Mdm2 overexpression. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular analysis of the PROP1 and HESX1 genes in patients with septo-optic dysplasia and/or pituitary hormone deficiency

2010 ◽  
Vol 54 (5) ◽  
pp. 482-487 ◽  
Author(s):  
Juliana B. Cruz ◽  
Vania S. Nunes ◽  
Sueli A. Clara ◽  
Denise Perone ◽  
Peter Kopp ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Genetic Alterations ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Exon 1 ◽  
Genetic Mechanisms ◽  
Direct Sequence Analysis ◽  
Prop1 Gene ◽  
Pathogenic Process

OBJECTIVE: The present study aimed at evaluating the PROP1 and HESX1 genes in a group of patients with septo-optic dysplasia (SOD) and pituitary hormone deficiency (combined - CPHD; isolated GH deficiency - GHD). Eleven patients with a clinical and biochemical presentation consistent with CPHD, GHD or SOD were evaluated. SUBJECTS AND METHODS: In all patients, the HESX1 gene was analyzed by direct sequence analysis and in cases of CPHD the PROP1 gene was also sequenced. RESULTS: A polymorphism (1772 A > G; N125S) was identified in a patient with SOD. We found three patients carrying the allelic variants 27 T > C; A9A and 59 A > G; N20S in exon 1 of the PROP1 gene. Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic GHD, CPHD and SOD. CONCLUSION: Genetic alterations in one or several other genes, or non-genetic mechanisms, must be implicated in the pathogenic process.

scholarly journals FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma

Oncogene ◽  
2005 ◽  
Vol 24 (33) ◽  
pp. 5218-5225 ◽  
Author(s):  
Adel H Jebar ◽  
Carolyn D Hurst ◽  
Darren C Tomlinson ◽  
Colin Johnston ◽  
Claire F Taylor ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Gene Mutations ◽  
Urothelial Cell ◽  
Urothelial Cell Carcinoma ◽  
Ras Gene ◽  
Genetic Events

Mutations in the RAS Signaling, B-Cell Development, TP53/RB1, and JAK Signaling Pathways Are Common in High Risk B-Precursor Childhood Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group (COG) High-Risk (HR) ALL TARGET Project.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 85-85 ◽  
Author(s):  
Jinghui Zhang ◽  
Charles G. Mullighan ◽  
Richard C. Harvey ◽  
Kenneth E Buetow ◽  
William L. Carroll ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
T Cell ◽  
B Cell ◽  
Signaling Pathways ◽  
Somatic Mutations ◽  
Genetic Alterations ◽  
Cell Development ◽  
B Cell Development ◽  
Ras Signaling ◽  
Ras Pathway

Abstract Abstract 85 Despite the overall favorable treatment outcome for childhood ALL, about 20% of patients still experience relapse. Moreover, many ALL cases lack sentinel chromosomal alterations, and the genetic factors contributing to leukemogenesis in these cases are poorly understood. Genome-wide profiling of DNA copy number alterations (CNA) coupled with focused candidate gene resequencing has identified novel genetic alterations that contribute to leukemogenesis and are associated with treatment outcome in ALL. However, large-scale analysis of somatic sequence mutations in ALL has not yet been performed. As part of the COG HR-ALL TARGET (Therapeutically Applicable Research to Generate Effective Targets) Project, 125 genes (selected based on recurrent CNAs, gene expression profiles and known cancer genes) were sequenced in 187 HR B-precursor ALL patients enrolled in COG P9906. The entire coding region and UTRs of each gene were sequenced and more than 98% of the targeted nucleotides have high quality sequence coverage. We found that somatic mutations are frequent in genes that encode for proteins involved in signal transduction, B-cell development and p53/RB signaling. A notable finding was the presence of somatic mutations resulting in constitutive activation of RAS signaling in at least 39% of the cohort. Seventy-three cases have at least one mutation in NRAS (30), KRAS (28), PTPN11 (9), FLT3 (7) and NF1 (6), including 7 patients with multiple mutations (KRAS and NRAS (3), FLT3 and NF1 (1), PTPN11 and FLT3 (1), PTPN11 and FLT3 (1), PTPN11 and NRAS (1), PTPN11 and KRAS (1)). There was no association between RAS pathway mutations and event-free survival or cumulative incidence of relapse in this HR patient cohort. Notably, RAS pathway mutations were uncommon in ALL cases with TCF3-PBX1 (1/22 cases) or MLL translocations (2/18 cases), but occurred frequently in cases lacking known sentinel cytogenetic lesions (68/145 cases, 47%, p<0.0001). Sequence mutations that are known or predicted to impair normal B-cell development were observed in at least 14% of the cohort (PAX5 (21), IKZF1 (7)), with confirmatory germline sequencing underway to clarify whether lymphoblast sequence alterations present in other B-cell development genes including BLK, ETV6, IKZF3, TCF3, RAG1, and BCL11A are somatic or germline. Sequence mutations disrupting TP53/RB1 signaling ((TP53 (10), RB1 (4), CDKN2A (4)) occurred in 10% of cases. Activating sequence mutations in JAK family members (JAK2 (16) and JAK1 (3)) were present in 10% of the cases. Of the 103 cases (55%) with at least one sequence mutation in these four (RAS signaling, B-cell development, p53/RB, and JAK) pathways, 30 have somatic mutations in multiple pathways. When both CNAs and sequence mutations are considered, 94% of the cases have lesions in at least one of the pathways and 31% of the cases have somatic alterations in all three of the B-cell development, RAS, and p53/RB1 signaling pathways, suggesting that aberrations in multiple pathways may be central to development of HR-ALL. Our results contrast sharply with known genetic alterations in T-cell ALL, where RAS pathway alterations are relatively uncommon (<10% of cases). PTEN somatic mutations and deletions occur in approximately 25% of cases of T-cell ALL, but we found no PTEN alterations in this cohort, suggesting differential activation of RAS and PI-3K signaling pathways in T-cell and HR B-precursor ALL. Validation of putative deleterious mutations in other sequenced genes (e.g., TBL1XR1, BLK, and CREBBP) is ongoing. These results from the TARGET COG HR-ALL Pilot Project confirm and extend prior knowledge of genetics of this subtype of ALL and point the way to new potential therapeutic strategies for this patient population. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Molecular analysis of the androgen receptor gene in testicular cancer

2005 ◽  
Vol 12 (3) ◽  
pp. 645-655 ◽  
Author(s):  
A Garolla ◽  
A Ferlin ◽  
C Vinanzi ◽  
A Roverato ◽  
G Sotti ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Testicular Cancer ◽  
Novel Mutation ◽  
Receptor Gene ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Androgen Receptor Gene ◽  
Joint Analysis ◽  
Increased Risk ◽  
Exon 1

Testicular cancer (TC) is the most common solid tumour in white males aged 20–34 years, and its incidence has doubled over the past 40 years. Some risk factors for TC have been proposed, such as cryptorchidism, infertility and testicular dysgenesis. However, the causes of TC remain still largely unknown. Recently a genetic basis for TC has been proposed, but specific genetic alterations have not been identified. The risk of TC is markedly increased in subjects with androgen insensitivity and some authors have suggested that mutations in the androgen receptor (AR) gene or disorders of CAG and GGC repeats could be related to TC. However, definitive data have not been produced. In this study, we analysed the AR gene for mutations and CAG and GGC triplets in exon 1 in 123 patients affected by TC. In three patients (2.3%) we found a mutation in the AR gene, two of which represent a novel mutation. Evaluation of CAG and GGC repeat numbers showed no difference with respect to controls when these variables were analysed separately. However, when joint distributions of CAG and GGC were considered, we found that the combination CAG=20/GGC=17 was significantly more frequent in TC patients (8.1%) with respect to controls (1.7%, P<0.05). Furthermore, we observed that in TC subjects, differently from controls, the joint analysis of CAG and GGC showed a statistically significant dependence among these variable repeats. In conclusion, our data show for the first time a high prevalence of AR gene mutations in patients affected by TC and suggest that some CAG/GGC combinations might be more frequently associated with an increased risk of TC.

scholarly journals Genomic Heterogeneity Contributed To The Different Survival Between Adult and Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Yanxin Chen ◽  
Yongzhi Zheng ◽  
Yunda Hong ◽  
Jingjing Wen ◽  
Jiazheng Li ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Adult Population ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Common Mutation ◽  
A Genome ◽  
Pediatric All ◽  
Two Populations ◽  
Biological Differences

Abstract Prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to children. Hence, ALL is still a challenging disease to be cured in adult population. Aberrant genetic alterations have been observed previously in ALL, while the patterns of differential gene alteration have not much been comprehensively determined in the adult and pediatric ALL on a genome-wide scale. This study was attempted to investigate the biological differences in genomic profiling between the adults and children with ALL, and the relationship between the genomic heterogeneity and prognosis. The results showed the similar common mutation types in two populations but the increased prevalence of genetic alterations in adult ALL. The median number of detected gene mutations was 17 (range: 1–53) per sample in adult ALL and 4.5 (range: 1–19) in pediatric ALL(P<0.001). A significant correlation between the increased number of gene mutations and age was found (R2 = 0.5853, P<0.001). 122 and 53 driver genes were identified in adult and pediatric ALL samples, respectively. The IKZF1, IDH1 and TTN mutations were significantly enriched in adult ALL. The incidence of relapse was 40.0% and 9.6% in the adult and pediatric ALL, respectively(P=0.0003). The overall survival (OS) and relapse free survival (RFS) of adult ALL were poorer than pediatric ALL (P=0.0002, P<0.001, respectively). This genomic landscape enhanced the understanding of the biological differences of ALL between the two populations and provided a clue for novel therapeutic approaches.

p53 and K-ras Gene Mutations Correlate With Tumor Aggressiveness But Are Not of Routine Prognostic Value in Colorectal Cancer

1999 ◽  
Vol 17 (5) ◽  
pp. 1375-1375 ◽  
Author(s):  
Silvia Tortola ◽  
Eugenio Marcuello ◽  
Isabel González ◽  
Germán Reyes ◽  
Rosa Arribas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
P53 Gene ◽  
Radical Resection ◽  
Genetic Alterations ◽  
Rank Test ◽  
P53 Mutations ◽  
Ras Gene ◽  
Ras Mutations

PURPOSE: p53 gene and K-ras mutations are among the most common genetic alterations present in colorectal cancer. The prognostic utility of such mutations remains controversial. The purpose of this study was to prospectively evaluate the prognostic significance of p53 and K-ras gene mutations in colorectal cancer. PATIENTS AND METHODS: One hundred forty patients were analyzed. Tumors belonging to the microsatellite mutator phenotype were excluded (n = 8). Mutations at the K-ras and p53 genes were detected and characterized by restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing, as appropriate. RESULTS: p53 mutations were detected in 66 (50%) and K-ras mutations were detected in 54 (41%) of the 132 patients. In 26 cases (20%), ras and p53 mutations coexisted; in 38 cases (29%), neither mutation was found. Multivariate analysis of the whole population analyzed (n = 132) showed that survival was strongly correlated with the presence of p53 mutations alone or in combination with K-ras mutations (P = .002; log-rank test). When only patients undergoing a radical resection were considered (R0; n = 101), p53 mutations were no longer of prognostic significance. CONCLUSION: p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome. However, the routine use of these mutations as prognostic markers in the clinical setting is not recommended.

scholarly journals Comprehensive Genetic Analysis in Cases of Juvenile Myelomonocytic Leukemia for Prognostic Estimation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3159-3159
Author(s):  
Norihiro Murakami ◽  
Hideki Muramatsu ◽  
Yusuke Okuno ◽  
Hirotoshi Sakaguchi ◽  
Kenichi Yoshida ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Research Funding ◽  
Survival Rates ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Juvenile Myelomonocytic Leukemia ◽  
Genetic Mutations ◽  
Ras Pathway ◽  
Pathway Gene ◽  
Myelomonocytic Leukemia

Abstract Introduction: Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm (MPN) that occurs during childhood and has a poor prognosis. Somatic or germline mutations in canonical RAS pathway genes, i.e., PTPN11, NF1, NRAS, KRAS, and CBL, are reported be detected in approximately 85% patients. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for JMML. Although spontaneous remission is occasionally observed in others with supportive therapy, some patients show aggressive disease progression despite HSCT. Recent studies have identified several additional genetic events in an array of genes, including SETBP1 and JAK3, but the relationship between genetic alterations and clinical outcomes remains unclear. Patients and Methods: A total of 131 patients (88 boys, 43 girls) with JMML were enrolled in the study. The median age was 15 months (range, 1-160 months). Eighty-two of 131 patients underwent HSCT, and 36 patients died (disease related, n = 27, transplantation-related complications, n = 16, infection, n = 5, unknown, n = 3). We performed comprehensive genetic analyses of the 131 JMML patients using whole-exome sequencing (n = 68, 52%) or targeted deep sequencing (n = 92, 70%), and assessed the impact of genetic alterations on clinical outcomes in 119 patients, excluding 12 patients with Noonan syndrome-related myeloproliferative disorder (NS/MPD). Results: We identified canonical RAS pathway gene mutations in 115 of 131 patients (88%). Although most RAS pathway mutations were mutually exclusive, coexisting secondary RAS pathway mutations were found in nine patients (8%). In addition, 28 patients harbored secondary genetic alterations in other genes, including SETBP1 (n = 10), JAK3 (n = 12), ASXL1 (n = 6), SH3BP1 (n = 1), RRAS2 (n = 2), and SOS1 (n = 3). In total, 34 of 131 patients harbored secondary genetic mutations. In univariate analysis, patients with secondary genetic mutations showed poorer survival rates than patients without these mutations [5-year transplantation-free survival (TFS) (95% CI) = 8.8% (2.3%-21.1%) vs. 24.1% (15.2%-34.1%), p = 0.007; 5-year overall survival (OS) (95% CI) = 49.6% (32.0%-65.0%) vs. 62.3% (50.8%-71.8%), p = 0.135]. On the basis of the dominant canonical RAS pathway mutations classification, patients with PTPN11 and NF1 mutations were significantly associated with the presence of secondary genetic mutations compared to patients with other RAS pathway gene mutations (PTPN11 (20 of 43, 47%), NF1 (5 of 7, 71%), NRAS (2 of 18, 11%), KRAS (4 of 20, 20%), CBL (1 of 17, 6%), p < 0.001). Consistent with previous reports, patients with PTPN11 and NF1 mutations had inferior survival rates than other JMML patients [5-year TFS (95% CI) = 0% vs. 32.7% (21.5%-44.3%), p < 0.001; 5-year OS (95% CI) = 45.3% (31.1%-58.5%) vs. 68.1% (55.2%-78.0%), p = 0.006]. Multivariate survival analysis identified the RAS pathway mutations (i.e., patients with PTPN11 and NF1 mutations vs. others) [TFS: HR (95% CI) = 3.732 (2.382-5.847), p < 0.001; OS: HR (95% CI) = 1.983 (1.117-3.521), p < 0.019] and low platelet count (<33 × 109/L vs. ≥ 33 × 109/L) [TFS: HR (95% CI) = 1.816 (1.160-2.843), p < 0.001] as independent risk factors for TFS and OS. In subgroup analysis of 50 patients with PTPN11 and NF1 mutations, there were no significant survival differences between patients with (n = 25) or without (n = 25) secondary genetic mutations [5-year TFS (95% CI) = 0% vs. 0%, p = 0.753; 5-year OS (95% CI) = 39.6% (20.8%-57.9%) vs. 51.7% (30.9%-69.1%), p = 0.589]. Discussion: Consistent with previous studies, secondary genetic mutations were associated with inferior survival rates, but high correlations were observed in JMML patientswith PTPN11 and NF1 mutations. Our results suggest that comprehensive genetic mutational profiling is essential to estimate prognosis and to stratify JMML patients who require HSCT and/or novel treatment modalities. Disclosures Ogawa: Sumitomo Dainippon Pharma: Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Kan research institute: Consultancy, Research Funding. Kojima:SANOFI: Honoraria, Research Funding.

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