Impact Of Mutations In Patients Research Articles

Differential impact of different TP53 gain-of-function mutations on overall survival of patients with metastatic colorectal cancer: Results from a large integrated healthcare system.

3585 Background: TP53 mutation is present in approximately 50% of metastatic colorectal cancer (CRC). The spectrum of the TP53 mutations is extremely broad including approximately 80% missense mutations. Several missense mutations have been found to possess gain-of-function (GOF) properties in cell line and animal studies, however, confirmation of the concept of GOF in human malignancies is still lacking. Methods: We investigated the impact of TP53 GOF mutations in patients with metastatic CRC using the NGS data within Kaiser Permanente Northern California (KPNC), a large integrated healthcare system. Results: From November 2017 to January 2021, genomic profiling by StrataNGS was performed on 8658 patients, with 1056 patients being metastatic CRC, among whom 740 patients harbored a TP53 mutation (TP53mut) and 316 patients had wild-type TP53 (TP53wt). Ras (KRAS and NRAS) and BRAF mutation appropriately discriminated the overall survival (OS) of patient populations with either TP53wt or TP53mut, confirming the validity of our dataset. We identified seven GOF TP53 mutations (R175H, R248W, R248Q, R249S, R273H, R273L, R282W) in these CRC patients. We show that different GOF mutation differentially impacts the OS. Patients whose CRC harbored TP53mut R248W, R249S, and R282W (poor prognostic TP53mut, N = 47) had significantly worse OS versus patients whose CRC harbored TP53mut R248Q, R175H, R273H and R273L (N = 160, median OS 29.4 vs 44.2 months, HR 0.47, p = 0.007). The OS of the poor prognostic TP53mut patients was also significantly inferior compared to patients whose CRC harbored all other TP53 mutations (N = 1099, median OS 50.1 months, HR 0.55, p = 0.01) or TP53wt (N = 316, median OS 47,5 months, HR 0.54, p = 0.01). The demographics and the percent of Ras, BRAF, and PI3KCA mutations were similar except that the patients with the poor prognostic TP53mut had significantly higher percent of Ras mutation compared to the rest of the GOF TP53mut patients (p = 0.035). When compared to R248Q alone, R248W confers worse OS (median OS 36.3 vs 63.2 months, p = 0.05). Conclusions: Our data suggest that different TP53 GOF mutations are associated with very different clinical outcomes. Additional studies identifying specific TP53 GOF mutations that impact outcomes may provide further insight for drug development and clinical trial design.

Prevalence and prognostic impact of somatic mutations in patients with heart failure and reduced ejection fraction

Abstract Introduction Somatic mutations in hematopoietic cells are associated with age and have been associated with higher mortality in apparently healthy adults, especially due to atherosclerotic disease. In animal models, somatic mutations are associated with atherosclerosis progression and myocardial dysfunction, especially when gene TET2 is affected. Preliminary clinical data, referred to ischemic heart failure (HF), have associate the presence of these acquired mutations with impaired prognosis. Purpose To study the prevalence of somatic mutations in patients with heart failure with reduced ejection fraction (HFrEF) and their impact on long-term prognosis. Methods We studied a cohort of elderly patients (more than 60 years old) hospitalized with HFrEF (LVEF<45%). The presence of somatic mutations was assessed using next generation sequencing (Illumina HiSeq 2500), with a mutated allelic fraction of at least 2% and a panel of 55 genes related with clonal hematopoiesis. Patients were followed-up for a median of three years. The study endpoint was a composite of death or readmission for worsening HF. Kaplan-Meier analysis (log-rank test) and Cox proportional hazards regression models were performed adjusting for age, sex and LVEF. Results A total of 62 patients (46 males (74.2%), age 74±7.5 years) with HFrEF (LVEF 29.7±7.8%) were enrolled in the study. The ischemic etiology was present in 54% of patients. Somatic mutations in Dnmt3a or Tet2 were present in 11 patients (17.7%). No differences existed in baseline characteristics except for a higher prevalence of atrial fibrillation in patients with somatic mutations (70% vs. 40%, p=0.007). During the follow-up period, 40 patients (64.5%) died and 38 (61.3%) had HF re-admission. The KM survival analysis for the combined event is shown in Figure 1. Compared with patients without somatic mutations and after adjusting for covariates, there was an increased risk of adverse outcomes when the somatic mutations were present (HR 3.6, 95% CI [1.6, 7.8], p=0.0014). This results remains considering death as a competing risk (Gray's test p=0.0097) and adjusting for covariates (HR = 2.21 95% CI [0.98, 5], p=0.0556). Conclusions Somatic mutation are present in patients with HFrEF and determine a higher risk of adverse events in the follow-up. Further studies are needed to assess the clinical implications of these findings. Figure 1 Funding Acknowledgement Type of funding source: None

Variable patterns of mutation density among NaV1.1, NaV1.2 and NaV1.6 point to channel-specific functional differences associated with childhood epilepsy.

Variants implicated in childhood epilepsy have been identified in all four voltage-gated sodium channels that initiate action potentials in the central nervous system. Previous research has focused on the functional effects of particular variants within the most studied of these channels (NaV1.1, NaV1.2 and NaV1.6); however, there have been few comparative studies across channels to infer the impact of mutations in patients with epilepsy. Here we compare patterns of variation in patient and public databases to test the hypothesis that regions of known functional significance within voltage-gated sodium (NaV) channels have an increased burden of deleterious variants. We assessed mutational burden in different regions of the Nav channels by (1) performing Fisher exact tests on odds ratios to infer excess variants in domains, segments, and loops of each channel in patient databases versus public "control" databases, and (2) comparing the cumulative distribution of variant sites along DNA sequences of each gene in patient and public databases (i.e., independent of protein structure). Patient variant density was concordant among channels in regions known to play a role in channel function, with statistically significant higher patient variant density in S4-S6 and DIII-DIV and an excess of public variants in SI-S3, DI-DII, DII-DIII. On the other hand, channel-specific patterns of patient burden were found in the NaV1.6 inactivation gate and NaV1.1 S5-S6 linkers, while NaV1.2 and NaV1.6 S4-S5 linkers and S5 segments shared patient variant patterns that contrasted with those in NaV1.1. These different patterns may reflect different roles played by the NaV1.6 inactivation gate in action potential propagation, and by NaV1.1 S5-S6 linkers in loss of function and haploinsufficiency. Interestingly, NaV1.2 and NaV1.6 both lack amino acid substitutions over significantly long stretches in both the patient and public databases suggesting that new mutations in these regions may cause embryonic lethality or a non-epileptic disease phenotype.

59 - Prognostic Impact of Mutations in Patients with Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms with Normal Karyotype

Studies of morphology of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) refer to the definitions produced by the French-American-British (FAB) group and by the World Health Organization expert group. To clarify some points regarding the dysgranulopoiesis that are still unclear we analyzed a series of 98 neutrophils from MDS patients with regard to granularity, nuclear segmentation, the appearance of the chromatin, the presence of giant neutrophils, and the presence of nuclear chromatin extensions. We found that cells with at least 2/3 reduction of the content of granules, Pelger-like neutrophils, dysplastic non-Pelger cells, neutrophils with abnormal clumping of the chromatin, and macropolycytes could be recognized as dysplastic and included in the 10% count recommended by these two classifications. In addition, we suggest that neutrophils with more than 4 nuclear projections could be recognized as a relevant dysplastic feature.

Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes.

A subset of patients with myelodysplastic syndromes (MDS) who are predicted to have lower-risk disease as defined by the International Prognostic Scoring System (IPSS) demonstrate more aggressive disease and shorter overall survival than expected. The identification of patients with greater-than-predicted prognostic risk could influence the selection of therapy and improve the care of patients with lower-risk MDS. We performed an independent validation of the MD Anderson Lower-Risk Prognostic Scoring System (LR-PSS) in a cohort of 288 patients with low- or intermediate-1 IPSS risk MDS and examined bone marrow samples from these patients for mutations in 22 genes, including SF3B1, SRSF2, U2AF1, and DNMT3A. The LR-PSS successfully stratified patients with lower-risk MDS into three risk categories with significant differences in overall survival (20% in category 1 with median of 5.19 years [95% CI, 3.01 to 10.34 years], 56% in category 2 with median of 2.65 years [95% CI, 2.18 to 3.30 years], and 25% in category 3 with median of 1.11 years [95% CI, 0.82 to 1.51 years]), thus validating this prognostic model. Mutations were identified in 71% of all samples, and mutations associated with a poor prognosis were enriched in the highest-risk LR-PSS category. Mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with shorter overall survival independent of the LR-PSS. Only EZH2 mutations retained prognostic significance in a multivariable model that included LR-PSS and other mutations (hazard ratio, 2.90; 95% CI, 1.85 to 4.52). Combining the LR-PSS and EZH2 mutation status identifies 29% of patients with lower-risk MDS with a worse-than-expected prognosis. These patients may benefit from earlier initiation of disease-modifying therapy.

KIT Mutations Are Rare Among Elderly AML Patients: A SWOG Report

Abstract 2510 Background:KIT receptor tyrosine kinase mutations are recurrent genetic alteration found in acute myeloid leukemia (AML) with higher prevalence in those with core binding factor (CBF) AML. Different prognostic significance of these mutations has been found in pediatric and adult AML studies. However, prevalence and prognostic impact of KIT mutations in elderly patients with AML has not been established. In this study, we evaluated the prevalence of KIT mutation and its correlation with cytogenetic, molecular subtypes and clinical outcome in elderly AML patients. Methods:Diagnostic specimens from for 207 patients with AML registered on SWOG trials S-9031 and S-9333 were available for KIT mutation analysis. Both of these clinical protocols enrolled AML patients > 55 years. The samples were analyzed for the presence of KIT mutations via direct sequencing of exons 8 and 17. Results:In the cohort of 207 patients tested, the median age, WBC, and blast count at diagnosis were 68 years (range, 56–88 years), 29,6 × 109/L (range, 7–289 × 109/L) and 67% (0–99%), respectively. Favorable, intermediate and unfavorable cytogenetics were present in 8%, 57% and 26% of the patients, respectively. Nine percent of the patients had cytogenetics abnormalities of unknown significance. Normal cytogenetics was present in 48% of the patients. Fifty-three patients (26%) harbored mutations for FLT3-ITD, 37 (19%) for DNMT3A, 52 (31%) for NPM1 and 50 (24%) for IDH1/2. Only 3 patients were positive for CEBPA mutation. Of the 207 patient specimens tested, KIT exon 17 mutations were detected in 4 patients (2%). Exon 8 mutations were not identified. The characteristics of the 4 patients with KIT mutations are described in the table. Of the 4 patients who harbored the KIT mutation, 2 had intermediate, 1 had unfavorable risk cytogenetics and 1 patient did not have available cytogenetic data. None of the patients with CBF had KIT mutations. In terms of other molecular markers, all 4 patients were wild-type for NPM1, CEBPA, DNMT3A, IDH1/2 and FLT3-ITD. The very small number of KIT mutations in this group of patient precluded correlation between KIT mutations and clinical outcome. Conclusion:The prognostic impact of KIT mutations has been shown to vary according to cytogenetics subgroups. Most studies report a negative prognostic impact of these mutations in patients with CBF AML. The prognostic implications of KIT mutations also seem to vary among different age groups, with pediatric studies indicating they have no prognostic significance and adult studies indicating a negative prognostic impact. To date, there is no large study reporting on the incidence and prognostic impact of KIT mutations in elderly patients with AML. The very low incidence of KIT mutations in our study highlights the age-specific characteristics of AML and may correlate with lower prevalence of CBF translocations in older AML. Further studies investigating the relationship among different somatic mutations in elderly AML patients may help to clarify the pathogenetic mechanism of certain AML subtypes in this patient population.TablePatient characteristics of the 4 patients with KIT mutationsPatient1234KIT mutationsExon 17 (D816V)Exon 17 (D816V)Exon 17 (D816Y)Exon 17 (D816V)SexFFMMAge at diagnosis (years)56786572WBC x109/L68.3215.629.912.8BM blast (%)72405130Cytogenetics46,XX,t(6;11) (q27;q23)t(6;14) (q11;q11)[20]/ 46,XX,t(6;14) (q11;q11)[1]46,XX[20]No data46,XY[19]/47,XY,+2[1]NPM1WTWTWTWTFLT3-ITDWTWTWTWTCEBPAWTWTWTWTDNMT3AWTWTWTWTIDH1/2WTWTWTWTResponse to induction chemotherapyCRRDCRRDRelapse-free survival (days)270–386–Overall survival (days)646264978575Abbreviations: WBC, white blood count; BM, bone marrow; CR, complete remission; RD, refractory disease; WT, wild-type; F, female; M, male. Disclosures:No relevant conflicts of interest to declare.