Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.

Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.

Prognostic relevance of 6q deletion in Waldenström's macroglobulinemia: a multicenter study.

The deletion of the long arm of chromosome 6 is the most common cytogenetic abnormality in Waldenstrom's macroglobulinemia (WM), but its prognostic significance is unclear. We investigated 77 patients with WM by interphase cytoplasmic immunoglobulin M fluorescence in situ hybridization (cIgM-FISH) and correlated the 6q status with the patients' clinical features and survival. cIg-FISH detected hemizygous 6q deletions in 32 patients (41.6%). The 6q deletions were correlated with higher C-reactive protein levels (P = .02) and CD23 expression (P = .03) but not with other clinical laboratory features of WM. There was no significant difference in time to the initial treatment between deleted and non-deleted groups (median, 5.6 months vs. 2.6 months; P = .46), or overall survivals in patients with and without del (6q) (163 months vs. not reached; P = .83). Our study confirms that the 6q deletion is a frequent event, but it does not appear to affect the clinical outcome of WM.

Attention and motor deficits index non-specific background liabilities that predict autism recurrence in siblings.

BACKGROUND: Recent research has demonstrated that subclinical autistic traits of parents amplify the effects of deleterious mutations in the causation of autism spectrum disorder (ASD) in their offspring. Here, we examined the extent to which two neurodevelopmental traits that are non-specific to ASD-inattention/hyperactivity and motor coordination-might contribute to ASD recurrence in siblings of ASD probands. METHODS: Data from a quantitative trait study of 114 ASD probands and their brothers, 26% of whom also had ASD, were analyzed. Autistic trait severity was ascertained using the Social Responsiveness Scale-2, attention/hyperactivity problems using the Achenbach System of Empirically Based Assessment, and motor coordination (in a subset of participants) using the Developmental Coordination Disorder Questionnaire. RESULTS: Among siblings (affected and unaffected), both categorical recurrence of ASD (Nagelkerke R 2 = 0.53) and quantitative ASD trait burden (R 2 = 0.55) were predicted by sibling ADHD and motor coordination impairment scores, even though these traits, on average, were not elevated among the unaffected siblings. CONCLUSIONS: These findings in a clinical family cohort confirm observations from general population studies that inattention/hyperactivity and motor impairment-axes of behavioral development that are non-specific to ASD, and often appreciable before ASD is typically diagnosed-jointly account for over 50% of the variation in autistic impairment of siblings, whether ascertained quantitatively or categorically. This finding within a sibling design suggests that background ASD susceptibilities that are inherited but non-specific ("BASINS") may contribute to additive genetic liability in the same manner that ASD-specific susceptibilities (such as parental subclinical ASD traits and deleterious mutations) engender ASD risk.

Prognostic value of immunophenotyping and gene mutations in elderly patients with acute myeloid leukemia with normal karyotype.

Elderly patients with acute myeloid leukemia generally have a poor prognosis and a highly heterogeneous clinical outcome. Prognostic indicators are required for and aid in patient stratification. However, the prognostic value of genetic mutations and immunophenotypic features in elderly normal karyotype acute myeloid leukemia, the largest cytogenetic risk group, remains unclear. We investigated the genetic mutations NPM1, FLT3-ITD, and FLT3-TKD and expression of the membrane antigens CD7, CD15, CD34, and CD56 in 144 elderly patients with de novo normal karyotype acute myeloid leukemia to retrospectively analyze the prognostic and clinical relevance of these parameters. CD7, CD15, CD34, and CD56 were expressed in 24%, 47%, 52%, and 15% of patients, respectively. NPM1 and FLT3-ITD mutations were detected in 51% and 17% of patients, respectively. Complete remission was obtained in 94 patients (65%), and the median overall survival was 16.5 months. Univariate analysis detected 5 markers with prognostic relevance: high leukocyte count, FLT3-ITD mutations, NPM1 mutations, CD34 expression, and CD56 expression in acute myeloid leukemia blasts. In multivariate analysis, patients with NPM1 predicted a higher complete remission (CR) rate (P = .016), longer event-free survival (P = .008), and longer overall survival (P = .049). FLT3-ITD mutations predicted a shorter event-free survival (P = .002) and shorter overall survival (P < .001). CD56 remained an independent predictor for lower CR rate (P = .021) and shorter event-free survival (P = .002). Our data highlight the prognostic importance of both genetic and immunophenotypic characteristics in this population of elderly patients with newly diagnosed normal karyotype acute myeloid leukemia. By combining genetic and immunophenotypic markers, we can divide patients into distinct prognostic groups with important implications for prognostic stratification and risk-adapted therapy.

Genomic stratification of multiple myeloma treated with novel agents.

Cytogenetic testing is now routinely performed for the prognostic work-up of multiple myeloma (MM). The abnormalities del(17p), t(4;14) and del(13q) have been established as predictors of poor outcome in patients with MM treated with conventional chemotherapy or stem cell transplant; chromosome 1q gains and 1p losses have also been identified as novel prognostic factors. In recent years, bortezomib and lenalidomide have emerged as effective treatments for both relapsed/refractory and newly diagnosed MM. However, the effect of cytogenetic abnormalities is unclear among patients with MM treated with these novel agents. Here we review recent studies that analyze the impact of specific genomic aberrations on the outcome of MM treated with bortezomib and/or lenalidomide.

Prognostic factors in normal karyotype acute myeloid leukemia in the absence of the FLT3-ITD mutation.

Patients with normal karyotype acute myeloid leukemia (NK-AML) without the FLT3 internal tandem duplication (FLT3-ITD) mutation account for approximately 30% of all AML cases, and exhibit a heterogeneous clinical outcome. Except for NPM1 mutations, prognostic factors in this subgroup of AML are still unclear. Here we explored the impact of immunophenotypic markers along with NPM1 mutations and clinical features on the outcome of 133 FLT3-ITD negative NK-AML patients. CD34 expression was associated with poorer complete remission (CR) rate, disease-free survival (DFS), event-free survival (EFS), and overall survival (OS), whereas CD56 expression adversely affected EFS and OS. In contrast, NPM1 mutations correlated with an improved CR rate, DFS, and EFS. Moreover, males experienced shorter DFS and EFS, while older patients (≥60 years) had shorter EFS. Multivariate analysis of age, gender, NPM1, CD34, and CD56 showed NPM1 mutation was an independent predictor of better CR rate, DFS, and EFS (P<0.001, P=0.003, and P=0.006, respectively). In addition, older age was associated with shorter DFS and EFS (P=0.045 and P=0.028, respectively), and CD56 positivity predicted shorter EFS (P=0.012). Our results confirm the favorable impact of NPM1 mutations and identify the adverse prognostic relevance of CD56 expression in this subgroup of AML.

Aberrant nuclear p53 expression predicts hemizygous 17p (TP53) deletion in chronic lymphocytic leukemia.

Hemizygous TP53 gene deletion is the most important adverse risk factor in chronic lymphocytic leukemia (CLL), but its relationship with p53 protein expression is unclear. We investigated 110 CLL cases and correlated nuclear p53 protein immunoreactivity with TP53 gene deletion status and other CLL-associated genetic risk factors. Fluorescence in situ hybridization detected hemizygous TP53 deletions in 15 cases (13.6%), whereas immunohistochemical analysis detected nuclear p53 protein expression in 14 (12.7%). All cases expressing nuclear p53 protein had hemizygous TP53 deletions. Hemizygous TP53 gene deletion and p53 protein expression were strongly correlated (P < .001). There was no association between p53 expression and del(13q), del(11q) or trisomy 12 in CLL cases. Our data indicate that nuclear p53 protein expression, detected by a widely available immunohistochemical method, is strongly associated with TP53 deletion and that p53 immunohistochemical analysis may be adopted as a rapid, robust diagnostic tool for risk stratification of CLL.

Impact of genomic aberrations including chromosome 1 abnormalities on the outcome of patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone.

Previous literature suggests that cytogenetics may be used for risk-adapted therapy in patients with relapsed/refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone. However, the significance of each abnormality is still unclear, and chromosome 1 abnormalities have yet to be studied in this population. We therefore evaluated genetic risk factors including chromosome 1q gain and 1p loss by cIg-FISH in 143 patients with relapsed/refractory MM treated with lenalidomide and dexamethasone, and correlated the genomic aberrations with patient clinical outcomes. Patients had a median of two (range 1-7) previous therapies in this cohort. A total of 119 out of 143 (83%) patients had an objective response, with median time to progression (TTP) and overall survival (OS) of 11 and 28 months, respectively. Patients with del(1p21) or del(17p) (p53) deletions had a significantly shorter TTP. OS was shorter in patients with 1p21 or 17p deletions, but did not reach statistical significance. Prior bortezomib or thalidomide treatment was associated with shorter TTP and OS. Multivariate analysis identified del(17p), del(1p21), and prior bortezomib or thalidomide therapy as independent risk factors for shorter TTP. Our data suggest that chromosome 17p and 1p21 deletions adversely impact the outcome of lenalidomide and dexamethasone treated patients with relapsed/refractory MM. Improved therapeutic strategies are required for these patients.