High Frequency of 1p36.32 Deletion or Loss of Heterozygosity in Follicular Lymphoma (FL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 183-183 ◽  
Author(s):  
K.-John Cheung ◽  
Adele Telenius ◽  
Betty Lai ◽  
Nathalie Johnson ◽  
Thomas Relander ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Array Cgh ◽  
Neutral Loss ◽  
Snp Array ◽  
Uniparental Disomy ◽  
B Cell Lymphoma ◽  
Chromosome 1 ◽  
Comparative Genomic ◽  
Polymorphism Analysis ◽  
Genetic Event

Abstract Background: The initial genetic event in ∼85% of follicular lymphomas (FL), the most common B-cell lymphoma in North America, is the t(14;18)(q32;q21) resulting in over-expression of the anti-apoptotic protein Bcl-2. The secondary events associated with disease progression are not well understood. Alterations affecting the p arm of chromosome 1 are evident by standard karyotype analysis in ∼20% of FL. We have further examined the relationship between 1p deletion and FL using high resolution genomic analyses. Methods: The prevalence of 1p alterations was investigated in 139 cases of indolent and transformed FL using whole genome tiling path BAC array Comparative Genomic Hybridization (array CGH). Array-based single nucleotide polymorphism analysis was performed on a subset of cases using Affymetrix 500K SNP arrays. Results: Array CGH identified a minimum region of deletion spanning ∼0.5MB within 1p36.32 in 51 cases (37%). In 38 cases (27%) this loss was exhibited in the transformed sample but not the pre-transformation sample. The majority of cases displayed heterozygous deletion, while two cases showed homozygous deletion. The mechanisms of loss included simple deletions, unbalanced translocations with various partner chromosomes and eleven cases with an unbalanced t(1;1)(p36;q12). The Affymetrix 500 SNP array analyses showed copy neutral loss of heterozygosity or acquired uniparental disomy (aUPD) in three of ten cases that were negative for loss by aCGH. Contained within the 1p36.32 minimally deleted region are only a few candidate genes including tumor necrosis factor receptor superfamily 14 (TNFRS14), which has been implicated in growth inhibition of HT-29 human colon adenocarcinoma cells and induction of Fas-mediated apoptosis in non-Hodgkin’s lymphoma. Conclusions: Our data indicate that loss of heterozygosity at 1p36.32 through deletion or aUPD constitutes the most common secondary cytogenetic event in FL. LOH at 1p36 may represent an important step in the progression of indolent to transformed FL. Further studies have been initiated to investigate other possible gene inactivation events such as methylation and mutation.

Loss of Heterozygosity in Childhood Acute Lymphoblastic Leukaemia Detected by Genome-Wide Microarray Single Nucleotide Polymorphism Analysis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1088-1088
Author(s):  
Andrew G. Hall ◽  
Lisa C. Bloodworth ◽  
Linda A. Hogarth ◽  
Nick P. Bown ◽  
Julie A. Irving
Keyword(s):  
Acute Lymphoblastic Leukaemia ◽  
Loss Of Heterozygosity ◽  
Lymphoblastic Leukaemia ◽  
Poor Prognosis ◽  
Snp Array ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Polymorphism Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Abstract Loss of heterozygosity (LOH) is detectable in many forms of malignancy, including leukaemia, using techniques such as microsatellite analysis and comparative genomic hybridisation. However, these techniques are laborious and require the use of relatively large amounts of DNA if the whole genome is to be examined. Here we describe the use of oligonucleotide microarrays to characterise single nucleotide polymorphisms (SNPs) in lymphoblasts isolated from children with acute lymphoblastic leukaemia for the pan-genomic mapping of LOH with a resolution of 100–200kb. Results were compared with DNA obtained during remission and on relapse. Abnormalities were seen in 8 of 10 cases. The two cases with no abnormalities and one case which showed identical changes affecting whole chromosomes at relapse and presentation remain in remission 1–9 years following retreatment. The 7 cases which showed LOH not affecting entire chromosomes died following relapse, suggesting that partial LOH may be associated with a poor prognosis. In 4 cases LOH was only detectable at relapse suggesting that progressive LOH may be a cause of disease progression and/or drug resistance. This was supported by detailed analysis of one case in which LOH involving the glucocorticoid receptor (GR) was associated with mutation of the remaining allele. In cell line models the loss of a functional GR is associated with profound resistance to steroids. The most frequent abnormality detected in this series involved chromosome 9p. In each of the four cases where this was observed LOH included the INK4 locus. In three of the four cases INK4 loss was only observed at relapse (see figure), suggesting that this abnormality may be commonly associated with treatment failure, supporting previous reports that 9p abnormailities are associated with a poor prognosis. One case was reported as showing monosomy 20 as the sole cytogenetic aberration but LOH analysis identified 9p LOH and loss of 20q, with retention of heterozygocity for 20p. These findings strongly implicate unbalanced translocation der(9)t(9;20),-20 as described by Clark et al (Leukaemia, 2000, 14:241). Our observations demonstrate that SNP array analysis is a powerful new tool for the analysis of allelic imbalance and unbalanced translocations in leukaemic blasts.

Genetic Profiling of BCR/ABL Negative Myeloproliferative Disorders Using High-Resolution Microarrays

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1538-1538
Author(s):  
Frank Stegelmann ◽  
Martin Griesshammer ◽  
Sandra Ruf ◽  
Susanne Kuhn ◽  
Frank G. Rücker ◽  
...  
Keyword(s):  
High Resolution ◽  
Array Cgh ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Myeloproliferative Disorders ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Snp Analysis ◽  
Genomic Imbalances ◽  
Trisomy 9

Abstract Recently, the identification of the gain of function mutation JAK2V617F delivered important insights into the pathogenesis of BCR/ABL negative myeloproliferative disorders (MPD). JAK2V617F is detectable in more than 90% of polycythemia vera (PV) patients (pts) and in approximately 50% of pts with essential thrombocythemia (ET) or primary myelofibrosis (PMF), representing the genetic hallmark of BCR/ABL negative disease. However, about 30% of MPD pts lack the JAK2V617F mutation and previous studies on ET and PV demonstrated that clonality exceeds the percentage of V617F mutated cells. These findings suggest that additional genetic alterations are involved in the pathogenesis of MPD, in both JAK2 mutated and unmutated pts. To identify novel genetic aberrations and to determine whether specific lesions are associated with disease phenotype, genomic DNA from granulocytes of 72 MPD pts classified according to the WHO criteria was analyzed using high-resolution, genome-wide microarray techniques [disease, number analyzed, JAK2 mutation status: PMF, n=14, 9/14; post-ET MF, n=5, 3/5; post-PV MF, n=5, 5/5; PV, n=37, 37/37; ET, n=11, 11/11]. In a first approach, all cases were investigated by comparative genomic hybridization to 8k arrays (array CGH) with an average probe spacing of less than 1 Mb. While no genomic imbalances were found in ET, 11% of PV pts (n=4) exhibited large (>10 Mb) deletions on 20q (n=2) or gains on 9p and 1q (n=1, each). In addition, small (<1 Mb) recurrent gains in 1q21.1 (n=2) and 22q11.23 (n=2) were identified. In MF pts the incidence of large genomic imbalances was 25% (n=6) with trisomy 9 (n=3) being the most frequent aberration followed by loss of 20q, 5q, and 13q in single cases. Furthermore, in one pt with post-PV MF small genomic losses in 17q11.2 (2 Mb) and 17p13.2 (0.8 Mb) were identified harbouring NF1 but not TP53. Deletion of the NF1 allele without concomitant loss of TP53 was confirmed by FISH. To further increase resolution and to investigate the role of uniparental disomy (UPD), single nucleotide polymorphism (SNP) analysis using the Affymetrix 250k Nsp SNP array was performed in all MF cases. Copy number estimation and loss of heterozygosity probability were analyzed using a set of 117 remission samples from acute myeloid leukemia pts as a common reference. SNP analysis confirmed all anomalies detected by array CGH. In addition, SNP analysis revealed small genomic losses (1.6–2.6 Mb) in 1q21.2 (n=3), 5q13.2, and 3p13 (n=1, each), and in one secondary MF pt another microdeletion in 17q11.2 (1.2 Mb). UPDs recurrently affected 9p (n=5) in a region harbouring the JAK2 locus. In single cases, large UPDs of 1q (25 Mb), 2p (14 Mb), 5q (4 Mb), 6p (11 Mb), and 7q (11 Mb) were identified. Of note, all JAK2V617F mutated post-PV and post-ET MF cases exhibited 9p abnormalities represented either by trisomy 9 or UPD of 9p. In conclusion, using a combined microarray approach we were able to detect novel submicroscopic alterations in addition to known abnormalities. Parallel analysis of both techniques clearly demonstrated the superiority of array-SNP mapping. Further analyses on larger pt populations and correlation with global gene expression data will facilitate the identification of disease-related genes that are involved in the pathogenesis of BCR/ABL negative MPD.

scholarly journals Prenatal diagnosis of 7 cases with uniparental disomy by utilization of single nucleotide polymorphism array

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lili Zhou ◽  
Zhaoke Zheng ◽  
Yunzhi Xu ◽  
Xiaoxiao Lv ◽  
Chenyang Xu ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prenatal Diagnosis ◽  
Molecular Analysis ◽  
Correct Diagnosis ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 1 ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Rescue Mechanism

Abstract Background The phenotypes of uniparental disomy (UPD) are variable, which may either have no clinical impact, lead to clinical signs and symptoms. Molecular analysis is essential for making a correct diagnosis. This study involved a retrospective analysis of 4512 prenatal diagnosis samples and explored the molecular characteristics and prenatal phenotypes of UPD using a single nucleotide polymorphism (SNP) array. Results Out of the 4512 samples, a total of seven cases of UPD were detected with an overall frequency of 0.16%. Among the seven cases of UPD, two cases are associated with chromosomal aberrations (2/7), four cases (4/7) had abnormal ultrasonographic findings. One case presented with iso-UPD (14), and two case presented with mixed hetero/iso-UPD (15), which were confirmed by Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as maternal UPD (15) associated with Prader-Willi syndrome (PWS). Four cases had iso-UPD for chromosome 1, 3, 14, and 16, respectively; this is consistent with the monosomy rescue mechanism. Another three cases presented with mixed hetero/isodisomy were consistent with a trisomy rescue mechanism. Conclusion The prenatal phenotypes of UPD are variable and molecular analysis is essential for making a correct diagnosis and genetic counselling of UPD. The SNP array is a useful genetic test in prenatal diagnosis cases with UPD.

scholarly journals A case report and mechanism analysis of a normal phenotype mosaic 47, XXY complicated by paternal iUPD (9) who had a normal PGD result

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Dan Li ◽  
Yun Wang ◽  
Nan Zhao ◽  
Liang Chang ◽  
Ping Liu ◽  
...  
Keyword(s):  
Case Report ◽  
Karyotype Analysis ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Comparative Genomic ◽  
Klinefelter’S Syndrome ◽  
Mechanism Analysis ◽  
Klinefelter's Syndrome ◽  
Preimplantation Genetic Testing ◽  
First Case

Abstract Background Uniparental disomy (UPD) refers to the situation in which two copies of homologous chromosomes or part of a chromosome originate from the one parent and no copy is supplied by the other parent. Case presentation Here, we reported a woman whose karyotype was 46, XX, t (1;17)(q42;q21), has obtained 5 embryos by intracytoplasmic sperm injection (ICSI) after one cycle of in vitro fertility (IVF). After microarray-based comparative genomic hybridization (array-CGH) for preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR), two embryos were balanced, one balanced embryo was implanted and the patient successfully achieved pregnancy. Amniocentesis was performed at the 19th week of gestation for karyotype analysis and single nucleotide polymorphism (SNP)-array test. The result of karyotype analysis was: mos 47, XXY [19]/46, XY [81]; SNP-array results revealed 46, XY, iUPD (9) pat. After full genetic counseling for mosaic Klinefelter’s syndrome and paternal iUPD (9), the couple decided to continue pregnancy, and the patient gave birth to a healthy boy. The newborn is now 3.5 years old, and developed normally. This case will provide counseling evidences of paternal iUPD (9) for doctors. Conclusions This is the first case report of paternal iUPD9 with mosaic Klinefelter’s syndrome, and no abnormality has been observed during the 3.5-year follow-up. Further observation is required to determine whether the imprinted genes on the chromosomes are pathogenic and whether recessive pathogenetic genes are activated.

scholarly journals SNP Array Analysis Reveals Novel Genomic Abnormalities Including Copy Neutral Loss of Heterozygosity in Anaplastic Oligodendrogliomas

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e45950 ◽  
Author(s):  
Ahmed Idbaih ◽  
François Ducray ◽  
Caroline Dehais ◽  
Célia Courdy ◽  
Catherine Carpentier ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Neutral Loss ◽  
Snp Array ◽  
Array Analysis ◽  
Snp Array Analysis

Chromosomal defects Detected by SNP-Array-Based Karyotyping Are Independent Predictors of Survival in Acute Myeloid Leukemia (AML)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 431-431 ◽  
Author(s):  
Ramon V. Tiu ◽  
Lukasz P Gondek ◽  
Bhavana Bhatnagar ◽  
Christine O’Keefe ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Detection Rate ◽  
Significant Proportion ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Simultaneous Detection ◽  
Gene Copy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Chromosomal Defects

Abstract Cytogenetics is the most important predictor of outcomes in AML. Traditional metaphase cytogenetics (MC), can detect abnormalities in only 40–60% of AML patients. Whole genome scanning by single nucleotide polymorphism arrays (SNP-A) can identify somatic chromosomal changes in hematopoietic malignancies and, due to its superb resolution, may detect previously cryptic unbalanced defects, even in samples deemed “normal” or uninformative using MC. Through simultaneous detection of loss of heterozygosity (LOH) and gene copy number changes, SNP-A also facilitate the identification of somatic segmental uniparental disomy (UPD). Here we tested whether SNP-A analysis could improve the detection rate of chromosomal defects in AML and enhances the prognostic value of MC. Analyses were performed using 250K and/or 6.0 Affymetrix SNP arrays on 140 primary (p) and secondary AML (sAML) patients (newly diagnosed= 107, relapsed=15, remission= 12, persistent=6) and 116 healthy controls. Data on cytogenetic detection rate, complete remission (CR), overall survival [OS], relapse free survival [RFS], remission duration [RD], and event free survival [EFS]) rates were obtained from patients who received induction chemotherapy. We also performed Flt-3 ITD, Flt-3 TKD and NPM-1 mutation analysis and integrated the clinical outcomes with SNP-A results. For patients in whom new defects were detected, germ-line DNA was also analyzed whenever technically possible. The cytogenetic abnormality detection rate in patients with active disease was higher with SNP-A compared to MC (pAML, 75% vs 43% p=<0.0001; sAML, 81% vs 53% p=0.0015). UPD comprised a significant proportion of the SNP-A detected defects (36% in pAML and 40% in sAML) and included chromosomal defects not described in a previous 10K SNP study, such as 1p, 3p, 7q, 11q, 13q, 17q, 20, and 21q. Newly diagnosed AML patients with SNP-A lesions had less favorable outcomes. This was true for all AML patients (OS [5.8 months vs not reached {NR}, p=<0.0001], RFS [6.4 months vs NR, p=0.04] RD [6.9 months vs NR, p=0.04], EFS [2.7 vs 17 months, p=0.0007]); pAML w/normal MC (OS [10.8 months vs NR, p=0.007], RFS [14.2 months vs NR, p=.04], EFS [7.1 months vs NR, p=0.009]); and pAML/sAML with abnormal MC (OS [4.6 months vs 8.5, p=0.04], EFS [2.5 vs 12.4 months,p=0.05]). Of key importance, the presence of copy-neutral loss of heterozygosity (LOH) also translates to worse outcomes (OS [4.2 vs 15.1 months, p=0.0018], EFS [2.6 vs 8.6 months, p=0.007]), a finding comparable to gains or traditional LOH. SNP-A also improved the ability to predict outcomes in both mutant and wild types (WT) based on Flt-3 ITD and NPM-1 mutation status, with inferior survival in patients with new defects detected by SNP-A (Flt-3 ITD mutant [OS: 8 months vs NR, p=0.0011; LFS: 14.2 months vs NR, p=0.04]; Flt-3 ITD WT [8.5 months vs NR, p=0.024]; NPM-1 mutant [OS: 12.1 months vs NR, p=0.03; LFS: 12.3 months vs NR, p=0.05]; and NPM-1 WT [OS: 5.7 months vs 15.1 months, p=0.04]). Multivariate analysis using the Cox proportional hazard method showed that the presence or absence of SNP-A defects is an independent predictive factor for OS (p=0.0076) and EFS (p=0.007). In conclusion, SNP-A improves the cytogenetic detection rate of MC. The detection of new chromosomal lesions, particularly copy-neutral LOH such as UPD, provides additional informative data to MC that is prognostically significant.

TNFRSF14 Is Mutated in a Subset of Follicular Lymphoma and Correlated with Inferior Prognosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1919-1919
Author(s):  
K-John Cheung ◽  
Nathalie Johnson ◽  
Joslynn Affleck ◽  
Tesa Severson ◽  
Christian Steidl ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Conflicts Of Interest ◽  
Neutral Loss ◽  
Methylation Status ◽  
Snp Array ◽  
Suppressor Gene ◽  
Homozygous Deletion ◽  
Chromosome Band ◽  
Comparative Genomic ◽  
Driver Genes

Abstract Abstract 1919 Poster Board I-942 The secondary genetic events associated with follicular lymphoma (FL) development are obscure as to the identification of critical driver genes. Clinical correlative studies have implicated chromosome band 1p36 deletions and linked them to a propensity for transformation and poor outcome. This region also showed a high frequency of copy-neutral loss of heterozygosity as demonstrated by SNP array analysis. In this study, we applied BAC array comparative genomic hybridization (array CGH) to 141 FL specimens and detected deletion of 1p36 in 20% of the cases with a minimum region of deletion (MRD) of ∼100 kb within the band 1p36.32. The majority of cases displayed heterozygous deletion, while two cases showed homozygous deletion. The MRD encompassed five genes: HES5, LOC115110, TNFRSF14, C1orf93 and MMEL1. Methylation status of CpG in the promoter region of genes in the MRD revealed no difference among samples differing in 1p36 status. However, exonic sequencing of the MRD genes identified somatic base mutations only in the TNFRSF14 gene in four of five selected cases with 1p36 deletion. Lower expression of TNFRSF14 was also found in 1p36 deleted cases. Validation of TNFRSF14 mutations was undertaken in an expanded cohort of 251 FL patients which showed that 45 cases (18%) displayed a total of 50 mutations and that inferior prognosis was significantly associated with TNFRSF14 mutation status. We propose that TNFRSF14, a gene previously implicated in growth inhibition and Fas-induced apoptosis, is a candidate tumor suppressor gene in FL. Disclosures: No relevant conflicts of interest to declare.

Somatic and Germline Copy Neutral Loss of Heterozygosity Are Common in Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4567-4567
Author(s):  
Megan Hanna ◽  
Bethany Tesar ◽  
Kristen E. Stevenson ◽  
Alexander R. Vartanov ◽  
Stacey M. Fernandes ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Neutral Loss ◽  
Snp Array ◽  
Lymphocytic Leukemia ◽  
Alternative Mechanism ◽  
Large Set ◽  
The Impact ◽  
13Q Deletion

Abstract Abstract 4567 Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults, and prognosis is still difficult to predict, although cytogenetic abnormalities identified by FISH are most helpful. Isolated reports have suggested that copy neutral loss of heterozygosity (cnLOH) can involve 13q and 17p in CLL, but the extent and the impact on clinical outcome is not well established. We therefore embarked upon characterization of cnLOH in a large set of 230 CLLs with matched normal DNA. The median age at diagnosis of CLL in this patient population was 54 (33–79). 87% of patients were Rai 0–1 at diagnosis, and 79% were chemotherapy naive at sampling. 121 of 230 patients were treated, with a median TTFT of 42 months. The median follow-up for surviving patients is 74 months. 44% of patients carried one somatic copy number abnormality (CNA) by SNP array, 20% two, 7% three, 5% four and 4% more than five. cnLOH was called by the Affymetrix Genotyping Console Software, which evaluates each SNP for copy number and then subtracts the A allele value from the B allele value within an individual sample, thereby allowing independent evaluation of tumor (somatic) and normal (germline). All calls were manually reviewed. A size cut-off of 1.0 Mb was used to determine significant cnLOH events. In total, of 230 patients, we found 26 events of somatic cnLOH (11%) and 36 events of germline cnLOH (16%), affecting 56 separate patients (24%). This frequency of cnLOH was surprisingly high and suggested that cnLOH might be an alternative mechanism affecting known loci in CLL. This was the case, as the most common events overall involved 13q in 25 patients, the X chromosome in 9 patients, chromosomes 17 and 18 in five patients each, and chromosomes 9, 11 and 12 in four patients each. Interestingly, germline events were quite common. Six patients had small regions of germline LOH with much more extensive adjacent somatic LOH, two on chr 13, one on chr 17, two on chr X and one on chr 20; these were coded as germline in the analysis. In addition, of the 25 patients with cnLOH on chromosome 13, 18 of these were in the germline and 7 were somatic. The region(s) of cnLOH were typically adjacent to a 13q deletion, and often involved the entire chromosome arm. Somatic cnLOH at 13q was associated with intermediate sized deletions including the RB gene (p=0.002). Of the 18 patients with germline cnLOH at 13q, 7 of them had no 13q deletion, while 7 had monoallelic deletion and 4 biallelic deletion. Thus 7 patients (3%) had cnLOH events at 13q, in the absence of 13q deletion, again suggesting an alternative mechanism affecting this locus. Germline cnLOH was associated with treatment prior to sampling (44% vs 17%, p<0.001), possibly due to its association with unmutated IGHV(58% vs 32%, p=0.008), and ZAP70 positivity (59% vs 36%, p=0.024). Somatic cnLOH was not associated with any patient characteristics. Neither somatic nor germline cnLOH was associated with >= 1 somatic CNA, but an association between both LOH types and >= 2 somatic CNAs was observed (p=0.053 germline and p=0.030 somatic). TTFT was reduced in patients with either germline cnLOH (61 mos vs 103, p=0.004) or somatic cnLOH (53 mos vs 107, p=0.008). Presence of two or more CNAs was also associated with short TTFT (48 mos vs 115, p<0.001). In order to assess the impact of cnLOH and CNAs on outcome independent of prior therapy, we evaluated TTFT in the 181 chemotherapy naive patients. In this subgroup, germline cnLOH was not associated with short TTFT, while somatic cnLOH (80 mos vs 125, p=0.018) and two or more somatic CNAs (80 mos vs 125, p=0.009) were. In multivariable Cox modeling including germline cnLOH, IGHV, and del 11q or 17p by FISH, the only significant predictor of TTFT was unmutated IGHV (hazard ratio (HR) 4.48, p<0.001). In multivariable Cox modeling including somatic cnLOH and the variables above, the only significant predictor of TTFT was again unmutated IGHV (HR 4.41, p<0.001). When the presence of two or more somatic CNAs was added to these models, this variable was significant along with IGHV (HR 2.04, p=0.009 in germline model; HR 1.84, p=0.033 in somatic model). We conclude that both somatic and germline cnLOH are common in CLL, affecting one quarter of patients in this dataset, and frequently involve chromosomal regions known to be important in CLL. cnLOH is associated with increased somatic CNAs and unmutated IGHV, and therefore poor prognosis. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document