Optical Genome Mapping: A Promising New Tool to Assess Genomic Complexity in Chronic Lymphocytic Leukemia (CLL)
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Samples
2.2. DNA Extraction, Labelling and Data Collection for Optical Mapping
2.3. Data Assembly, Structural Variant Calling and Filtering
2.4. Chromosome Banding Analyses and Fluorescence In Situ Hybridization
2.5. Chromosomal Microarray Analyses
2.6. Comparison among Techniques
2.7. Statistical Analyses
3. Results
3.1. Global SV and CNV Detection by OGM
3.2. Concordance Rate of OGM Results with Standard Techniques
3.3. Novel Abnormalities Detected by OGM
3.4. Global Genomic Complexity Found by OGM
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Non-CK Group | CK Group | p-Value | |
---|---|---|---|
n = 24; n (%) | n = 18; n (%) | ||
Gender | |||
Male | 17 (70.8%) | 11 (61.1%) | 0.530 |
Median age at diagnosis (range) | 66 (42–85) | 69 (37–88) | 0.297 |
Stage at diagnosis | |||
MBL | 0 (0.0%) | 3 (16.7%) | 0.071 |
CLL | 24 (100%) | 15 (83.3%) | |
Binet A | 22 (91.7%) | 10 (66.7%) | 0.085 |
Binet B/C | 2 (8.4%) | 5 (33.3%) | |
Common CLL genomic aberrations * | |||
del(13)(q14) | 19 (79.2%) | 11 (61.1%) | 0.302 |
Trisomy 12 | 3 (12.5%) | 5 (27.8%) | 0.256 |
del(11)(q22q23) | 5 (20.8%) | 7 (38.9%) | 0.302 |
Aberrations in TP53 | 0 (0.0%) | 8 (44.4%) | <0.001 |
del(17)(p13) | 0 (0.0%) | 7 (38.9%) | 0.001 |
TP53 mutation | 0 (0.0%) | 7 (38.9%) | 0.001 |
Unmutated IGHV | 12/23 (52.2%) | 12/18 (66.7%) | 0.524 |
Time from diagnosis to cytogenetic study (range) | 22.5 months (0–123) | 6 months (0–174) | 0.867 |
Median follow-up (range) | 44.5 months (0–95) | 31.5 months (0–78) | 0.065 |
Treatment | |||
Treated patients | 13 (54.2%) | 13 (72.2%) | 0.338 |
Median time to first treatment (95% CI) | 43 months (26–54) | 9 months (8–30) | 0.165 |
Patient ID | Undetected Alteration | Size (Kb) | Potential Cause of Discrepancy | Comments |
---|---|---|---|---|
12 | Translocation t(13;?)(p11;?) | - | Involvement of (peri-)centromeric regions | |
CK4 | Translocation t(17;?)(p11;?) | - | Involvement of (peri-)centromeric regions | |
CK8 | Translocation t(17;18)(q10;q10) | - | Involvement of (peri-)centromeric regions | |
CK9 | Translocation t(13;21)(q11;p11) | - | Involvement of (peri-)centromeric regions | |
CK10 | Translocation t(14;?)(p11;?) | - | Involvement of (peri-)centromeric regions | |
CK12 | Translocation t(11;?)(p11;?) | - | Involvement of (peri-)centromeric regions | |
CK13 | Translocation t(14;17)(q11;p11) | - | Involvement of (peri-)centromeric regions | |
CK16 | Translocation t(14;18)(p11;q11) | - | Involvement of (peri-)centromeric regions | |
CK16 | Translocation t(15;22)(p11;q15) | - | Involvement of (peri-)centromeric regions | |
CK17 | Translocation t(15;?)(p11;?) | - | Involvement of (peri-)centromeric regions | |
CK4 | Translocation t(6;19)(q12;p13) | - | Involvement of telomeric region | |
7 | Gain Yq11.223q11.23(24637115_28799654) | 4163 | Masked region (partial CNV on chr. Y) | Detected at 50% by CMA, and visually suggested in the whole genome CNV view |
CK2 | Deletion 17p13.3p13.3(525_2489182) | 2489 | Masked region (telomere) | |
CK6 | Deletion 1p36.33p36.32(1997349_3740109) | 1743 | Masked region (telomere) | |
20 | Deletion 6q21 | NA | Sensitivity | Detected in 12% of nuclei by FISH (CMA not available) |
21 | Deletion 13q14 (D13S319) | NA | Sensitivity | Detected in 17% of nuclei by FISH (not detected by CMA) |
CK3 | Gain 6pterq16 | NA | Sensitivity | Detected in 3% of nuclei by FISH, confirmed in metaphases (not detected by CMA) |
CK8 | Deletion 17p13.3p11.2(526_21347924) | 21347 | Sensitivity | Detected in 15% of nuclei by FISH (also visually found by CMA) |
CK12 | Gain 11q14.2q14.2(86177075_86856206) | 679 | Sensitivity | Detected at 25% by CMA, and visually suggested in the whole genome CNV view |
CK12 | Gain 11q22.3q22.3(106600681_106991146) | 390 | Sensitivity | Detected at 25% by CMA, and visually suggested in the whole genome CNV view |
CK12 | Gain 11q24.3q24.3(129345165_130249509) | 904 | Sensitivity | Detected at 25% by CMA, and visually suggested in the whole genome CNV view |
CK12 | Gain 19q13.2q13.42(41644540_54499334) | 12855 | Sensitivity | Detected at 20% by CMA |
CK13 | Gain 1p22pter | NA | Sensitivity | Detected in 5% of nuclei by FISH (not detected by CMA) |
7 | Translocation t(X;?)(p22;?) | Sensitivity | Percentage not available, could be a minor clone expanded during CBA culture | |
CK4 | Translocation t(12;?)(q24;?) | Sensitivity | Percentage not available, could be a minor clone (“add(12)(q24)” detected as clonal evolution in only two out of eight abnormal metaphases) | |
CK6 | Translocation t(9;?)(q34;?) | Sensitivity | Percentage not available, could be a minor clone expanded during CBA culture (CK defined as a composite karyotype) | |
CK8 | Translocation t(6;?)(p25;?) | Sensitivity | Percentage not available, could be a minor clone (“add(6)(p25)” detected as clonal evolution from abnormal cells with monosomy of chr. 17, as the TP53 deletion was detected at 15% the abnormality was probably below that percentage) | |
8 | Deletion 13q32.1(95520821_95658848) | 138 | Small deletion within chromothripsis | Small deletion, part of a complex CMA profile on chr. 13 properly detected |
CK16 | Translocation t(11;?)(q23;?) | Unknown cause of discrepancy | The “add(11)(q23)” was present in the main clone. Although not called as SV, some imaged molecules showed fusions between different regions of chr 11; WCP for chr. 11 confirmed hybridization in the whole abnormal chromosome | |
CK17 | Translocation t(9;?)(q34;?) | Unknown cause of discrepancy | Percentage not available; although the “add(9)(q34)” could be a minor clone (detected as clonal evolution in only two out of 13 abnormal metaphases), other abnormalities from the same clone were properly detected. WCP revealed that the additional material was from chr. 17 and, as seen by CBA, the chr. 17 telomeric region could be involved in the fusion (telomeric regions are masked by the SV pipeline) |
Characteristics | NC-OGM (n = 30) | C-OGM (n = 12) | p-Value |
---|---|---|---|
Age at diagnosis | 68 (37–85) | 67 (55–88) | 0.944 |
Males | 20 (66.7%) | 8 (66.7%) | 1.000 |
Advanced Binet stage (B or C) | 3 (10.0%) | 4 (33.3%) | 0.088 |
Time from diagnosis to OGM study (months) | 8 (0–174) | 25 (0–125) | 0.854 |
Number of abnormalities by OGM (filtered data) | 4 (1–11) | 32 (16–70) | <0.001 |
Copy number variants (CNV gains and losses) | 1 (0–4) | 12 (2–25) | <0.001 |
Translocations (intra and interchromosomal) | 2 (0–8) | 22 (9–42) | <0.001 |
Genomic complexity by conventional methods | |||
Low/intermediate-CK by CBA (3–4 abn.) | 6 (21.4%) | 2 (7.1%) | 1.000 |
High-CK by CBA (≥5 abn.) | 2 (6.7%) | 8 (66.7%) | <0.001 |
Intermediate-GC by CMA (3–4 abn. *) (n = 40) | 6/28 (21.4%) | 3/12 (25.0%) | 1.000 |
High-GC by CMA (≥5 abn. *) (n = 40) | 2/28 (7.1%) | 8/12 (66.7%) | 0.001 |
High complexity by CBA and/or CMA (≥5 abn.) | 2 (6.7%) | 11 (91.7%) | <0.001 |
Chromothripsis | 0 (0.0%) | 9 (75.0%) | <0.001 |
FISH abnormalities | |||
del(13q) | 22 (73.3%) | 8 (66.7%) | 0.715 |
Trisomy 12 | 7 (23.3%) | 1 (8.3%) | 0.402 |
del(11q) [ATM] | 8 (26.7%) | 4 (33.3%) | 0.715 |
del(17p) [TP53] | 1 (3.3%) | 6 (50.0%) | 0.001 |
TP53 abnormalities (del/mut) | 1 (3.3%) | 7 (58.3%) | <0.001 |
Unmutated IGHV (n = 41) | 15/29 (51.7%) | 9/12 (75.0%) | 0.296 |
Last follow-up (n = 40) ¥ | |||
Treated patients | 16/30 (53.3%) | 8/10 (80.0%) | 0.090 |
Time to first treatment (months, 95% CI) | 43 (28.0–52.6) | 2 (1.9–23.0) | 0.014 |
Follow-up (months) | 42 (0–95) | 26 (0–82) | 0.070 |
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Puiggros, A.; Ramos-Campoy, S.; Kamaso, J.; de la Rosa, M.; Salido, M.; Melero, C.; Rodríguez-Rivera, M.; Bougeon, S.; Collado, R.; Gimeno, E.; et al. Optical Genome Mapping: A Promising New Tool to Assess Genomic Complexity in Chronic Lymphocytic Leukemia (CLL). Cancers 2022, 14, 3376. https://doi.org/10.3390/cancers14143376
Puiggros A, Ramos-Campoy S, Kamaso J, de la Rosa M, Salido M, Melero C, Rodríguez-Rivera M, Bougeon S, Collado R, Gimeno E, et al. Optical Genome Mapping: A Promising New Tool to Assess Genomic Complexity in Chronic Lymphocytic Leukemia (CLL). Cancers. 2022; 14(14):3376. https://doi.org/10.3390/cancers14143376
Chicago/Turabian StylePuiggros, Anna, Silvia Ramos-Campoy, Joanna Kamaso, Mireia de la Rosa, Marta Salido, Carme Melero, María Rodríguez-Rivera, Sandrine Bougeon, Rosa Collado, Eva Gimeno, and et al. 2022. "Optical Genome Mapping: A Promising New Tool to Assess Genomic Complexity in Chronic Lymphocytic Leukemia (CLL)" Cancers 14, no. 14: 3376. https://doi.org/10.3390/cancers14143376