Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors
Abstract
:1. Introduction
2. Results
3. Discussion
3.1. ALK Gene
3.2. APC Gene
3.3. CHEK2 Gene
3.4. ELP1 Gene
3.5. MLH1 and MSH2 Genes
3.6. NF1 Gene
3.7. NF2 Gene
3.8. TP53 Gene
3.9. Detecting Germline Variants in the Emerging Era of Precision Medicine
4. Materials and Methods
4.1. Patients
4.2. Genetic Testing and Data Analysis
4.3. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | Absolute Numbers | % |
---|---|---|
Sex | ||
Male | 29 | 57% |
Female | 22 | 43% |
Tumor pathology | ||
High-grade glioma (HGG) | 15 | 29% |
Medulloblastoma | 11 | 21% |
Low-grade glioma (LGG) | 8 | 16% |
Ependymoma | 3 | 6% |
Atypical teratoid rhabdoid tumor (ATRT) | 2 | 4% |
Choroid plexus tumor (CPT) | 2 | 4% |
Craniopharyngioma | 1 | 2% |
Germ cell tumor (GCT) | 1 | 2% |
Diffuse glioneuronal leptomeningeal tumor | 1 | 2% |
Other 1 | 2 | 4% |
Unknown 2 | 5 | 10% |
Secondary malignancies | 3 | 6% |
Lethal outcome | 7 | 14% |
Jongmans et al. tool suggestions for genetics exploration | 29 | 57% |
MIPOGG suggestions for genetics exploration | 39 | 76% |
Patients with germline variants in predisposing genes | 14 | 27% |
Pt. No. | Sex | Age | Location | Type | Gene | Variant | Zygosity | Clin Var | Family History | Radiation Therapy | Systemic Therapy | Other Relevant Data |
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | m | 11 | IT | MBL | ALK | NM_004304.4 c.1572del p.(Asp525MetfsTer10) | HZ | FSI LP | BT (12.5%) | CSI 35.2 Gy/22 + FCP boost 19.8 Gy/11 | VCR, Cis, CCNU | |
2 | m | 4 | IT | MBL | ALK | NM_004304.4 c.2543C>T (p.Ala848Val) | HZ | MS VUS | LC (12.5%), LrC (12.5%) | ? | VCR, Cyc + ? | postoperative mutism |
3 | m | 15 | ST | HGG | ALK | NM_004304.4 c.3115G>A p.(Val1039Met) | HZ | MS VUS | / | 59.4 Gy/33 | TMZ | |
4 | f | 13 | BS | HGG | APC | NM_000038.5 c.1690C>T p.(Arg564Ter) rs137854574 | HZ | SG (NV) P | FAP (50%), BC (25%) | (MBL) CSI 23.4 Gy/13 + FCP boost 30.6 Gy/17 | VCR, Cis, CCNU, TMZ | treated for MBL |
5 | m | 2 | IT | MBL | CHEK2 | NM_007194.3 c.470T>C p.(Ile157Thr) rs17879961 | HZ | MS LP | LY (25%), AC (12.5%), PC (25%) | CSI 24 Gy/15 + FCP boost 30.6 Gy/17 | VCR, Cis, VP, Cyc, MTX, HDCT | |
6 | f | 12 | ST | HGG | ELP1 | NM_003640.4 c.1908+1G>T | HZ | MS VUS | LEU (25%) | 30 Gy/15 + 16 Gy/9 | VCR, Cis, CCNU, TMZ | treated for MBL |
7 | f | 14 | IT | MBL | ELP1 | NM_003640.4 c.1952del p.(Leu651TyrfsTer3) | HZ | FSI (NV) LP | CRC (25%) | CSI 23.4 Gy/13 + FCP boost 30.6 Gy/17 | VCR, Cis, CCNU | hair depigmentation, VCR neuropathy |
8 | m | 12 | BS | PA | ELP1 | NM_003640.4 c.2495C>T p.Pro832Leu | HZ | SD (NV) LP | BT (25%), 6 UT (6.25–25%) | 50.4 Gy/30 + boost 3.6 Gy/2 | TR, DF | |
9 | m | 15 | ST | HGG | MLH1/ MLH1 | NM_000249.3 c.1611del p.(Gln537HisfsTer54)/NM_000249.3 c.1613G>T p.(Trp538Leu) | HZ/ HZ | FSI. P/ MS. VUS | CRC (50%) | 59.4 Gy/33 | TMZ | skin hem-angioma |
10 | m | 2 | IT | EP | MSH2 | NM_000251.2 c.274C>G (p.Leu92Val) | HZ | MS VUS | / | 54 Gy/30 + 5.4 Gy/3 | / | |
11 | f | 12 | ST | HGG | MSH2 | NM_000251.2 c.2382dup p.(Pro795ThrfsTer4) | HZ | FSI (NV) LP | SC (25%), HT (25%) | CSI 36 Gy/20 + boost 19.8 Gy/11 | TMZ | |
12 | m | 5 | BS SC | UNK | NF1 | NM_001042492.2 c.3974+1G>A | HZ | SD (NV) P | Fs, OPGs (25–50%) | / | VCR, Carbo, VBL | multiple café au lait spots |
13 | f | 11 | BSSC | many | NF2 | NM_000268.3 c.999+1G>A | HZ | SD (NV) P | PC (25%) | 59.4 Gy/33 | BV, EV | multiple café au lait spots |
14 | f | 4 | ST | HGG | TP53 | NM_000546.5 c.490A>G p.(Lys164Glu) rs879254249 | HZ | MS LP | CP (50%), BrC (25%) | 54 Gy/30 | TMZ |
Genes with Reported Germline Variants in Particular Tumor Types | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Gene | ATRT | MBL | PBL | LGG | HGG | EP | GCT | MN | VS | UKN | NR |
ALK | |||||||||||
APC | * | ||||||||||
CHEK2 | |||||||||||
DICER1 | |||||||||||
ELP1 | |||||||||||
FANCI | |||||||||||
KDM4C | |||||||||||
MLH1 | |||||||||||
MSH2 | |||||||||||
MSH6 | |||||||||||
NF1 | |||||||||||
NF2 | |||||||||||
PTCH1 | |||||||||||
SMARCB1 | |||||||||||
TP53 | |||||||||||
TSC1 | |||||||||||
TSC2 | |||||||||||
VHL | |||||||||||
WRN | |||||||||||
Recent NGS studies of germline variants in pediatric neuro-oncology cohorts | |||||||||||
Study | Color | Patient number | Sampling remarks | ||||||||
Barsan et al. (2019) [19] | 58 | non-consecutive patients who underwent NGS on clinical oncologist’s demand | |||||||||
Fukushima et al. (2022) [21] | 38 | consecutive patients from a single center, mostly germ cell tumors | |||||||||
Diaz de Ståhl et al. (2023) [20] | 82 | purposive sampling from the national biobank to represent major tumor type frequencies | |||||||||
Jovanović et al. (2023) [this article] | 51 | consecutive patients from the national tertiary referral center |
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Jovanović, A.; Tošić, N.; Marjanović, I.; Komazec, J.; Zukić, B.; Nikitović, M.; Ilić, R.; Grujičić, D.; Janić, D.; Pavlović, S. Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors. Int. J. Mol. Sci. 2023, 24, 17387. https://doi.org/10.3390/ijms242417387
Jovanović A, Tošić N, Marjanović I, Komazec J, Zukić B, Nikitović M, Ilić R, Grujičić D, Janić D, Pavlović S. Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors. International Journal of Molecular Sciences. 2023; 24(24):17387. https://doi.org/10.3390/ijms242417387
Chicago/Turabian StyleJovanović, Aleksa, Nataša Tošić, Irena Marjanović, Jovana Komazec, Branka Zukić, Marina Nikitović, Rosanda Ilić, Danica Grujičić, Dragana Janić, and Sonja Pavlović. 2023. "Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors" International Journal of Molecular Sciences 24, no. 24: 17387. https://doi.org/10.3390/ijms242417387