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1. Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group

Author

Guerrini-Rousseau, L, Masliah-Planchon, J, Waszak, SM, Alhopuro, P, Benusiglio, PR, Bourdeaut, F, Brecht, IB, Del Baldo, G, Dhanda, SK, Garre, ML, Gidding, CEM, Hirsch, S, Hoarau, P, Jorgensen, M, Kratz, C, Lafay-Cousin, L, Mastronuzzi, A, Pastorino, L, Pfister, SM, Schroeder, C, Smith, MJ, Vahteristo, P, Vibert, R, Vilain, C, Waespe, N, Winship, IM, Evans, DG, Brugieres, L, Guerrini-Rousseau, L, Masliah-Planchon, J, Waszak, SM, Alhopuro, P, Benusiglio, PR, Bourdeaut, F, Brecht, IB, Del Baldo, G, Dhanda, SK, Garre, ML, Gidding, CEM, Hirsch, S, Hoarau, P, Jorgensen, M, Kratz, C, Lafay-Cousin, L, Mastronuzzi, A, Pastorino, L, Pfister, SM, Schroeder, C, Smith, MJ, Vahteristo, P, Vibert, R, Vilain, C, Waespe, N, Winship, IM, Evans, DG, and Brugieres, L

Abstract

BACKGROUND: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. METHODS: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. RESULTS: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. CONCLUSION: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.

Published
2022

2. Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Author

Hurkmans, EGE, Klumpers, MJ, Dello Russo, C, De Witte, W, Guchelaar, H-J, Gelderblom, H, Cleton-Jansen, A-M, Vermeulen, SH, Kaal, S, van der Graaf, WTA, Flucke, U, Gidding, CEM, Schreuder, HWB, de Bont, ESJM, Caron, HN, Gattuso, G, Schiavello, E, Terenziani, M, Massimino, M, McCowage, G, Nagabushan, S, Limaye, A, Rose, V, Catchpoole, D, Jorgensen, AL, Barton, C, Delaney, L, Hawcutt, DB, Pirmohamed, M, Pizer, B, Coenen, MJH, Te Loo, DMWM, Hurkmans, EGE, Klumpers, MJ, Dello Russo, C, De Witte, W, Guchelaar, H-J, Gelderblom, H, Cleton-Jansen, A-M, Vermeulen, SH, Kaal, S, van der Graaf, WTA, Flucke, U, Gidding, CEM, Schreuder, HWB, de Bont, ESJM, Caron, HN, Gattuso, G, Schiavello, E, Terenziani, M, Massimino, M, McCowage, G, Nagabushan, S, Limaye, A, Rose, V, Catchpoole, D, Jorgensen, AL, Barton, C, Delaney, L, Hawcutt, DB, Pirmohamed, M, Pizer, B, Coenen, MJH, and Te Loo, DMWM

Abstract

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Published
2022

3. An automated method for the bioanalysis of vincristine suitable for therapeutic drug monitoring and pharmacokinetic studies in young children

Author

Koopmans, P, Gidding, CEM, Uges, DRA, Faculteit Medische Wetenschappen/UMCG, and Groningen Research Institute of Pharmacy

Subjects
small sample volume, children, analysis, electrochemical detection, LIQUID-CHROMATOGRAPHY, on-column SPE, LLQ, vincristine
Abstract

Pharmacokinetic studies in young children require very sensitive methods using low plasma volumes. Although vincristine has been used as an antineoplastic drug for almost 40 years, data on vincristine pharmacokinetics and pharmacodynamics are scarce, especially in young children. One of the reasons for this is the lack of a specific and sensitive assay suitable for small plasma volumes. Therefore the authors aimed to improve an existing high-performance liquid chromatography (HPLC) assay by changing the solid-phase extraction material and by using a more sensitive and controlled electrochemical detector. An on-line solid-phase extraction was used with a preconcentration column of 10 . 3 min ID containing octadecyl silane (ODS) reversed-phase material and an analytical microsphere C18 column. The mobile phase was unchanged and consisted of 35% phosphate buffer 0.02 mol (pH 7.00 +/- 0.10), 50% methanol, and 15% acetonitrile. Detection was performed with a new electrochemical detector. This detector comprised a highly stable Faraday-shielded oven compartment that accommodated a column and flowcell. The flowcell had a spacer thickness of 0.25 mum set at 830 mV. It also had an excellent signal-to-noise ratio, which resulted in very sensitive electrochemical analysis. These improvements resulted in a lower required sample volume of only 0.3 mL instead of 1.2 mL plasma with a very low Emit of quantitation of 0.483 mug/L according to good laboratory practice (GLP) rules. The intraday coefficients of variation were 6.2% (0.483 mug/L) and 4.2% (18.4 mug/L). The interday coefficients of variation were 10.3% (0.483 mug/L) and 8.5% (18.4 mug/L).

Published
2001

4. The influence of recombinant human insulin-like growth factor-I (rhIGF-I) on cell growth and cytotoxicity of drugs in childhood rhabdomyosarcoma cell lines and xenograft models

Author

Gidding, CEM, Germain, GS, Dilling, MB, Meeuwsen-de Boer, TGJ, Ashmun, RA, Veverka, KA, Kamps, WA, Houghton, PJ, and Faculteit Medische Wetenschappen/UMCG

Subjects
EXPRESSION, MICE, FACTOR RECEPTOR, REGENERATION, HUMAN NEUROBLASTOMA, cytotoxicity, VINCRISTINE NEUROPATHY, WILMS-TUMOR, SCIATIC-NERVE, vincristine, IGF-I, APOPTOSIS
Abstract

Purpose: Recombinant human insulin-like growth factor I (rhIGF-I) has been reported to ameliorate vincristine-induced neuropathy, the dose-limiting side effect of this antimitotic anticancer drug. However, rhIGF-I also might have adverse effects, as has been shown in vitro, where it stimulates growth of cancer cells and protects them from cytotoxicity of anticancer drugs. The influence of rhIGF-I on the cytotoxicity of vincristine has not yet been studied. Furthermore, studies performed have been done under serum-free conditions, which are far from physiological. Methods: We studied the influence of rhIGF-I on the growth of two rhabdomyosarcoma cell lines (Rh30 and Rh1) and on the antitumor effects of vincristine, cisplatin, etoposide, doxorubicin, and topotecan under serum-free and serum-containing conditions. To extend the in vitro data, we grew Rh30 cells as xenografts in mice and determined the effects of vincristine, rhIGF-I or their combination on tumor growth. Results: In vitro, both cell lines demonstrated a functional type I IGF receptor, as shown by the rapid activation of ribosomal p70 S6 kinase after stimulation with rhIGF-I. Under serum-free conditions, rhIGF-I stimulated growth of both cell lines. Exposure to cytotoxic drugs with and without rhIGF-I resulted in higher cell numbers in cultures exposed to rhIGF-I. However, relative to the appropriate control, fractional growth inhibition and or cell kill of the cytotoxic drugs was identical with and without rhIGF-I. Under serum-containing conditions, rhIGF-I had no effect on cell growth or drug cytotoxicity. In vivo we did not find a significant influence of rhIGF-I on HxRh30 cell growth, or on the antitumor activity of vincristine. Conclusions: These studies show that rhIGF-I has no adverse effects on human rhabdomyosarcoma growth or on the antitumor effect of cytotoxic drugs under serum-containing conditions in vitro or in tumor-bearing mice. Potentially, therefore, rhIGF-I may ameliorate vincristine-induced neuropathy without adversely influencing tumor growth or vincristine cytotoxicity in children.

Published
2000

5. N-METHYLADRENALINE - AGE-DEPENDENT URINARY-EXCRETION, PERINATAL ORGAN CONTENT AND RELATION WITH CLASSICAL CATECHOLAMINES

Author

KEMA, IP, SCHOOTS, CJF, GIDDING, CEM, OKKEN, A, AARNOUDSE, JG, MUSKIET, FAJ, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Lifestyle Medicine (LM)

Subjects
EXTRA ADRENAL CHROMAFFIN TISSUE, PLASMA, ADRENALINE, PHENYLETHANOLAMINE-N-METHYLTRANSFERASE, CHILDREN, HIGH PERFORMANCE LIQUID CHROMATOGRAPHY, METABOLITES, EPINEPHRINE SYNTHESIS, URINES, DOPAMINE, NOREPINEPHRINE, ACID, LIQUID-CHROMATOGRAPHY, AMPEROMETRIC DETECTION
Abstract

Using high performance liquid chromatography with electrochemical detection we determined free dopamine, noradrenaline, adrenaline and N-methyladrenaline in: (1) urines from newborns (n=32), children (n=45) and adults (n=19) and (2) adrenals, organ of Zuckerkandl, dorsal roots and perirenal brown adipose tissue from deceased fetuses (n=2), very premature (n=6) and term (n=2) newborns and infants (n=2). Data from children and adults showed that contributions of adrenaline and N-methyladrenaline to the sum of urinary free catecholamines increase with age, Relative amounts of adrenaline and N-methyladrenaline increased in both adrenal and extra adrenal chromaffin tissues from late gestation up to several months of postnatal life. Increase of adrenal N-methyladrenaline content follows endocrine maturation of the medulla, phenylethanolamine-N-methyltransferase induction and subsequent adrenaline synthesis. Relative amounts of N-methyladrenaline in extra adrenal chromaffin tissue increase in a period that is associated with its regression. Further investigations are necessary to elucidate the function and possible clinical chemical usefulness of N-methyladrenaline.

Published
1995

6. Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Author

Hurkmans EGE, Klumpers MJ, Dello Russo C, De Witte W, Guchelaar HJ, Gelderblom H, Cleton-Jansen AM, Vermeulen SH, Kaal S, van der Graaf WTA, Flucke U, Gidding CEM, Schreuder HWB, de Bont ESJM, Caron HN, Gattuso G, Schiavello E, Terenziani M, Massimino M, McCowage G, Nagabushan S, Limaye A, Rose V, Catchpoole D, Jorgensen AL, Barton C, Delaney L, Hawcutt DB, Pirmohamed M, Pizer B, Coenen MJH, and Te Loo DMWM

Abstract

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p -value <10 -5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p -value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p -value 5.0 × 10 -7 ). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hurkmans, Klumpers, Dello Russo, De Witte, Guchelaar, Gelderblom, Cleton-Jansen, Vermeulen, Kaal, van der Graaf, Flucke, Gidding, Schreuder, de Bont, Caron, Gattuso, Schiavello, Terenziani, Massimino, McCowage, Nagabushan, Limaye, Rose, Catchpoole, Jorgensen, Barton, Delaney, Hawcutt, Pirmohamed, Pizer, Coenen and te Loo.)

Published
2023
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7. Contribution of common and rare genetic variants in CEP72 on vincristine-induced peripheral neuropathy in brain tumour patients.

Author

Klumpers MJ, Brand ACAM, Hakobjan M, Gattuso G, Schiavello E, Terenziani M, Massimino M, Gidding CEM, Guchelaar HJ, Te Loo DMWM, and Coenen MJH

Subjects
Genotype, Humans, Microtubule-Associated Proteins adverse effects, Microtubule-Associated Proteins genetics, Prospective Studies, Vincristine adverse effects, Brain Neoplasms chemically induced, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases genetics
Abstract

Aims: Studies implicated a role for a genetic variant in CEP72 in vincristine-induced peripheral neuropathy. This study aims to evaluate this association in a cohort of brain tumour patients, to perform a cross-disease meta-analysis and explore the protein-coding region of CEP72., Methods: In total, 104 vincristine-treated brain tumour patients were genotyped for CEP72 rs924607, and sequenced for the protein-coding region. Data regarding patient and treatment characteristics, and peripheral neuropathy, were collected. Logistic regression and meta-analysis were performed for rs924607 replication. A weighted burden analysis was applied to evaluate impact of overall genetic variation in CEP72., Results: Analysis of 24 cases and 80 controls did not show a significant association between CEP72 rs924607 and neuropathy (odds ratio, OR [95% confidence interval, CI] 2.076 [0.359-11.989], P = .414). When combined with 8 cohorts (1095 cancer patients), a significant increase in risk for neuropathy was found for patients with a TT genotype (OR [95% CI] 2.15 [1.35-3.43], P = .001). Additionally, a missense variant (rs12522955) was significantly associated (OR [95% CI] 2.3 [1.2-4.4], P = .041) and patients with severe neuropathy carried more impactful variants in CEP72 coding regions (P = .039)., Conclusion: The association of CEP72 rs924607 in vincristine-induced neuropathy was not confirmed in a cohort of brain tumour patients, but did contribute to its suggested effect when combined in a cross-disease meta-analysis. The importance of other genetic variations in CEP72 on vincristine-induced neuropathy was demonstrated. This study contributes to evidence of the importance of genetic variants in CEP72 in development of vincristine-induced toxicity, and provides guidance for future prospective studies., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Published
2022
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8. Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group.

Author

Guerrini-Rousseau L, Masliah-Planchon J, Waszak SM, Alhopuro P, Benusiglio PR, Bourdeaut F, Brecht IB, Del Baldo G, Dhanda SK, Garrè ML, Gidding CEM, Hirsch S, Hoarau P, Jorgensen M, Kratz C, Lafay-Cousin L, Mastronuzzi A, Pastorino L, Pfister SM, Schroeder C, Smith MJ, Vahteristo P, Vibert R, Vilain C, Waespe N, Winship IM, Evans DG, and Brugieres L

Abstract

Background: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome., Methods: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator., Results: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated., Conclusion: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Published
2022
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9. Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury.

Author

Klumpers MJ, Witte W, Gattuso G, Schiavello E, Terenziani M, Massimino M, Gidding CEM, Vermeulen SH, Driessen CM, Van Herpen CM, Van Meerten E, Guchelaar HJ, Coenen MJH, and Te Loo DMWM

Abstract

Nephrotoxicity is a common and dose-limiting side effect of platinum compounds, which often manifests as acute kidney injury or hypomagnesemia. This study aimed to investigate the genetic risk loci for platinum-induced nephrotoxicity. Platinum-treated brain tumor and head-neck tumor patients were genotyped with genome-wide coverage. The data regarding the patient and treatment characteristics and the laboratory results reflecting the nephrotoxicity during and after the platinum treatment were collected from the medical records. Linear and logistic regression analyses were performed to investigate the associations between the genetic variants and the acute kidney injury and hypomagnesemia phenotypes. A cohort of 195 platinum-treated patients was included, and 9,799,032 DNA variants passed the quality control. An association was identified between RBMS3 rs10663797 and acute kidney injury (coefficient -0.10 (95% confidence interval -0.13--0.06), p -value 2.72 × 10 -8 ). The patients who carried an AC deletion at this locus had statistically significantly lower glomerular filtration rates after platinum treatment. Previously reported associations, such as BACH2 rs4388268, could not be replicated in this study's cohort. No statistically significant associations were identified for platinum-induced hypomagnesemia. The genetic variant in RBMS3 was not previously linked to nephrotoxicity or related traits. The validation of this study's results in independent cohorts is needed to confirm this novel association.

Published
2022
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10. Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma.

Author

Zomerman WW, Plasschaert SLA, Conroy S, Scherpen FJ, Meeuwsen-de Boer TGJ, Lourens HJ, Guerrero Llobet S, Smit MJ, Slagter-Menkema L, Seitz A, Gidding CEM, Hulleman E, Wesseling P, Meijer L, van Kempen LC, van den Berg A, Warmerdam DO, Kruyt FAE, Foijer F, van Vugt MATM, den Dunnen WFA, Hoving EW, Guryev V, de Bont ESJM, and Bruggeman SWM

Subjects
Cell Line, Tumor, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Gene Expression Profiling, Humans, Medulloblastoma genetics, Medulloblastoma pathology, Phosphorylation, Proto-Oncogene Proteins c-myc biosynthesis, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction, Tumor Suppressor Protein p53 genetics, Cerebellar Neoplasms metabolism, Hedgehog Proteins metabolism, Medulloblastoma metabolism
Abstract

The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2018
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