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Received: 31 May 2022
Pediatric Blood & Cancer
SOCIÉTÉ INTERNATIONALE D’ONCOLOGIE PÉDIATRIQUE SKOP INTERNATIONAL SOCIETY OF PAEDIATRIC ONCOLOGY
aspho The American Society of Pediatric Hematology/Oncology
ELANE neutropenia and solid tumors: Four cases from the French severe chronic neutropenia registry
Jean Donadieu1 ☐ İD Fares Bou Mitri1 -
İD ☐ Blandine Beaupain1 ☐ Nathalie Alajidi2 İD Jean Francois Viallard3 ☐ Jean-Philippe Le Paih4 ☐ Mokrane Yacoub5
Thierry Leblanc6 ☐ Laurent Quero’ 7
☐ Alexia Rouland® ☐ Louis Labbe9
Claire Deback10 Christine Bellanne-Chantelot11 ☐ Jean-François Emile12
1 French Registry for Severe Chronic Neutropenia, Armand-Trousseau Hospital, APHP, Paris, France
2 Onco-hematology Unit, Pediatic Department, Children Hospital, Groupe Hospitalier Pellegrin, Bordeaux, France
3 Internal Medicine and Infectious Disease Department, Haut-Lévêque Hospital, University of Bordeaux, Bordeaux, France
4 Urology Department, Bordeaux University Hospital, Bordeaux, France
5 Pathology Department, Bordeaux University Hospital, Bordeaux, France
6 Hematology Unit, Robert Debré Hospital, APHP, Paris, France
7 Oncology and Radiotherapy Department, Hopital Saint Louis, APHP, Paris, France
8 Endocrinology Department, Dijon University Hospital, Dijon, France
9 Endocrinology Department, Hotel Dieu, Le Creusot, France
10 Virology Department, Paul Brousse Hospital, Villejuif, France
11 Genetics Department, Pitié-Salpêtrière Hospital, APHP, Paris, France
12 Pathology Department, Ambroise-Paré Hospital, APHP, Boulogne, France
Correspondence
Jean Donadieu, Service d’Hémato-Oncologie Pédiatrique Hopital, Trousseau 26 avenue du Dr Netter, F 75012 Paris, France. Email: jean.donadieu@aphp.fr
Funding information Inserm
Abstract
Neutropenia related to ELANE gene mutations predisposes patients to infection and leukemia/myelodysplasia, but little is known about the predisposition to cancer. Among a cohort of 147 patients, we identified four with malignant solid tumors (papillary thyroid cancer, anal squamous cell cancer, papillary renal cell carcinoma, and adreno- cortical carcinoma), all aged 25-50 years. Three occurred with cyclic neutropenia, and one occurred with severe chronic neutropenia. Previous radiotherapy was identified as a risk factor in one patient. No genetic predisposition was identified in the three other patients.
KEYWORDS ELANE neutropenia, registry, SCN, solid tumor
ABBREVIATIONS: CyN, cyclic neutropenia; DNMT3A, DNA methyltransferase 3A; G-CSF, granulocyte colony-stimulating factor; HSCT, hematopoietic stem cell transplantation; NGS, next-generation sequencing; SCN, severe congenital neutropenia; TAD, time averaged dose.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. @ 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.
1 INTRODUCTION
Neutropenia related to ELANE gene mutations (ELANE-N) is a rare hematological disorder, caused by heterozygous mutations in the ELANE gene. ELANE-N is commonly classified as cyclic neutropenia (CyN) or severe congenital neutropenia (SCN).1,2
2 METHODS
As of April 31, 2021, the French severe chronic neutropenia registry included 147 patients with ELANE-N.3 The World Health Organiza- tion classification of cancers was applied during a centralized review of the tumor samples. ELANE-N variants were identified and cancer- susceptibility genes were studied by a 112 genes panel (Table 1, Panel #1). Next-generation sequencing (NGS) was performed to detect somatic mutations (Table 1, Panel #2) in tumor cells, when available.
3 RESULTS
Among a cohort of 147 patients with ELANE-N (median follow-up: 16.4 years, for a total of 3312 person-years), four developed solid malignant tumors (Table 1) when they were between 29 and 50 years old. The solid-tumor rate was 2.6% (95% confidence interval [CI]: 0.4-16.25%) by the age of 30 years. It increased dramatically during the 5th decade; among 50-year-olds, the rate was 21.8% (95% CI: 7.9-51.9%). The ini- tial diagnoses were CyN (n = 3) and SCN (n = 1). In one case, the cancer (thyroid) developed in an area that, 30 years prior, had been treated for persistent adenomegaly with radiotherapy (dose = 8 grays). In the three other cases, no local risk factor was found, and the study of a NGS-panel of 112 genes associated with cancer susceptibility was inconclusive (Table 1). Two patients had received granulocyte colony- stimulating factor (G-CSF) prior to the solid tumor diagnosis. None of the four patients had been diagnosed with myelodysplasia or had undergone a hematopoietic stem cell transplantation (HSCT). In two patients with solid tumors, somatic myeloid NGS was performed, which included the CSF3R and RUNX1 genes, but no pathogenic variant was found. Of note, during a 147-person-year follow-up, no cancer was observed after HSCT in the 18 patients with ELANE-N that survived HSCT.4
3.1. Patient #5247
This male patient was diagnosed with CyN at age 3 years. He had presented with recurrent infections. At age 5 years, he received radio- therapy (8 Grays) for chronic cervical adenitis, which did not respond to antibiotics. G-CSF therapy was started at age 28 years to prevent stomatitis. For 7.2 years prior to the cancer diagnosis, he received intermittent G-CSF therapy (time-averaged dose [TAD]: 3.3 µg/kg; cumulative dose: 3445 µg/kg). At age 35 years, he experienced enlarge- ment in the upper right thyroid lobe, which was diagnosed as papillary
adenocarcinoma. The maximum size was 1 cm, and no secondary local- ization was detected (classification: T1N0M0). He underwent a total thyroidectomy. No additional chemotherapy was proposed. At the last update (age 55 years), no relapse was observed.
3.2. Patient #5107
This female patient was diagnosed with CyN. Her history was marked with mastoiditis, recurrent stomatitis, and drug addiction. She recov- ered from drug addiction at age 26 years, but her condition was complicated by hepatitis C virus. No G-CSF treatment was admin- istered prior to the cancer treatment. At age 46 years, she was diagnosed with anal squamous cell cancer (11 mm). The extension assessment showed invasion to the anus elevator muscle and the presence of pararectal and inguinal lymphadenopathy (classification: T2N1M0). She was treated with standard chemotherapy (two cycles of 5-fluorouracil and mitomycin), combined with pelvic and inguinal radio- therapy (dose: 45 Grays). Her treatment included G-CSF (twice/week). No major infections or complications were noted. Ten months later, 4 months after conclusion of chemotherapy, she experienced progressive respiratory difficulties. An investigation revealed pulmonary hyper- tension, probably secondary to mitomycin. She died 1 month later, at home, from sudden death of unknown cause.
3.3. Patient #8582
This male was diagnosed with CyN. He mainly experienced pharyngitis, recurrent apthosis and stomatitis, but no prior G-CSF treatment was reported. At age 50 years, a routine abdominal ultrasound revealed a left renal mass. A thoraco-abdomino-pelvic CT scan showed a lower- left, polar renal mass without distant metastases. Treatment consisted of a left partial nephrectomy. Histological examination revealed pap- illary carcinoma with an intact margin (classification: pT1bN0M0). Unfortunately, due to poor DNA quality, NGS was not performed. He received peri-operative G-CSF (5 µg/kg), and developed no infectious complications. One year after the diagnosis, he was alive and free of cancer recurrence.
3.4. Patient # 5205
This female patient was diagnosed at birth with SCN. She experienced multiple severe infections and recurrent gingivitis. Starting at age 6 months, she received continuous G-CSF treatment (TAD: 25 µg/kg/day; cumulative period: 29 years; cumulative dose: 119,971 µg/kg). Dur- ing follow up, bone-marrow and blood tests never showed features of myelodysplastic syndromes. However, at the time of the can- cer diagnosis, clonal hematopoiesis was detected in the blood and bone marrow, with a DNA methyltransferase 3A [DNMT3A] variant clone at a frequency of 1%. This clone (c.2256C>A) was considered as pathogenic, but was previously found since age of 27 years old,
| Patient number | Sex/age (years) at solid tumor diagnosis, and ELANE mutation | Germline cancer susceptibility geneª | G-CSF dose for prior solid tumor | Cancer type | Somatic NGS panel in the tumorb | TNM classification | Treatment | Survival (months) vital status at last follow up (cause of death) |
|---|---|---|---|---|---|---|---|---|
| #5247 | M/35 c.597+1G>A; p.Val 190_Phe199del | Not studied | TAD: 3.3 µg/kg/day CD: 3345µU/kg | Papillary thyroid carcinoma | Not evaluable | T1N0M0 | Surgery | 204 Living |
| #5107 | F/46 c.416C>T; p.Pro139Leu | No variant identified (ACMG class 5, 4, 3) | No G-CSF | Anal SCC | None | T2N1M0 | Chemotherapy and radiotherapy | 10 Dead (Pulmonary embolism suspected in context of pulmonary hypertension) |
| #8582 | M/50 c.377C>T; p.Ser 126Leu | No variant identified (ACMG class 5, 4, 3) | No G-CSF | Papillary renal cell carcinoma | Not evaluable | pT1bN0M0 | Surgery | 12 Living |
| #5205 | F/29 c.242G>C; p.Arg81Pro | No variant identified (ACMG class 5, 4, 3) | TAD: 25 µg/kg/day CD: 119,971µg/kg | Adrenocortical carcinoma | None | T3N1M1 | Surgery and chemotherapy with mitotane | 12 Living |
Abbreviations: ACMG, American College of Medical Genetics and Genomics; CD, cumulative dose; F, female; G-CSF, granulocyte colony-stimulating factor; M, male; NGS, next-generation sequencing; TAD, time- averaged dose; SCC, squamous cell carcinoma.
a Panel# 1 Studied genes associated with cancer susceptibility: AIP, ALK, APC, ATM, AXIN2, BAP1, BLM, BMPR1A, BRCA1, BRCA2, BRIP1, CDC73, CDH1, CDK4, CDKN1B, CDKN2A, CTNNA1, CTR9, CYLD, DDB2, DICER1, DIS3L2, DLST, EGLN1, EPAS1, EPCAM, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ESR2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FH, FLCN, GNA11, GPC3, GREM1, KIT, LZTR1, MAD2L2, MAX, MBD4, MDH2, MEN1, MET, MLH1, MRE11, MSH2, MSH3, MSH6, MUTYH, NBN, NF1, NF2, NTHL1, PALB2, PBRM1, PHOX2B, PMS2, POLD1, POLE, POLH, POT1, PRKAR1A, PTCH1, PTEN, RAD50, RAD51, RAD51C, RAD51D, RB1, RECQL4, REST, RET, RFWD3, RNF43, SDHA, SDHAF2, SDHB, SDHC, SDHD, SLC25A11, SLX4, SMAD4, SMARCA4, SMARCB1, SMARCE1, SPRED1, STK11, SUFU, TMEM127, TP53, TRIM28, TSC1, TSC2, UBE2T,VHL, WRN, WT1, XPA, XPC,XRCC2.
bPanel #2 Oncogenes analyzed in the somatic NGS panel: AKT1, ALK, ARAF, ASXL1, BRAF, CARL, CBL, CDK4, CDKN1B, CDKN2A, CEBPA, CSF3R, CTNNB1, DNMT3A, EGFR, ETV6, EZH2, FLT3, GATA2, GNA11, GNAQ, GNAS, HERC1, HRAS, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, KTM2D, MAML3, MAMLD1, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, MAP3K1, MAP3K8, MAP3K9, MAP3K10, MAP3K19, MAP4K4, MAPK1, MAPK11, MAPK9, MPL, NF1, NOTCH1, NOTCH2, NPM1, NRAS, PDGFRA, PIK3CA, PPP6C, PTEN, PTPN11, RAC1, RAF1, RIT1, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, STK19, SYNGAP1, TAOK1, TAOK2, TET2, TP53, U2AF1, WT1, ZRS.
with VAF remaining around 1%. At age 29 years, she was diagnosed with unilateral cortico-adrenal carcinoma, after developing hypercor- tisolism syndrome. Computed tomography showed a heterogeneous, right adrenal lesion of 70 x 40 mm, with calcifications, associated with two enlarged lymph nodes. She underwent a right nephrectomy and adrenalectomy. Histological examinations showed a right cortico- adrenal carcinoma, with two major criteria for malignancy, according to the Lin-Weiss-Bisceglia system: more than five mitoses within 50 fields at high magnification and vascular invasion. Targeted NGS on the tumor, which included DNMT3A, did not identify any somatic mutations. Follow-up imaging showed suspicious mediastinal and hilar lymphadenopathy with multiple diffuse bilateral pulmonary nodules (classification: T3N2M1). Accordingly, she was treated with mitotane, and continued treatment for 1 year after onset.
4 DISCUSSION
We found four cases of solid malignant tumors, among a national cohort of 147 patients with ELANE-N. To date, no previous study has reported a cancer related to ELANE-N, including two larger series.5,6 In a large recent series of 1752 patients with severe chronic neu- tropenia treated by GCSF, 58 solid tumors have been diagnosed. This series included patients with both hereditary and acquired neu- tropenia and did not provide the individual genetic diagnoses for those with solid tumors, so the number of solid tumors observed in ELANE-N was not determined.7 ELANE-N is a known risk factor for myelodysplasia and leukemia,8,9 which are frequently preceded by clonal hematopoiesis.10,11 This complication nearly always arises in the context of G-CSF treatments, and can be prevented with early HSCT.4 Among the four patients described here, one appeared to develop a thyroid malignant tumor secondary to local radiotherapy, performed 30 years prior. The three other patients did not present any common risk factors for solid tumors or any known genetic susceptibility. More- over, two out four tumors occurred in the absence of G-CSF therapy. In one patient, a DNMT3A variant clone was detected in bone marrow and blood, but not in the solid tumor. Additional studies are needed to determine whether ELANE-N predisposes to cancer. Those stud- ies require cooperation between registries. Of note, adult ELANE-N follow-ups have been underreported.
Importantly, the pathogenic ELANE variants observed in ELANE-N do not completely delete the neutrophil elastase protein; rather, they generate defective proteins.12,13 Neutrophil elastase is antagonized by alpha 1 antitrypsin, and the balance between the protease and its inhibitors is important in oncogenesis.14 Recent studies have shown that neutrophil elastase expression in tumor-associated neutrophils played important roles in the progression of various solid tumors.15-18 Finally, secretory leukocyte protease inhibitor, a neutrophil elastase inhibitor, is also involved in cancer risk. 19,20
ACKNOWLEDGMENTS
The French registry is supported by grants from Inserm and by a grant from the 111 les arts. This study was supported by constant, unlimited
support from the Association Sportive de Saint Quentin Fallavier, since 2004, and the unlimited commitment of Mr. Gonnot. The authors would like to thank the IRIS association for support.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
ORCID
Jean Donadieu ID https://orcid.org/0000-0002-4485-146X Fares Bou Mitri 1D https://orcid.org/0000-0002-2773-048X Nathalie Alajidi ID https://orcid.org/0000-0003-0231-4460
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How to cite this article: Donadieu J, Bou Mitri F, Beaupain B, et al. ELANE neutropenia and solid tumors: Four cases from the French severe chronic neutropenia registry. Pediatr Blood Cancer. 2022;69:e29923. https://doi.org/10.1002/pbc.29923