Analysis of germline variants in pediatric patients diagnosed with desmoid tumors and nuchal-type fibromas

Introduction

Desmoid tumors (DTs), also known as desmoid-type fibromatosis or aggressive fibromatosis, is a rare soft tissue neoplasm characterized by a local aggressive and infiltrative growth (1). The incidence is approximately 5 cases per million with two peaks of incidences between the ages of 6 and 15 years and around 40 years, being more prevalent in women (2:1, female:male rate) (2).

DTs can arise in different sites classified into three groups located intra-abdominal, abdominal-wall and extra-abdominal (3). These neoplasms are characterized clinically by a variable and unpredictable course and can arise in many patients in the context of a hereditary cancer predisposition syndrome (4). Around 5–10% of patients who are diagnosed with DT have a pathogenic variant in the APC gene (5).

Nuchal-type fibroma is a benign tumor that develops from connective tissue and is usually located in the posterior neck. Other localizations are back, chest or shoulder. There are described several cases of nuchal-type fibroma associated to Gardner syndrome, a rare autosomal dominant syndrome caused by germline variants in the APC gene (6,7). Nuchal-type fibromas associated with Gardner syndrome are called Gardner-associated fibromas or Gardner fibromas (8).

Gardner syndrome is a variant of familial adenomatous polyposis (FAP) characterized by the presence of extracolonic manifestations including osteomas, dental abnormalities, epidermal cysts, and soft tissue tumors, particularly DTs. Gardner-associated fibromas may occur in pediatric patients as precursor lesions to the DTs of Gardner syndrome (8). Soft-tissue manifestation in the early ages may serve as the sentinel event leading to diagnostic suspicion of Gardner syndrome (9).

Kostakis et al. described a cohort of 107 patients with nuchal-type fibroma, of whom 18.7% had Gardner syndrome. In addition, these patients with Gardner syndrome were younger than the patients with sporadic fibroma (7). Gardner-associated fibromas usually have a higher recurrence after surgical excision. Some of these relapses can appear as DTs (10,11).

FAP is an autosomal dominant disease arising from a germline variation in the APC gene. FAP is characterized by the development of multiple colorectal adenomatous polyps during the second decade of life, that predisposes to colorectal cancer (9). There are other extraintestinal manifestations that can appear in childhood, such as DTs, which occur in approximately 10–25% of FAP patients in the context of Gardner syndrome (12,13). Identifying FAP in young patients is important for colonoscopic surveillance to prevent the development of colorectal tumors (14).

APC is considered a tumor suppressor gene on 5q21 and codes for a protein involved in the WNT pathway. The role of APC in cytoplasm is a negative regulation of the canonical WNT signaling pathway (15). APC interacts with β-catenin in the cytoplasm through β-catenin phosphorylation, ubiquitination and proteolytic degradation. All these facts occur in the cytosol. When APC function is lost, β-catenin is accumulated in the cell nuclei, regulating cell proliferation, differentiation and apoptosis (16).

FAP accounts for 1% of all colorectal cancer cases. Approximately 15–20% of FAP are caused by APC de novo mutations (17). FAP has been described patients with mosaic APC variants. However, this mosaicism is underdiagnosed and the number of mosaic carriers is expected to be higher (18,19).

According to several studies, extracolonic manifestations of polyposis syndromes are frequently associated with FAP and APC germline mutations.

Many other inherited adenomatous polyposis syndromes exist including MUTYH associated polyposis (MAP) with the presence of MUTYH germline mutations and polymerase proofreading associated polyposis (PPAP) with germline mutations in POLD1 and POLE genes (20).

This study aimed to evaluate the spectrum of APC germline variants in pediatric patients diagnosed with nuchal-type fibroma and DTs that may be associated with Gardner syndrome. Moreover, we analyzed MUTYH, POLD1 and POLE germline variants in the patients that present APC wild-type but have a family history of colon polyposis and colon cancer. We present this article in accordance with the MDAR reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-23-60/rc).

Methods

Study population

This study included five pediatric patients diagnosed with DTs or nuchal-type fibromas in the Hospital Universitario Cruces (Barakaldo, Spain) who were evaluated for genetic counseling between 2018–2020.

Germline APC gene testing was offered as a part of standard clinical care. MUTYH, POLD1 and POLE genetic tests were performed in patients without APC germline pathogenic variants.

After performing genetic counseling, peripheral blood samples were collected from each patient. In addition, clinical information was obtained, such as personal and family history, histopathology findings, treatment response and patient follow-up. The clinical characteristics of the patients are shown in Table 1.

Ethical statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patients’ parents or legal guardians for publication of this report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. Ethical approval was granted by the Research Ethics Committee of the Hospital Universitario Cruces (No. E17/58).

Genetic testing

Genomic DNA was extracted from peripheral blood samples stored in EDTA using Magna Pure Compact Nucleic Acid Isolation Kit (Roche, Basel, Switzerland).

APC, MUTYH, POLE and POLD1 genes were sequenced using Custom Hereditary Cancer Solution Kit (Sophia Genetics, Lausanne, Switzerland) in MiSeq v3 (Illumina, San Diego, CA, USA).

The identified variants were compared with different databases to analyze the clinical significance of the sequence differences found with respect to a reference genome (hg19). The variants were classified according to international recommendations (21) as pathogenic, likely pathogenic, benign, likely benign or of uncertain significance. Different web tools and databases were used: ClinVar, Varsome and LOVD. Variants of uncertain significance (VUS) were analyzed using different pathogenicity prediction tools based on sequence homology and conservation, genetic context, epigenetic information, protein features and integration of different prediction scores: Eigen, Eigen-PC, REVEL, PROVEAN, PrimateAI, CADD, DEOGEN2, CHASM, UMDPredictor, Polyphen-2 HDIV, Polyphen-2 HVAR, HOPE.

Results

Patient characteristics

A total of 5 patients were included in the study: three were diagnosed with nuchal-type fibromas and two with DTs. Two patients with fibromas also had pilomatrixomas. Two patients had a previous lesion diagnosed as lipoma and dentigerous cysts. The mean age at diagnosis was 11.4 years (range, 1.8–14.9 years). There were 2 females and 3 males. Clinical characteristics are described in Table 1. Two patients diagnosed with DTs had a family history of colorectal polyposis or colon cancer (patients 2 and 5). One patient had three relatives with colorectal polyps and three with colon cancer. The other patient had three family members with colorectal polyps, one of them with pancreas cancer and a relative with a fibrosarcoma. The pedigrees of patients with a family history are shown in Figure 1. All patients were treated with surgery at first line of treatment except one patient that was treated with chemotherapy. Tumors progressed in two of the patients (patients 4 and 5).

Figure 1 Pedigrees of patients with colorectal polyposis or colon cancer family history. (A) Patient 2 diagnosed with desmoid tumor. (B) Patient 5 diagnosed with desmoid tumor with an APC germline pathogenic variant. Proband is indicated by arrow.

APC germline variants

Blood DNA was analyzed for the study of APC variants in the germline. Two pathogenic variants were identified in two female patients (patients 4 and 5) (Table 1, Figure 2A). APC c.4611del (p. Glu1538Asnfs*27) pathogenic variant was identified in patient 4. This patient had a nuchal-type fibroma and a pilomatrixoma in the parietal region. She underwent partial excision of the lesion. A conservative approach was decided initially and the lesion was stable for two years. Due to progression to DT, she was treated with low dose chemotherapy: methotrexate and vinorelbine (three months) without response, so it was changed to methotrexate plus vinblastine (one year) with partial response. Two months after the end of the treatment, tumor progression was observed and she was treated with pazopanib during eight months. However, tumor progressed after this tyrosine kinase inhibitor, and she was treated again with chemotherapy (methotrexate and vinblastine, during five months) without response, so oral vinorelbine monotherapy was decided as a bridge to cryotherapy.

Figure 2 Germline variants identified in the analyzed patients. (A) APC germline pathogenic variants. (B) POLD1 germline variants of uncertain significance. AA, amino acids; EB1, End-binding protein 1; DLG, Discs large protein.

The variant identified in the APC gene is classified as a pathogenic variant due to its effect on exon 16, resulting in a change of the reading frame in residue 1538 with a premature stop codon in residue 1565. To the best of our knowledge this variant has not been previously described in germline and it was not found in the progenitors. However, it has been described in many patients as a frameshift variant in the adjacent nucleotide (c.4612del) classified in ClinVar as pathogenic variant associated to FAP and Gardner syndrome (rs387906236).

An APC c.5826_5829del (p.Asp1942Glufs*27) pathogenic variant was found in patient 5. This patient had a familial history of cancer (Figure 1B) and was diagnosed with a cervical DT in childhood. She was treated with chemotherapy (vincristine, actinomycin and cyclophosphamide). After 21 years, this patient developed abdominal DTs. The genetic test was performed at this age. DTs were treated with tamoxifen and sulindac. Due to tumor progression, she was treated with pazopanib with a partial response. At the present, the patient had abdominal DTs treated with radiotherapy. The APC c.5826_5829del variant had been described and classified as a pathogenic variant (22,23).

POLD1 germline variants

Two VUSs were found in two male patients (patient 1 and patient 3) (Table 1, Figure 2B).

A POLD1 c.2275G>A VUS was found in the patient 1, diagnosed with a nuchal-type fibroma and a pilomatrixoma (Table 1, Figure 2B). This patient had no familial history of colon cancer. He had a lipoma at birth in the same region of the fibroma. The lipoma was excised.

The POLD1 c.2275G>A missense variant results in a change in the Valine 759 to an isoleucine. This variant has been reported in ClinVar as a benign variant, likely benign variant and VUS. The minor allele frequency (MAF) of this variant is 0.001842 according to GnomAD Exomes and it is described in Ashkenazi Jews with colorectal cancer, multiple polyps and other extracolonic tumors (24). POLD1 759 residue is part of the DNA polymerase type-B domain. Different prediction tools based on the structural changes introduced by an amino acid substitution predict this variant does not cause structural damage. However, other prediction tools predict this variant as likely pathogenic. Therefore, there are disagreements on its pathogenicity (Table S1).

Another POLD1 VUS was identified in a patient diagnosed with a nuchal fibroma. He had no family history of cancer. The POLD1 c.353C>T (p.Ser118Phe) variant has been reported in ClinVar and classified as a VUS. This variant is present in population databases with a GnomAD Exomes 0.0002. POLD1 c.353C>T variant affected the Serine 118 that changes to Phenylalanine. This amino acid residue is not localized in a functional domain of the protein. However, the mutant residue is bigger and more hydrophobic than the wild-type. Prediction tools do not agree on the potential impact of this missense change (Table S1).

Colonic surveillance

According to current ESPGHAN recommendations, colonic surveillance should begin between the ages 12 to 14 years. However, colonoscopy should be performed at any age in the event of rectal bleeding or mucous discharge (14).

Patients 1 and 4 are younger than 12 years old and they have not undergone colonoscopy yet. Patients 3 and 5 are under follow-up by gastroenterologist and they has no colorectal polyps on colonoscopy to date. Patient 2 has not been referred to the gastroenterologist because no germline variant has been identified in this patient.

APC, MUTYH, POLD1 and POLE germline pathogenic variants described in pediatric patients diagnosed with DTs

Nine patients diagnosed at pediatric age with DT and six with fibroma had been described in the literature with an APC pathogenic germline variant (Table 2). Eleven patients had a family history of tumor. Three patients developed medulloblastoma subsequently, two patients developed colon polyposis and one of them thyroid carcinoma. The incidence of these findings is limited by outcome data. Most of the patients would be expected to develop colon polyposis if long-term outcomes were available. All the variants identified in the APC gene except one were localized in exon 16.

No pathogenic germline variants in MUTYH, POLD1 or POLE have been described in patients diagnosed with DTs in pediatric age.

Discussion

The appearance of fibromatous soft tissue lesions, DTs and nuchal-type fibromas, in childhood may be caused by germline mutations in genes associated with inherited adenomatous polyposis syndromes.

Gardner syndrome is a known variant of FAP. The name Gardner-associated fibroma was coined by one group of authors for nuchal-type fibroma arising in patients with Gardner’s syndrome (10,30). The term Gardner fibroma has been described in the most recent WHO classification to define Gardner-associated fibroma (28). However, nuchal-type fibroma and Gardner fibroma are microscopically indistinguishable. It has been described that there are differences in the age groups, being Gardner fibroma associated to children (31,32). For this reason, the germline genetic study in the pediatric age is important.

Nuchal-type fibromas and DTs are distinct pathologic entities (28). However, both types of pathologies can appear in the pediatric age and may be associated with Gardner syndrome. In addition, DTs can arise in the same location of surgically excised Gardner-associated fibroma (8). Typically, these soft-tissue lesions occur first, alerting the clinician to the possibility of Gardner syndrome, because they occur before the development of intestinal polyps. It is important, therefore, to identify Gardner syndrome in early ages to prevent colorectal cancer (14).

We have analyzed variants in APC, MUTYH, POLD1 and POLE genes in five patients diagnosed with DTs and nuchal-type fibromas. We have found two APC pathogenic germline variants in two different patients diagnosed with nuchal-type fibromas and DTs associated to Gardner syndrome. Both variants have been localized in APC exon 16. Several studies described that desmoid neoplasms are more frequent in patients with pathogenic/likely pathogenic variants localized after codon 1399. Moreover, 3' of codon 1399 variants are more symptomatic and more often lethal than 5' mutations in codon 400 (33). One of the identified variants (APC c.5826_5829del) has been associated with the development of DTs and Gardner fibroma in pediatric patients and colorectal adenomas in adults (22,23). To the best of our knowledge, the APC c.4611del variant has not been described in the germline. We found this variant in a patient with a Gardner fibroma that did not respond to treatment with chemotherapy and target therapy with pazopanib.

All reported pediatric patients with DTs associated with a hereditary syndrome, have APC germline pathogenic variants. Most of these extraintestinal neoplasms have been associated with APC germline mutations. However, some reports showed other extraintestinal manifestations like pilomatrixomas associated with MUTYH or POLE mutations too (34,35). Two patients in our cohort had pilomatrixomas, one had a VUS in POLD1 gene and the other one had an APC pathogenic variant in the germline. In addition, some soft tissue neoplasms have been described in adult patients with MUTYH pathogenic variants in the germline (36,37).

We identified two POLD1 VUSs in the germline in two different patients. POLD1 protein is the catalytic subunit of the DNA polymerase δ complex p125. POLD1 is involved in DNA synthesis of the lagging strand during DNA replication, proofreading activity during polymerization and DNA repair (20). POLD1 c.353C>T (p.Val759Ile) variant is localized in the DNA polymerase type-B domain. This variant has previously been described in a cohort of Ashkenazi Jewish subjects with multiple colorectal adenomas and early-onset mismatch repair proficient colorectal cancers. They identified a POLD1 c.353C>T variant in eight unrelated individuals. Six of these patients had a family history of cancer. However, none of them developed a soft tissue neoplasm. The POLD1 c.353C>T variant has been proposed to be a low-to-moderate risk founder mutation (24). No cases of DTs associated with POLD1 germline mutations have been reported previously. The other variant identified in POLD1 (c.353C>T) has been described in ClinVar as a VUS (ClinVar Variation Id: 239345). The role of this variant in disease is unknown.

No variants were identified in the genes analyzed in a patient with a family history of polyposis and colon cancer. It is possible that this family could have a variant in an intronic region of the analyzed genes (38) or have a pathogenic variant in another gene associated with hereditary colon cancer such as CHEK2, AXIN2, CDH1, TP53, EPCAM or mismatch repair genes (20). Some cases with DTs and colon cancer have been associated with PTEN or TP53 germline mutations but these variants were associated with other neoplasms and clinical manifestations too (39,40). Double mutations in APC and MSH2 genes were reported in a patient with adenomas and a DT (41). Further investigation about genetic risk of DTs and colon cancer development is necessary.

In this study, two germline pathogenic variants in APC and two germline VUSes in POLD1 have been identified in four different patients diagnosed with DTs. Two patients had a family history of colon cancer but we only identified an APC germline pathogenic variant in one of these patients. Further studies are necessary to identify and characterize germline variants associated with the development of DTs in a cancer predisposition syndrome context.

The two patients with APC germline pathogenic variants still have progressive lesions. DTs are known as aggressive and locally invasive neoplasms with difficult surgical cure (42). Currently, there are several studies focused on identifying effective treatment, such as γ-secretase inhibitors and cryoablation (5,43,44).

The identification of hereditary cancer predisposition syndromes in patients with DTs and nuchal-type fibromas is necessary for the correct clinical management and genetic counseling. Due to the risk of developing colon cancer, surveillance via lower gastrointestinal tract endoscopy is crucial in patients with APC germline mutations in a Gardner syndrome context (45). In addition, more studies to identify effective therapies for patients with progressing tumors are required.

Acknowledgments

Funding: This work was funded by Research Projects from Jesús de Gangoiti Barrera Foundation (Nos. FJGB18/004 and FJGB19/001), La Cuadri del Hospi (No. BC/A/17/008), EITB Media AND BIOEF, SAU (Nos. BIO20/CI/015/BCB and BIO20/CI/011/BCB) and the Basque Government Health Department (No. 2021111030).

Footnote

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-23-60/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-23-60/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-60/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patients’ parents or legal guardians for publication of this report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. Ethical approval was granted by the Research Ethics Committee of the Hospital Universitario Cruces (No. E17/58).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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