Next-generation sequencing reveals germline mutations in an infant with synchronous occurrence of nephro- and neuroblastoma

Abstract

Although neuro- and nephroblastoma are common solid tumors in children, the simultaneous occurrence is very rare and is often associated with syndromes. Here, we present a unique case of synchronous occurrence of neuro- and nephroblastoma in an infant with no signs of congenital anomalies or a syndrome. We performed genetic testing for possible candidate genes as underlying mutation using the next-generation sequencing (NGS) approach to target 94 genes and 284 single-nucleotide polymorphisms (SNPs) involved in cancer. We uncovered a novel heterozygous germline missense mutation p.F58L (c.172T→C) in the anaplastic lymphoma kinase (ALK) gene and one novel heterozygous rearrangement Q418Hfs(*)11 (c.1254_1264delins TTACTTAGTACAAGAACTG) in the Fanconi anemia gene FANCD2 leading to a truncated protein. Besides, several SNPs associated with the occurrence of neuroblastoma and/or nephroblastoma or multiple primary tumors were identified. The next-generation sequencing approach might in the future be useful not only in understanding tumor etiology but also in recognizing new genetic markers and targets for future personalized therapy.

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

“…In NB, high expression levels of ALK closely correlates with poor outcomes, especially in high-risk NB [22, 42, 49]. It is reported that ALK with activating mutations in its tyrosine kinase domain occur in most cases of hereditary NB [17, 33].…”

Childhood cancer predisposition syndromes—A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology

“…Most children with NBL do not have an established and clinically obvious CPS. Rare germline mutations of ALK (gene product is a receptor tyrosine kinase, MIM 105590) (Mosse et al, ; Theruvath, Russo, Kron, Paret, & Wingerter, ), GALNT14 (encoding a Golgi protein involved in a complex transferring N‐acetyl‐D‐galactosamine, MIM 608225) (De Mariano et al, ), and PHOX2B (encoding a transcription factor, which is mutated in central hypoventilation syndrome with or without Hirschsprung disease, MIM 209880) (Mosse et al, ; Trochet et al, ) are associated with an increased NBL risk and should be considered in children with familial disease. Patients with Beckwith–Wiedemann syndrome (Mussa et al, ) (MIM 130650; complex pathogenesis: (i) hypomethylation of imprinting control region 2; (ii) hypermethylation of imprinting control region 1; (iii) paternal uniparental disomy 11p15; (iv) microdeletion/‐duplication in 11p15.5; or (v) CDKN1C mutation; The CDKN1C ‐mutated group is especially associated with NBL), Weaver (Tatton‐Brown & Rahman, ), Sotos (Kulkarni, Stobart, & Noga, ), Simpson–Golabi–Behmel ( GPC3 , GPC4 coding for heparan sulfate proteoglycans involved in regulating cell division and growth; MIM 312870) (Hughes‐Benzie, Hunter, Allanson, & Mackenzie, ), Rubinstein–Taybi (Stevens, ), and Costello ( HRAS ; MIM 218040) (Gripp, ) syndromes have an elevated NBL risk.…”

Research progress of neuroblastoma related gene variations

“…DNA repair genes have been reported in oncogenesis of multiple cancers including neuroblastoma, such as BRCA1/2, PALB2, FANCD2 and CHEK2 et al [50–55]. Pugh et al performed whole genome sequencing of peripheral blood DNA samples on 240 cases of NB patients, and found a few germline mutations including CHEK2 (c.433C > T, c.542G > A and c.539G > A), PINK1 (c.1040T > C and c.836G > A), BARD1(c.334C > T and c.1921C > T) and PALB2 (c.1684+1C > A) [12].…”

“…Brooks et al reported 20 cases of pediatric cancer including neuroblastoma among 379 families, uncovering mutations in either BRCA1 or BRCA2 [54]. Other studies also identified a deletion/insertion in the FANCD2 gene in nephro- and neuroblastomas [55]. Particularly, germline mutations in BRCA2 and PALB2, that PALB2 binds to the N terminus of BRCA2 and has a key role in localization and stabilization of BRCA2, have been detected that they were associated with the development of neuroblastoma [51, 52].…”