Shared Copy Number Variation in Simultaneous Nephroblastoma and Neuroblastoma due to Fanconi Anemia

Abstract

Concurrent emergence of nephroblastoma (Wilms Tumor; WT) and neuroblastoma (NB) is rare and mostly observed in patients with severe subtypes of Fanconi anemia (FA) with or without VACTER-L association (VL). We investigated the hypothesis that early consequences of genomic instability result in shared regions with copy number variation in different precursor cells that originate distinct embryonal tumors. We observed a newborn girl with FA and VL (aplasia of the thumbs, cloacal atresia (urogenital sinus), tethered cord at L3/L4, muscular ventricular septum defect, and horseshoe-kidney with a single ureter) who simultaneously acquired an epithelial-type WT in the left portion of the kidney and a poorly differentiated adrenal NB in infancy. A novel homozygous germline frameshift mutation in PALB2 (c.1676_c1677delAAinsG) leading to protein truncation (pGln526ArgfsX1) inherited from consanguineous parents formed the genetic basis of FA-N. Spontaneous and induced chromosomal instability was detected in the majority of cells analyzed from peripheral lymphocytes, bone marrow, and cultured fibroblasts. Bone marrow cells also showed complex chromosome rearrangements consistent with the myelodysplastic syndrome at 11 months of age. Array-comparative genomic hybridization analyses of both WT and NB showed shared gains or amplifications within the chromosomal regions 11p15.5 and 17q21.31-q25.3, including genes that are reportedly implicated in tumor development such as IGF2, H19, WT2, BIRC5, and HRAS.

A Comprehensive Review of Pediatric Tumors and Associated Cancer Predisposition Syndromes

“…Autosomal recessive inheritance of genes associated with cancer risk, including BRCA2, PALB2, and BLM, which cause chromosomal breakage syndromes, are also associated with an increased risk for WT (Md Zin et al 2011;Serra et al 2012). Each of these genes is associated with other clinical features and risks when inherited in a recessive manner.…”

A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development

“…These observations highlight a critical role for the HR pathway in protecting against cellular transformation, particularly of hormone-responsive, epithelial cells that have a high proliferative capacity. Interestingly, however, it has been shown that biallelic, null germline mutations in BRCA2 [ 10 – 14 ] and PALB2 [ 15 – 17 ], hypomorphic mutations in BRCA1 [ 18 , 19 ] and Rad51C [ 20 ], or in the case of RAD51 [ 21 ] a dominant mutation, all give rise to a spectrum of clinical symptoms that have features of Fanconi Anaemia (FA). Unlike Fanconi anaemia patients with mutations of one of the core complex Fanconi proteins, those with inherited mutations in the HR machinery, including PALB2 mutant patients, typically display severe developmental abnormalities, such as microcephaly, growth retardation, intellectual impairment as well as skeletal abnormalities.…”

Case report: Antenatal diagnostic of a polymalformative syndrome due to biallelic BRCA2 mutations

“… 5 10% of patients with FA have at least three of the component parts of the VACTERL‐H association. 6 FA is a recessive autosomal condition involving bone marrow failure, congenital malformations (skeletal defects, especially radial ray aplasia, small stature, renal and genital malformations, microcephaly with microstomia, and microphthalmia), and a predisposition to malignancy.…”