High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor

Abstract

Malignant rhabdoid tumors are highly aggressive neoplasms found primarily in infants and young children. The majority of rhabdoid tumors arise as a result of homozygous inactivating deletions or mutations of the INI1 gene located in chromosome band 22q11.2. Germline mutations of INI1 predispose to the development of rhabdoid tumors of the brain, kidney and extra-renal tissues, consistent with its function as a tumor suppressor gene. We now describe five patients with germline deletions in chromosome band 22q11.2 that included the INI1 gene locus, leading to the development of rhabdoid tumors. Two patients had phenotypic findings that were suggestive but not diagnostic for DiGeorge/Velocardiofacial syndrome (DGS/VCFS). The other three infants had highly aggressive disease with multiple tumors at the time of presentation. The extent of the deletions was determined by fluorescence in situ hybridization and high-density oligonucleotide based single nucleotide polymorphism arrays. The deletions in the two patients with features of DGS/VCFS were distal to the region typically deleted in patients with this genetic disorder. The three infants with multiple primary tumors had smaller but overlapping deletions, primarily involving INI1. The data suggest that the mechanisms underlying the deletions in these patients may be similar to those that lead to DGS/VCFS, as they also appear to be mediated by related, low copy repeats (LCRs) in 22q11.2. These are the first reported cases in which an association has been established between recurrent, interstitial deletions mediated by LCRs in 22q11.2 and a predisposition to cancer.

Detailed analysis of 22q11.2 with a high density MLPA probe set

“…MLPA-HD confirmed the findings of FISH with probes from the rhabdoid tumor region and microarray analysis [Jackson et al, 2007]. Figure 2, Patients 17-24, represent the findings on these patients.…”

Frequent hSNF5/INI1 Germline Mutations in Patients with Rhabdoid Tumor

“…In contrast, frameshift and nonsense mutations are mostly associated with RTs, with early development. Finally, germline 22q11.2 deletion, so far only observed in RTs, may be linked to a later onset of tumor (17,(29)(30)(31). In this respect, patients 24 and 25, both with germline 22q11.2 deletions, harbored the latest RTs ever reported in a context of hSNF5/INI1 constitutional mutations (8 and 22 years, respectively).…”

“…In this respect, patients 24 and 25, both with germline 22q11.2 deletions, harbored the latest RTs ever reported in a context of hSNF5/INI1 constitutional mutations (8 and 22 years, respectively). Miscellaneous polymalformative conditions, such as velocardiofacial and Goldenhar syndromes, have been reported in patients with large 22q11.2 deletions (17,30), but bladder exstrophy, occasionally related to 22q11.2 duplication (32, 33), has not been reported in these cases. Hence, the association between RPS and bladder exstrophy in our case remains unexplained.…”

The recurrent distal 22q11.2 microdeletions are often de novo and do not represent a single clinical entity: a proposed categorization system

“…10 Distal 22q11.2 microdeletions that span the LCR22-F to -G interval encompassing the tumor suppressor SMARCB1 gene (also called INI1) have been reported to manifest many of the presenting features mentioned above but also have high incidence of malignant rhabdoid tumors in infancy and early childhood, predominantly in the kidneys and central nervous system, which necessitates tumor surveillance in these patients. [19][20][21][22][23][24] Depending on the mediating LCR22s, the distal 22q11.2 microdeletions can vary in size between ~700 kb and ~3.0 Mb. To date, the distal 22q11.2 microdeletions have been grouped together as a single clinical entity despite the fact that these deletions comprise several partially overlapping and nonoverlapping deletions of varying size.…”

“…On the other hand, deletions in the distal 22q11.2 region that span the LCR22-F to -G interval including the SMARCB1 gene have been reported in multiple studies and were shown to be also variable in size and share many of the presenting features of the distal 22q11.2 microdeletion phenotype discussed earlier, in addition to a very high incidence of malignant rhabdoid tumors in infancy and early childhood. [19][20][21][22][23][24] Accordingly, we propose categorizing the distal 22q11.2 microdeletions into three genomic types: type I: with deletions flanked by LCR22-D and either -E or -F; type II: with deletions flanked by LCR22-E and -F; and type III: with any deletion in this region minimally spanning the LCR22-F to -G interval and encompassing the SMARCB1 gene (Figure 2). All three deletion types are thought to be pathogenic and are most often de novo.…”