Mitotic recombination mediated by the JJAZF1 (KIAA0160) gene causing somatic mosaicism and a new type of constitutional NF1 microdeletion in two children of a mosaic female with only few manifestations

Abstract

C olorectal cancer (CRC) is the third most common cancer diagnosed in both men and women, and the second most common cause of cancer deaths in the United States. There were approximately 150 000 new cases resulting in 57 000 deaths in 2002.1 CRC is one of the most studied cancer types and its underlying aetiology best elucidated. Colorectal tumorigenesis involves a multistep process including genetic and epigenetic alterations of numerous CRC related genes that may act as either oncogenes or tumour suppressor genes. [2][3][4][5] The majority of sporadic CRCs are characterised by deletions of large chromosomal segments, which are thought to represent the loss of wild type tumour suppressor genes.6 7 About 15% of sporadic CRCs, on the other hand, show microsatellite instability (MSI), characterised by the insertion and/or deletion of simple repeat sequences and indicative of the involvement of defective mismatch repair. Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is an inherited autosomal dominant syndrome characterised by a triad of cutaneous lesions consisting of fibrofolliculomas, trichodiscomas, and acrochordons. 10 A wide spectrum of neoplastic and non-neoplastic features has been described in BHD patients, 11 including diverse types of kidney tumours 12-17 and spontaneous pneumothorax.12-16 18 BHD has also been reported to be associated with colonic polyposis and colorectal neoplasia, 13 19-22 although a large study of 223 patients from 33 BHD families could not establish such a relation. 23 We recently reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. 13 The BHD gene has been mapped to chromosome subband 17p11.2 12 14 and recently identified to encode a novel protein named follicullin. 15 Based on the presence of inactivating BHD mutations in BHD patients, and the detection of LOH in a significant proportion of BHD related tumours, the BHD gene was considered to be a tumour suppressor gene. A 44% frequency of frameshift mutations within a mononucleotide (C) 8 tract (nt 1733-1740) has been detected in BHD patients, 15 and this repeat tract represents a BHD mutational hot spot.13 15 Other studies have reported the presence of frameshift mutations within intragenic mononucleotide tracts of the TGFBR2 and BAX genes in CRC cell lines and tumours with high level MSI.24 25 The poly C tract of the BHD gene may therefore be a potential site of mutation in CRC characterised by MSI.We have evaluated the role of the BHD gene in 47 unselected colorectal tumours (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analysing 46 of the tumours for LOH in the chromosome region surrounding the BHD locus. Furthermore, alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues where a sufficient quantity of DNA was available. We report the detection of two novel somatic missense mutations of ...

Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis

“…33 A second type of NF1 microdeletions of about 1.2 Mb in size is due to a mitotic intrachromosomal recombination between the JJAZ1 and the homologous JJAZ1P pseudogene. 34,35 The NF1 microdeletions in our leukemia patients seemed identical to this 1.2 Mb microdeletion type. 33 However, in contrast to patients with NF1 with similar NF1 deletions, our patients with leukemia did not meet the clinical criteria for NF1, lacking cafe-au-lait spots, mental retardation, and/or facial dysmorphism.…”

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

“…Figure S1) and is caused by non-allelic homologous recombination (NAHR) between paralogous sequences flanking the NF1 gene: the NF1 proximal and distal low-copy repeats (LCRs): NF1-REP-a and NF1- REP-c (Dorchner et al, 2000;López Correa et al, 2000;Jenne et al, 2001Jenne et al, , 2003Forbes et al, 2004;Raedt et al, 2006). The typical type-2 microdeletion is smaller (1.2 Mb) and has breakpoints located in the SUZ12 gene (suppressor of zeste 12 homolog; NM_015355) and its pseudogene SUZ12P (Petek et al, 2003;KehrerSawatzki et al, 2004;Steinmann et al, 2007;Roehl et al, 2010). Even less frequent, atypical NF1 microdeletions with non-recurring breakpoints have also been reported (Riva et al, 2000;Kehrer-Sawatzki et al, 2003Venturin et al, 2004a;Mantripragada et al, 2006;Pasmant et al, 2008).…”

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

“…8 Type 2 microdeletions have predominantly been seen as a result of mitotic NAHR and are 1.2 Mb in size with breakpoints within SUZ12 and its pseudogene SUZ12P adjacent to NF1-REP C and NF1-REP A, respectively (Figure 1). [12][13][14] The 1.0-Mb type 3 NF1 microdeletions are the smallest of the three, mediated by LCRs NF1-REP B and NF1-REP C (Figure 1). 6,11 NAHR between LCRs, such as NF1-REPs A, B, and C, lead to both deletion and duplication of the intervening sequence.…”