Germline truncating mutations in both MSH2 and BRCA2 in a single kindred

Abstract

There has been interest in the literature in the possible existence of a gene that predisposes to both breast cancer (BC) and colorectal cancer (CRC). We describe the detailed characterisation of one kindred, MON1080, with 10 cases of BC or CRC invasive cancer among 26 first-, second-or third-degree relatives. Linkage analysis suggested that a mutation was present in BRCA2. DNA sequencing from III: 22 (diagnosed with lobular BC) identified a BRCA2 exon 3 542G4T (L105X) mutation. Her sister (III: 25) had BC and endometrial cancer and carries the same mutation. Following immunohistochemical and microsatellite instability studies, mutation analysis by protein truncation test, cDNA sequencing and quantitative real-time PCR revealed a deletion of MSH2 exon 8 in III: 25, confirming her as a double heterozygote for truncating mutations in both BRCA2 and MSH2. The exon 8 deletion was identified as a 14.9 kb deletion occurring between two Alu sequences. The breakpoint lies within a sequence of 45 bp that is identical in both Alu sequences. In this large BC/CRC kindred, MON1080, disease-causing truncating mutations are present in both MSH2 and BRCA2. There appeared to be no increased susceptibility to the development of colorectal tumours in BRCA2 mutation carriers or to the development of breast tumours in MSH2 mutation carriers. Additionally, two double heterozygotes did not appear to have a different phenotype than would be expected from the presence of a mutation in each gene alone. Keywords: MSH2; BRCA2; microsatellite instability; colorectal cancer; breast cancer; astrocytoma; multiple primary cancers BRCA1 and BRCA2 are the most important susceptibility genes for breast and ovarian cancer, and mutations in these two genes account for 480% of all kindreds with hereditary breast/ovarian cancer and for about 2 -3% of breast cancer (BC) cases overall. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer (CRC) (Lynch and de la Chapelle, 1999) and is responsible for 0.5 -3% of all cases of CRC. Mutations in the DNA repair genes MLH1 and MSH2 segregate in up to 90% of HNPCC pedigrees (Peltomaki, 2001).Several groups have studied the genetic relationship between breast and colorectal cancer, with varying findings. In one large Dutch family with a segregating BRCA1 mutation, there are several mutation carriers who have developed CRC. However, detailed analysis suggested that the BRCA1 mutation was not contributing to the CRCs observed. By contrast, in a large international study, Thompson et al (2002) observed a relative risk of 2.03 (Po0.001) for CRC in BRCA1 mutation carriers, compared with general population cancer incidence. Studies in HNPCC kindreds have shown no excess of BC, or have shown that when BC does occur, microsatellite instability (MSI), a hallmark of HNPCC-related cancer, is usually absent (Aarnio et al, 1995;Caluseriu et al, 2001). Interestingly, Borg et al reported a family with two missense mutations in MLH1 and a single truncating mutation in BRCA1. ...

A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin

“…Except for the deletion previously described by Stella et al, 5 the other exon 8 deletions found in our families are different from those previously characterized and reported 4,7,25 in the LOVD (Leiden Open Variation Database) database.…”

“…[3][4][5][6][7][8] In this paper we describe the characterization of five different MSH2 exon 8 deletions identified in 13 unrelated Italian families with Lynch syndrome. Interestingly, 10 of the families carrying exon 8 deletions were of Sardinian origin, although the large majority of the probands with MSH2 mutations in our series of families did not have a Sardinian origin.…”

Distinct patterns of germ-line deletions inMLH1 andMSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC)

“…The role of genomic rearrangements in the etiology of HNPCC has been under-investigated, due to the lack of technically simple and reliable approaches for detecting this type of mutation. Recently, with the development of PCR-based semi-quantitative approaches for detecting gene dosage, it has become apparent that a substantial proportion of HNPCC cases are associated with germ-line genomic rearrangements in the MMR genes, mainly MLH1and MSH2 (Papadopoulos et al, 1994;Nystrom-Lahti et al, 1995;Mauillon et al, 1996;Wijnen et al, 1998;Charbonnier et al, 2000;Charbonnier et al, 2002;Gille et al, 2002;Viel et al, 2002;Wang et al, 2002;Nakagawa et al, 2003;Plaschke et al, 2003;Pyatt et al, 2003;Taylor et al, 2003;Wang et al, 2003;Di Fiore et al, 2004;Miyaki et al, 2004;Thiffault et al, 2004;Casey et al, 2005). A germ-line genomic deletion in HNPCC was first identified as a founder mutation at MLH1 among the Finnish population (Nystrom-Lahti et al, 1995).…”

High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families

“…More recently, this condition has been referred to as the constitutional mismatch repair deficiency syndrome (CMMR-D) (Wimmer and Etzler, 2008). The majority of reported Lynch syndrome-causing mutations have been point mutations; however, increasingly, gross genomic rearrangements have been observed due to the widespread use of reliable methods to detect them (Papadopoulos et al, 1994;Nystrom-Lahti et al, 1995;Mauillon et al, 1996;Wijnen et al, 1998;Charbonnier et al, 2000;Charbonnier et al, 2002;Gille et al, 2002;Viel et al, 2002;Wang et al, 2002;Nakagawa et al, 2003;Plaschke et al, 2003;Pyatt et al, 2003;Taylor et al, 2003;Wang et al, 2003;Di Fiore et al, 2004;Miyaki et al, 2004;Thiffault et al, 2004;Casey et al, 2005;van der Klift et al, 2005;Li et al, 2006). A germline genomic deletion in Lynch syndrome was first identified as a founder mutation in MLH1 within the Finnish population (Nystrom-Lahti et al, 1995).…”