Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients

Özçelik, Hilmi; Schmocker, Beverly; N, Di Nicola; Xh, Shi; Langer, B; Moore, Malcolm J.; Br, Taylor; Narod, SA; Darlington, Gerarda; Andrulis, IL; Gallinger, Steven; Redston, Mark

doi:10.1038/ng0597-17

Cited by 204 publications

(111 citation statements)

References 12 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…Heteroduplex analysis was used to screen for the deletion mutations and performed according to previously described protocols (Ozcelik et al, 1996;Ozcelik et al, 1997). A sample of the PCR product is mixed with an equal volume of PCR product from normal control DNA and electrophoresis loading buffer (15% sucrose + 0.05% xylene cyanol + 0.05% bromophenol blue).…”

Section: Heteroduplex Analysismentioning

confidence: 99%

Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: A founder mutation of BRCA1 identified in the Chinese population

et al. 2002

View full text Add to dashboard Cite

Previous mutational analysis for BRCA gene mutations in sporadic ovarian cancer occurring in Chinese patients in Hong Kong identified six germline BRCA1 mutations and one germline BRCA2 mutation, six of which were novel (Khoo et al., 2000). Knowledge of BRCA gene mutations in the Chinese population is relatively scant. In this study, we focussed on whether any of these mutations could be recurrent in our Chinese population, making use of archival paraffin embedded tissue. A consecutive series of 214 ovarian cancer cases, half of Southern Chinese origin from Hong Kong whilst the other half of Northern Chinese origin from Beijing were used for the study. We identified one further novel mutation, 1081delG, in BRCA1. This was found to occur in two unrelated individuals with shared haplotype as revealed by allelotype analysis, thus demonstrating founder effect. Two other recurrent mutations were also identified, the 2371-2372delTG mutation in BRCA1 and the 3337C>T mutation in BRCA2 recurring in two and three unrelated individuals respectively, giving an overall prevalence 4.7% of recurrent BRCA mutations in ovarian cancer in the Southern Chinese population. Most importantly, all our recurrent mutation carriers were identified from Southern Chinese patients from Hong Kong whilst such mutations were absent in samples from the Northern Chinese. Our findings indicate possible heterogeneity in the BRCA genotype between Northern and Southern Chinese. The identification of a founder mutation and two recurrent mutations moreover, has important implications towards screening strategies for breast and ovarian cancer among Chinese of southern ancestral origin who are now dispersed throughout the world.

show abstract

Section: Heteroduplex Analysismentioning

confidence: 99%

Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: A founder mutation of BRCA1 identified in the Chinese population

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Epidemiological data suggest that dominant susceptibility genes may be responsible for about 3% of all pancreatic cancer cases. 2,3 BRCA2 germline mutations have been identified in 4.9% and 7.3% of apparently sporadic PC cases 4,5 and about 17% of and familial pancreatic cancer (FPC) cases, 6,7 respectively. There is also some evidence that mutations in CDKN2a, PRSS1, Mismatch-Repair and Fanconi anaemia genes predispose to PC, but the contribution of these genes to PC tumorigenesis is considered to be small.…”

mentioning

confidence: 99%

RNASEL germline variants are associated with pancreatic cancer

Bartsch

Fendrich

Slater

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

The RNASEL (encoding ribonuclease L) gene Glu265X mutation has been implicated in familial prostate cancer, and an association between the RNASEL Arg462Gln variant and sporadic and familial prostate cancer, has also been suggested. Because prostate cancer occurs in some familial pancreatic cancer families, we evaluated the role of the RNASEL gene variants Glu265X and Arg462Gln in the etiology of pancreatic cancer. Exon 2 of the RNASEL gene was directly sequenced in the germline of 36 familial and 75 sporadic pancreatic cancer patients and in 108 controls. The Glu265X mutation was identified in one (2.8%) familial and one (1.3%) sporadic pancreatic cancer case, but not in any of the controls. Arg462Gln variants were identified in 61 (56%) controls and in 55 (73%) sporadic pancreatic cancer cases with 8 (7%) and 12 (16%) homozygotes, respectively (p 5 0.009). For homozygous carriers the increased risk for pancreatic cancer was 3.5 (odds ratio [OR] 5 3.53, 95% confidence interval [CI] 5 1.11-11.46, p 5 0.03). The population attributable fraction (PAF) was 38.7% (95% CI 5 0.08-0.80). In familial pancreatic cancer no association between Arg462Gln genotypes and pancreatic cancer risk was evident. In sporadic pancreatic cancer there were no significant differences between Arg462Gln genotypes regarding clinical characteristics. In familial pancreatic cancer, however, patients with Arg462Gln variants had more aggressive tumors with more high grade cancers (OR 5 15.40, p 5 0.009) and more distant metastases (OR 5 7.00, p 5 0.04) than patients with the wild-type genotype. Our results suggest that RNASEL variants Glu265X and Arg462Gln may contribute to the tumorigenesis of sporadic and familial pancreatic cancer, which has to be proven in large scale studies. ' 2005 Wiley-Liss, Inc.Key words: RNASEL; familial pancreatic cancer; sporadic pancreatic cancer Pancreatic cancer (PC) is the fifth leading cause of cancer death in Western countries with an overall 5-year survival rate of <5%. 1 The genetic basis of pancreatic cancer is complex and seems to involve multiple susceptibility genes. Epidemiological data suggest that dominant susceptibility genes may be responsible for about 3% of all pancreatic cancer cases. 2,3 BRCA2 germline mutations have been identified in 4.9% and 7.3% of apparently sporadic PC cases 4,5 and about 17% of and familial pancreatic cancer (FPC) cases, 6,7 respectively. There is also some evidence that mutations in CDKN2a, PRSS1, Mismatch-Repair and Fanconi anaemia genes predispose to PC, but the contribution of these genes to PC tumorigenesis is considered to be small. 8 The major underlying gene defect(s) of FPC are still unknown.The RNASEL (2 0 -5 0 oligoisoadenylate-synthetase dependent) gene located at chromosome 1q24-q25 plays a causal role in cell death by viral and non-viral stimuli and represents an important fragment of the apoptosis cascade. 9 The role of the ''2 0 -5 0 A-system'' in the control of cellular growth suggests that defects in this pathway could result in reduced immunity to virus...

show abstract

“…Germline mutations in the p16 (Goldstein et al, 1995;Lynch et al, 2000;Vasen et al, 2000;Bartsch et al, 2002), FANCC (van der Heijden et al, 2003;Rogers et al, 2004), FANCG (van der Heijden et al, 2003;Rogers et al, 2004), PRSS1 (Lowenfels et al, 1993(Lowenfels et al, , 1997, STK11 (Giardiello et al, 2000;Lim et al, 2004), and hMLH1 (Yamamoto et al, 2001) genes are infrequent causes of familial pancreatic cancer and are associated with a number of cancer syndromes, including familial multiple mole melanoma (FAMMM), hereditary pancreatitis, hereditary nonpolyposis colon cancer, and Peutz-Jeghers syndrome. In addition, germline BRCA2 mutations are observed in B5% of patients with apparently sporadic pancreatic cancer, that is, patients who do not appear to have an inherited predisposition to pancreatic or breast/ovarian cancer (Goggins et al, 1996;Ozcelik et al, 1997;The Breast Cancer Linkage Consortium, 1999;Figer et al, 2001). Murphy et al (2002) recently reported deleterious BRCA2 mutations in up to 17% of familial pancreatic cancers and Hahn et al (2003) found a prevalence of B12%.…”

Section: Introductionmentioning

confidence: 99%

“…Familial pancreatic cancer is defined as cancers occurring in families in which there are at least two firstdegree relatives with the disease in the absence of other known familial cancer syndromes. The inherited basis of B10-20% of familial pancreatic cancers has been identified and is reflected largely in germline mutations in the BRCA2 gene (Goggins et al, 1996;Ozcelik et al, 1997;Hahn et al, 2003) (The Breast Cancer Linkage Consortium, 1999;Murphy et al, 2002). Germline mutations in the p16 (Goldstein et al, 1995;Lynch et al, 2000;Vasen et al, 2000;Bartsch et al, 2002), FANCC (van der Heijden et al, 2003;Rogers et al, 2004), FANCG (van der Heijden et al, 2003;Rogers et al, 2004), PRSS1 (Lowenfels et al, 1993(Lowenfels et al, , 1997, STK11 (Giardiello et al, 2000;Lim et al, 2004), and hMLH1 (Yamamoto et al, 2001) genes are infrequent causes of familial pancreatic cancer and are associated with a number of cancer syndromes, including familial multiple mole melanoma (FAMMM), hereditary pancreatitis, hereditary nonpolyposis colon cancer, and Peutz-Jeghers syndrome.…”

Section: Introductionmentioning

confidence: 99%

Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer

et al. 2005

View full text Add to dashboard Cite

Germline BRCA2 mutations predispose to the development of pancreatic cancer. A polymorphic stop codon in the coding region of BRCA2 (K3326X) has been described, and although an initial epidemiological study suggested it was not disease causing, subsequent studies have been inconclusive. To investigate the biological significance of the K3326X polymorphism, we determined its prevalence in patients with sporadic and familial pancreatic cancer. Using a case-control design, we studied 250 patients with resected sporadic pancreatic adenocarcinomas, 144 patients with familial pancreatic adenocarcinoma, 115 spouses of patients with pancreatic cancer, and a disease control group of 135 patients without a personal history of cancer who had undergone cholecystectomy for non-neoplastic disease. The K3326X polymorphism was detected using heteroduplex analysis and DNA sequencing. The BRCA2 K3326X polymorphism was significantly more prevalent in individuals with familial pancreatic cancer: 8/144 (5.6%) vs 3/250 controls (1.2%) (odds ratio, 4.84; 95% CI, 1.27-18.55, Po0.01). One K3326X carrier with familial pancreatic cancer carried an alteration (IVS 16-2A>G) suspected to be deleterious. Excluding this case did not alter the significance of the association (OR: 4.24, Po0.01). In contrast, there was no difference in prevalence among individuals with sporadic pancreatic cancer -7/250 (OR: 2.37, 95% CI: 0.61-9.27). The increased prevalence of the BRCA2 K3326X polymorphism in patients with familial pancreatic cancer suggests that this polymorphism is deleterious and contributes to pancreatic cancer risk.

show abstract

Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients

Cited by 204 publications

References 12 publications

Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: A founder mutation of BRCA1 identified in the Chinese population

Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: A founder mutation of BRCA1 identified in the Chinese population

RNASEL germline variants are associated with pancreatic cancer

Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer

Contact Info

Product

Resources

About