BRCA2 germline mutations in familial pancreatic carcinoma

Hahn, Stephan A.; Greenhalf, Bill; Ellis, Ian O.; Sina-Frey, Mercedes; Rieder, Harald; Gerdes, Berthold; Kress, Ralf; Ziegler, Andreas; Rehder, Helga; Rothmund, M.; Schmiegel, Wolff; Neoptolemos, John P.; Bartsch, Detlef K.

doi:10.1016/s0016-5085(03)82772-5

Cited by 67 publications

(91 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In one study 19% of families with a history of hereditary pancreatic cancer had either a frameshift mutation or an unclassified variant of BRCA2/FANCD1 (Hahn et al 2003). Other FA gene mutations have also been identified in pancreatic cancer.…”

Section: Cancer Risk In Heterozygous Carriers Of Fa Gene Mutationmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

364

345

View full text Add to dashboard Cite

Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.

show abstract

Section: Cancer Risk In Heterozygous Carriers Of Fa Gene Mutationmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

364

345

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

“…Although the majority of cases of PAC are sporadic, up to one in 10 cases occurs in the setting of a hereditary cancer predisposition syndrome, the most common of which is a germline BRCA1 or BRCA2 mutation [2]. The lifetime risk for PAC in a BRCA2 mutation carrier is estimated at 3.5-10 times that of the general population [2,3]. Recently, BRCA1 was also implicated as carrying an elevated risk for the development of PAC, although this risk appears to be lower than that seen in BRCA2 mutation carriers; the frequency of BRCA1 mutations compared with BRCA2 mutations in familial pancreatic cancer kindreds is also less [4].…”

Section: Introductionmentioning

confidence: 99%

An Emerging Entity: Pancreatic Adenocarcinoma Associated with a Known BRCA Mutation: Clinical Descriptors, Treatment Implications, and Future Directions

et al. 2011

View full text Add to dashboard Cite

Learning Objectives After completing this course, the reader will be able to: Describe the genetic syndromes associated with pancreas adenocarcinoma. Explain the potential role of platinum‐based therapy and PARP inhibitors in BRCA‐mutated pancreas adenocarcinoma. This article is available for continuing medical education credit at http://CME.TheOncologist.com Background. BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA‐associated cancers have been shown to have greater sensitivity to platinum and poly(ADP‐ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA‐associated PAC have not been reported. Methods. Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan‐Kettering Cancer Center. Results. Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum‐based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion. BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA‐mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.

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

Self Cite

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

BRCA2 germline mutations in familial pancreatic carcinoma

Abstract: See "Notes" following "References." See "Appendix" for the names of the members of the German Familial Pancreatic Cancer (FaPaCa) study group of the Deutsche Krebshilfe and the EUROPAC study group.

Cited by 67 publications

References 5 publications

The Fanconi Anemia/BRCA pathway: new faces in the crowd

The Fanconi Anemia/BRCA pathway: new faces in the crowd

An Emerging Entity: Pancreatic Adenocarcinoma Associated with a Known BRCA Mutation: Clinical Descriptors, Treatment Implications, and Future Directions

RNASEL germline variants are associated with pancreatic cancer

Contact Info

Product

Resources

About