BRCA2 Germline Mutations in Familial Pancreatic Carcinoma

Hahn, Stephan A.; Greenhalf, Bill; Ellis, Ian; Sina-Frey, Mercedes; Rieder, Harald; Korte, Birgit; Gerdes, Berthold; Kress, Ralf; Ziegler, Andreas; Raeburn, J. A.; Campra, D; Grützmann, Robert; Rehder, Helga; Rothmund, M.; Schmiegel, Wolff; Neoptolemos, John P.; Bartsch, Detlef K.

doi:10.1093/jnci/95.3.214

Cited by 445 publications

(233 citation statements)

References 28 publications

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“…It has been reported that BRCA2, PALB2, and ataxia telangiectasia mutated germ‐line mutations are most frequently identified in familial PC cases 32, 33, 34. In July 2013 in Japan, JPS established the familial PC registry for early diagnosis, and already started this registry in 2015.…”

Section: Risk Factors and Early Diagnosismentioning

confidence: 99%

Early diagnosis of pancreatic cancer: Current trends and concerns

Hanada

Amano

Abe

2017

Annals of Gastroent Surgery

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Early detection of pancreatic cancer (PC) is essential for a better prognosis. Some recent studies have demonstrated that a slight dilatation of the main pancreatic duct (MPD) and small cystic lesions were detected initially in most cases diagnosed at an early stage. Detecting these abnormal findings in cases with high risk factors through an effective screening system including image diagnosis, some biological markers, or familial cancer registrations should contribute to early diagnosis of PC. It has been reported that endoscopic ultrasonography (EUS) is essential for detecting tumors <10 mm with a favorable prognosis. Additionally, EUS‐guided fine‐needle aspiration biopsy is useful for confirming final histological diagnosis. For the diagnosis of stage 0 PC, local irregular stenosis of MPD should be an important initial abnormal sign detected by EUS or magnetic resonance cholangiopancreatography. Cytodiagnosis multiple times using pancreatic juice obtained by endoscopic nasopancreatic drainage should be essential for the final diagnosis. Recently, activities of regional networks between specialist doctors in medical centers and general practitioners for early diagnosis of PC have been reported in Japan. In the future, these activities may play an important role in the early diagnosis of PC.

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Section: Risk Factors and Early Diagnosismentioning

confidence: 99%

Early diagnosis of pancreatic cancer: Current trends and concerns

Hanada

Amano

Abe

2017

Annals of Gastroent Surgery

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“…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%

“…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%

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

et al. 2005

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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.

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“…Germline BRCA2 mutations are identified in 4-17% of families with familial PDAC and are the most common germline genetic alteration identified in this condition (Murphy et al 2002, Hahn et al 2003, Couch et al 2007, Salo-Mullen et al 2015, Zhen et al 2015, Hu et al 2016, Roberts et al 2016. However, this rate varies depending on the definition of familial PDAC, i.e., the number of relatives affected to define a population at risk.…”

Section: Epidemiological Links Between Brca2 Mutations and Pdacmentioning

confidence: 99%

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

Mestier

Danset

Neuzillet

et al. 2016

Endocrine-Related Cancer

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Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation.

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BRCA2 Germline Mutations in Familial Pancreatic Carcinoma

Cited by 445 publications

References 28 publications

Early diagnosis of pancreatic cancer: Current trends and concerns

Early diagnosis of pancreatic cancer: Current trends and concerns

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

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

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