Germline BRCA1 mutations predispose to pancreatic adenocarcinoma

Al-Sukhni, Wigdan; Rothenmund, Heidi; Borgida, Ayelet; Zogopoulos, George; O’Shea, Anne‐Marie; Pollett, Aaron; Gallinger, Steven

doi:10.1007/s00439-008-0554-0

Cited by 63 publications

(31 citation statements)

References 29 publications

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“…The association between BRCA1 mutations and PC is less widely reported, but the relative risk of PC in BRCA1 mutation carriers is estimated to be twofold higher than in the general population [1][2][3][4][5][6][7][8][9][10][11]. An analysis of PC patients from the Polish population recently showed that there is no relationship between BRCA1 mutation and PC development, while American and Canadian studies concluded that BRCA1 germline mutations likely predispose to the development of PC [5,8,10]. In addition, recent findings in Ashkenazi BC/PC families suggest that the distribution of BRCA1 versus BRCA2 mutations in these families is nearly equal [9,11].…”

Section: Introductionmentioning

confidence: 99%

Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy

Ghiorzo

Pensotti

Fornarini³

et al. 2011

Familial Cancer

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Pancreatic adenocarcinoma (PC) is the third most common cancer associated with BRCA mutations. Most notice has been given to BRCA2, while the association between BRCA1 and PC is less widely reported. Recently, PALB2 has been implicated in both PC and breast cancer (BC) susceptibility. We selected 29 Italian PC patients from a case-control study of PC according to their personal and family history of both PC and breast/ovarian cancer (BC/OC) and tested them for presence of germline mutations in BRCA1, BRCA2 and PALB2. We identified no germline mutations or deletions in PALB2, but detected 7 BRCA mutations (4 in BRCA1 and 3 in BRCA2). These findings suggest that PALB2 does not play a major role in PC susceptibility in our population. As we found an almost equal frequency of germline mutations in BRCA1 and BRCA2, germline alterations in either of these genes may explain a subset of Italian families presenting both PC and BC/OC. Moreover, as we began the observation of these families from probands who are affected by PC, we provide here a direct assessment of the role of PALB2 and BRCA mutations in PC susceptibility.

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Section: Introductionmentioning

confidence: 99%

Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy

Ghiorzo

Pensotti

Fornarini³

et al. 2011

Familial Cancer

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“…Germline BRCA1 mutations only account for a small proportion of familial PDAC, although the risk of developing PDAC in BRCA1 mutation carriers appears to be similar to that of BRCA2 mutation carriers (Ford et al 1994, Thompson et al 2002, Al-Sukhni et al 2008, Vincent et al 2011, Ryan et al 2014, Neuzillet et al 2015. The PALB2 (partner and localizer of BRCA2) protein binds to the BRCA1/2 proteins and ensures nuclear addressing ).…”

Section: Other Gene Mutations Favoring Pdac Developmentmentioning

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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“…The tremendous relevance of an intact homologous recombination-mediated DSB repair machinery is underscored by the observation that patients carrying germline mutations in different homologous recombination genes, such as ATM, BRCA1, BRCA2, and RAD51C display a dramatically elevated risk for the development of neoplastic diseases (22)(23)(24)(25)(26)(27)(28). Furthermore, recurrent somatic proteindamaging mutations or focal deletions of ATM, BRCA1, BRCA2, CHEK2, RAD50, RAD51C, and others have been found in multiple cancer entities (29)(30)(31)(32)(33).…”

Section: Dsb Repair Defects As a Therapeutic Targetmentioning

confidence: 99%

Molecular Pathways: Exploiting Tumor-Specific Molecular Defects in DNA Repair Pathways for Precision Cancer Therapy

Dietlein

Reinhardt

2014

Clinical Cancer Research

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Disabling mutations in genome maintenance and DNA repair pathways are frequently observed in cancer. These DNA repair defects represent genetic aberrations that are specific to cancer cells and not present in healthy tissues. It is thought that these molecular defects produce a "mutator phenotype," which allows incipient cancer cells to accumulate additional cancer-promoting mutations. In recent years, our molecular understanding of DNA double-strand break (DSB) repair mechanisms has led to the development of targeted therapeutic approaches to selectively eradicate cancer cells that display defects in homologous recombination-mediated DNA DSB repair. These regimens for the treatment of homologous recombination-defective tumors predominantly aim at pharmacologically repressing the activity of PARP1, which is crucial for base excision repair, or to inhibit the nonhomologous end joining kinase DNA-PKcs (DNA-dependent protein kinase, catalytic subunit). Normal tissue can bypass PARP1-or DNA-PKcs inhibitor-induced genotoxic lesions via homologous recombination-mediated DNA DSB repair. In contrast, homologous recombination-defective cancer cells are unable to properly repair DNA DSBs, in the presence of PARP1 or DNA-PKcs inhibitors, ultimately leading to apoptotic cancer cell death. Clin Cancer Res; 20(23); 5882-7. Ó2014 AACR.

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Germline BRCA1 mutations predispose to pancreatic adenocarcinoma

Cited by 63 publications

References 29 publications

Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy

Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

Molecular Pathways: Exploiting Tumor-Specific Molecular Defects in DNA Repair Pathways for Precision Cancer Therapy

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