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Alison P Klein - One of the best experts on this subject based on the ideXlab platform.
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recent progress in Pancreatic Cancer
CA: A Cancer Journal for Clinicians, 2013Co-Authors: Christopher L Wolfgang, Alison P Klein, Dan Laheru, Joseph M Herman, Michael A Erdek, Elliot K Fishman, Ralph H HrubanAbstract:Pancreatic Cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in our understanding of the fundamental genetics of Pancreatic Cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with Pancreatic Cancer.
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genetic susceptibility to Pancreatic Cancer
Molecular Carcinogenesis, 2012Co-Authors: Alison P KleinAbstract:Pancreatic Cancer is the fourth leading cause of Cancer death in both men and women in the United States. However, it has the poorest prognosis of any major tumor type, with a 5-yr survival rate of approximately 5%. Cigarette smoking, increased body mass index, heavy alcohol consumption, and a diagnosis of diabetes mellitus have all been demonstrated to increase risk of Pancreatic Cancer. A family history of Pancreatic Cancer has also been associated with increased risk suggesting inherited genetic factors also play an important role, with approximately 5–10% of Pancreatic Cancer patients reporting family history of Pancreatic Cancer. While the genetic basis for the majority of the familial clustering of Pancreatic Cancer remains unclear, several important Pancreatic Cancer genes have been identified. These consist of high penetrance genes including BRCA2 or PALB2, to more common genetic variation associated with a modest increase risk of Pancreatic Cancer such as genetic variation at the ABO blood group locus. Recent advances in genotyping and genetic sequencing have accelerated the rate at which novel Pancreatic Cancer susceptibility genes have been identified with several genes identified within the past few years. This review addresses our current understanding of the familial aggregation of Pancreatic Cancer, established Pancreatic Cancer susceptablity genes and how this knowledge informs risk assessment and screening for high-risk families.
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update on familial Pancreatic Cancer
Advances in Surgery, 2010Co-Authors: Ralph H Hruban, Michael Goggins, Marcia I. Canto, Alison P Klein, Richard D SchulickAbstract:It has been suggested that ~10% of Pancreatic Cancer has a familial basis 1, 2. Individuals with a family history of Pancreatic Cancer have an increased risk of developing both Pancreatic and extraPancreatic malignancies, and an individual’s risk of developing Pancreatic Cancer can now be quantified based on their family Cancer history 1, 3, 4. While some of the aggregation of Pancreatic Cancer in families is due to chance, and some to shared environmental exposures such as cigarette smoking, it is now clear that much of this aggregation has a genetic basis 5. Several of the genes responsible for the familial clustering of Pancreatic Cancer have been discovered. For example, germline mutations in the BRCA2 gene cause familial breast Cancer, and individuals with germline BRCA2 gene mutations have an approximately 3.5-fold increased risk of Pancreatic Cancer 6–12. Germline mutations in the p16/CDKN2A gene cause the Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, and these individuals have a 13 to 37-fold increased risk of Pancreatic Cancer 10, 13–23. Inherited mutations in the STK11 gene cause the Peutz-Jeghers syndrome, and individuals with Peutz-Jeghers have a 130-fold increased risk of Pancreatic Cancer 24–30. The discovery of these familial Pancreatic Cancer genes has helped identify cellular pathways important for the development of Pancreatic Cancer, it has provided a basis for genetic counseling of individuals with a family history of Pancreatic Cancer, and it has established a foundation for prioritizing patients for screening for early pre-invasive disease 21, 29, 31–33. In addition, the discovery of familial Pancreatic Cancer genes has also lead to the development of gene-specific therapies as demonstrated by the remarkable sensitivity of Pancreatic Cancers harboring mutations in the BRCA2 gene to Poly[ADP-ribose] polymerase (PARP) inhibitors and to mitomycin C 34–41. The field of familial Pancreatic Cancer is getting even more exciting as we enter the era of whole genome sequencing. For example, this year the PALB2 gene was discovered to be a familial Pancreatic Cancer susceptibility gene through complete, unbiased, sequencing of all of the protein-coding genes in a single patient’s Cancer 42, 43. As the speed of “next generation” sequencing technologies rises and the costs fall, we can foresee the discovery of a number of new familial Pancreatic Cancer genes in the coming years. The known genetic syndromes account for less than 20% of the observed familial aggregation of Pancreatic Cancer, and the discovery of additional familial Pancreatic Cancer genes remains one of the most exciting opportunities in Pancreatic Cancer research 1, 2. As these genes are discovered, the challenge will be to use these scientific breakthroughs to improve clinical care.
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familial Pancreatic Cancer
Archives of Pathology & Laboratory Medicine, 2009Co-Authors: Chanjuan Shi, Ralph H Hruban, Alison P KleinAbstract:Context Approximately 5% to 10% of individuals with Pancreatic Cancer report a history of Pancreatic Cancer in a close family member. In addition, several known genetic syndromes, such as familial breast Cancer (BRCA2), the Peutz-Jeghers syndrome, and the familial atypical multiple mole melanoma syndrome, have been shown to be associated with an increased risk of Pancreatic Cancer. The known genes associated with these conditions can explain only a portion of the clustering of Pancreatic Cancer in families, and research to identify additional susceptibility genes is ongoing. Objective To provide an understanding of familial Pancreatic Cancer and the pathology of familial exocrine Pancreatic Cancers. Data sources Published literature on familial aggregation of Pancreatic Cancer and familial exocrine Pancreatic tumors. Conclusions Even in the absence of predictive genetic testing, the collection of a careful, detailed family history is an important step in the management of all patients with Pancreatic Cancer. While most Pancreatic Cancers that arise in patients with a family history are ductal adenocarcinomas, certain subtypes of Pancreatic Cancer have been associated with familial syndromes. Therefore, the histologic appearance of the Pancreatic Cancer itself, and/or the presence and appearance of preCancerous changes in the pancreas, may increase the clinical index of suspicion for a genetic syndrome.
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absence of germline brca1 mutations in familial Pancreatic Cancer patients
Cancer Biology & Therapy, 2009Co-Authors: Jennifer E Axilbund, Kieran Brune, Ralph H Hruban, Michael Goggins, Mihoko Kamiyama, Michael Borges, Pedram Argani, Emily Palmisano, Marian Raben, Alison P KleinAbstract:Recent studies have suggested that germ line mutations in the BRCA1 gene may confer an increased risk of developing Pancreatic Cancer. To determine if BRCA1 mutations explain a significant proportion of familial Pancreatic Cancer, we sequenced the BRCA1 gene in a large series of well-characterized patients with familial Pancreatic Cancer and we evaluated the pathology of breast neoplasms that developed in relatives of Pancreatic Cancer patients. The BRCA1 gene was fully sequenced in 66 Pancreatic Cancer patients enrolled in the National Familial Pancreas Tumor Registry who had at least two additional relatives with Pancreatic Cancer. None of the 66 (0/66: 97.5% one-side CI 0-0.054%) familial Pancreatic Cancer patients were found to have a deleterious mutation in the BRCA1 gene. While patients were not selected based upon their family history of breast and ovarian Cancer, over half of the patients whose samples were sequenced reported a family history of breast and/or ovarian Cancer. Our findings suggest that mutations in the BRCA1 gene are not highly, or even moderately, prevalent in families with a clustering of Pancreatic Cancer, including Pancreatic Cancer families who report a family history of breast and/or ovarian Cancer.
Gloria M Petersen - One of the best experts on this subject based on the ideXlab platform.
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familial Pancreatic Cancer
Seminars in Oncology, 2016Co-Authors: Gloria M PetersenAbstract:Familial Pancreatic Cancer (FPC) includes those kindreds that contain at least two first-degree relatives with Pancreatic ductal adenocarcinoma. At least 12 known hereditary syndromes or genes are associated with increased risk of developing Pancreatic Cancer, the foremost being BRCA2 and CDKN2A. Research into the identification of mutations in known Cancer predisposition genes and through next-generation sequencing has revealed extensive heterogeneity. The development of genetic panel testing has enabled genetic risk assessment and predisposition testing to be routinely offered. Precision oncology has opened the possibility of "incidental" germline mutations that may have implications for family members. However, in both cases, evidence-based recommendations for managing patients and at-risk family members in light of genetic status remain emergent, with current practice based on expert opinion.
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cigarette smoking and Pancreatic Cancer an analysis from the international Pancreatic Cancer case control consortium panc4
Annals of Oncology, 2012Co-Authors: Gloria M Petersen, Debra T. Silverman, E. Negri, C. Bosetti, Ersilia Lucenteforte, Paige M Bracci, Harvey A RischAbstract:Background: To evaluate the dose–response relationship between cigarette smoking and Pancreatic Cancer and to examine the effects of temporal variables. Methods: We analyzed data from 12 case–control studies within the International Pancreatic Cancer Case–Control Consortium (PanC4), including 6507 Pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. Results: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0–1.3) for former smokers and 2.2 (95% CI 1.7–2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR = 3.4 for ‡35 cigarettes per day, P for trend <0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR = 2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. Conclusions: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of Pancreatic Cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of Pancreatic Cancer reaches the level of never smokers 20 years after quitting.
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familial Pancreatic Cancer
Cancer Journal, 2008Co-Authors: Alison P Klein, Kieran Brune, Gloria M Petersen, Ralph H Hruban, Michael GogginsAbstract:Pancreatic Cancer is the fourth leading cause of Cancer death in both men and women in the United States and will be responsible for an estimated 28,900 deaths in 2001. Relatively little is known of its etiology, and the only well-established risk factor is cigarette smoking. Studies over the past 3 decades have shown that 4%-16% of patients with Pancreatic Cancer have a family history of the disease. A small fraction of this aggregation can be accounted for in inherited Cancer syndromes, including familial atypical multiple-mole melanoma, Peutz-Jeghers syndrome, hereditary breast-ovarian Cancer, hereditary pancreatitis, and hereditary nonpolyposis colorectal Cancer. These syndromes arise as a result of germline mutations in the BRCA2, pl6 (familial atypical multiple-mole melanoma), mismatch repair (hereditary nonpolyposis colorectal Cancer), and STK11 (Peutz-Jeghers syndrome) genes. In addition, hereditary plays a role in predisposing certain patients with apparently sporadic Pancreatic Cancer. Many patients with Pancreatic Cancers caused by a germline mutation in a Cancer-causing gene do not have a pedigree that is suggestive of a familial Cancer syndrome. A recent prospective analysis of the pedigrees in the National Familial Pancreatic Tumor Registry found that individuals with a family history of Pancreatic Cancer in multiple first-degree relatives have a high risk of Pancreatic Cancer themselves. The identification of such high-risk individuals will help clinicians target screening programs and develop preventive interventions with the hope of reducing the mortality of Pancreatic Cancer in these families.
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the prevalence of brca2 mutations in familial Pancreatic Cancer
Cancer Epidemiology Biomarkers & Prevention, 2007Co-Authors: Fergus J Couch, Kieran Brune, Mariza De Andrade, Steven Gallinger, Kari G Rabe, Michael Goggins, Alison P Klein, Michele Johnson, Heidi Rothenmund, Gloria M PetersenAbstract:Mutations in the BRCA2 gene have been implicated in Pancreatic Cancer susceptibility through studies of high-risk breast and ovarian Cancer families. To determine the contribution of mutations in BRCA2 to familial Pancreatic Cancer, we screened affected probands from 151 high-risk families identified through Pancreatic Cancer clinics for germ-line BRCA2 mutations. Of these families, 118 had two or more first- and second-degree relatives with Pancreatic Cancer, and an additional 33 had two or more affected second-degree relatives. The average age of onset for Pancreatic Cancer was 62.8 years. Five BRCA2 truncating mutations were identified, three in families with two or more first- and second-degree relatives with Pancreatic Cancer. Three of the families with mutations had a history of breast Cancer but not ovarian Cancer. Four of five families with mutations were identified through probands with early-onset (<55 years) Pancreatic Cancer. The results of this study were combined with those from a BRCA2 mutation study of 29 other families from the same Johns Hopkins University National Familial Pancreatic Tumor Registry to estimate the frequency of BRCA2 mutations. A total of 10 carriers from 180 families were identified, suggesting that BRCA2 mutations account for 6% of moderate and high-risk Pancreatic Cancer families.
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Pancreatic Cancer genetic epidemiology consortium
Cancer Epidemiology Biomarkers & Prevention, 2006Co-Authors: Gloria M Petersen, Sapna Syngal, Jeannette F. Korczak, Mariza De Andrade, Steven Gallinger, Melissa L Bondy, Ralph H Hruban, Michael Goggins, Henry T. Lynch, Kari G RabeAbstract:We have organized the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in familial Pancreatic Cancer (FPC). The Consortium comprises seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core. We recruit kindreds containing two or more affected blood relatives ascertained through incident Pancreatic adenocarcinoma cases, physician referrals, and/or through Internet recruitment. Accrual to a database containing core clinical, demographic, lifestyle, and family history information from questionnaires is ongoing, along with biospecimen collection. To date, 13,147 patients have been screened for family history, of whom 476 (50% male) probands and 1,912 of their adult (99% unaffected) relatives have been enrolled. Of these, 379 kindreds meet criteria for FPC, having at least two first-degree relatives with Pancreatic Cancer. Cumulative incidence curves using available age of diagnosis (onset) among and affected relatives were compared with those for incident Pancreatic Cancer cases reported to 13 U.S. Surveillance Epidemiology and End Results (SEER) sites from 1973 to 2000 ( N = 72,700). The mean age ± SD at diagnosis among 466 PACGENE probands and 670 affected relatives was 64.1 ± 11.8 and was 65.4 ± 11.6 for the subset of 369 FPC probands and 429 relatives. Both samples were significantly younger than the mean age at diagnosis in the SEER population (70.0 ± 12.1 years; differences in curves versus SEER, P < 0.001). Age at diagnosis (excluding probands) in FPC kindreds does not decrease with increasing number of affected individuals. In our sample, younger age at diagnosis was observed whether we grouped probands by recruitment sites that predominantly recruited through high-risk referrals, or through screening all Pancreatic Cancer patients for family history. Linkage studies are ongoing. The PACGENE Consortium will be a valuable family-based resource that will greatly enhance genetic epidemiology research in Pancreatic Cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(4):704–10)
Ralph H Hruban - One of the best experts on this subject based on the ideXlab platform.
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recent progress in Pancreatic Cancer
CA: A Cancer Journal for Clinicians, 2013Co-Authors: Christopher L Wolfgang, Alison P Klein, Dan Laheru, Joseph M Herman, Michael A Erdek, Elliot K Fishman, Ralph H HrubanAbstract:Pancreatic Cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in our understanding of the fundamental genetics of Pancreatic Cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with Pancreatic Cancer.
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update on familial Pancreatic Cancer
Advances in Surgery, 2010Co-Authors: Ralph H Hruban, Michael Goggins, Marcia I. Canto, Alison P Klein, Richard D SchulickAbstract:It has been suggested that ~10% of Pancreatic Cancer has a familial basis 1, 2. Individuals with a family history of Pancreatic Cancer have an increased risk of developing both Pancreatic and extraPancreatic malignancies, and an individual’s risk of developing Pancreatic Cancer can now be quantified based on their family Cancer history 1, 3, 4. While some of the aggregation of Pancreatic Cancer in families is due to chance, and some to shared environmental exposures such as cigarette smoking, it is now clear that much of this aggregation has a genetic basis 5. Several of the genes responsible for the familial clustering of Pancreatic Cancer have been discovered. For example, germline mutations in the BRCA2 gene cause familial breast Cancer, and individuals with germline BRCA2 gene mutations have an approximately 3.5-fold increased risk of Pancreatic Cancer 6–12. Germline mutations in the p16/CDKN2A gene cause the Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, and these individuals have a 13 to 37-fold increased risk of Pancreatic Cancer 10, 13–23. Inherited mutations in the STK11 gene cause the Peutz-Jeghers syndrome, and individuals with Peutz-Jeghers have a 130-fold increased risk of Pancreatic Cancer 24–30. The discovery of these familial Pancreatic Cancer genes has helped identify cellular pathways important for the development of Pancreatic Cancer, it has provided a basis for genetic counseling of individuals with a family history of Pancreatic Cancer, and it has established a foundation for prioritizing patients for screening for early pre-invasive disease 21, 29, 31–33. In addition, the discovery of familial Pancreatic Cancer genes has also lead to the development of gene-specific therapies as demonstrated by the remarkable sensitivity of Pancreatic Cancers harboring mutations in the BRCA2 gene to Poly[ADP-ribose] polymerase (PARP) inhibitors and to mitomycin C 34–41. The field of familial Pancreatic Cancer is getting even more exciting as we enter the era of whole genome sequencing. For example, this year the PALB2 gene was discovered to be a familial Pancreatic Cancer susceptibility gene through complete, unbiased, sequencing of all of the protein-coding genes in a single patient’s Cancer 42, 43. As the speed of “next generation” sequencing technologies rises and the costs fall, we can foresee the discovery of a number of new familial Pancreatic Cancer genes in the coming years. The known genetic syndromes account for less than 20% of the observed familial aggregation of Pancreatic Cancer, and the discovery of additional familial Pancreatic Cancer genes remains one of the most exciting opportunities in Pancreatic Cancer research 1, 2. As these genes are discovered, the challenge will be to use these scientific breakthroughs to improve clinical care.
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familial Pancreatic Cancer
Archives of Pathology & Laboratory Medicine, 2009Co-Authors: Chanjuan Shi, Ralph H Hruban, Alison P KleinAbstract:Context Approximately 5% to 10% of individuals with Pancreatic Cancer report a history of Pancreatic Cancer in a close family member. In addition, several known genetic syndromes, such as familial breast Cancer (BRCA2), the Peutz-Jeghers syndrome, and the familial atypical multiple mole melanoma syndrome, have been shown to be associated with an increased risk of Pancreatic Cancer. The known genes associated with these conditions can explain only a portion of the clustering of Pancreatic Cancer in families, and research to identify additional susceptibility genes is ongoing. Objective To provide an understanding of familial Pancreatic Cancer and the pathology of familial exocrine Pancreatic Cancers. Data sources Published literature on familial aggregation of Pancreatic Cancer and familial exocrine Pancreatic tumors. Conclusions Even in the absence of predictive genetic testing, the collection of a careful, detailed family history is an important step in the management of all patients with Pancreatic Cancer. While most Pancreatic Cancers that arise in patients with a family history are ductal adenocarcinomas, certain subtypes of Pancreatic Cancer have been associated with familial syndromes. Therefore, the histologic appearance of the Pancreatic Cancer itself, and/or the presence and appearance of preCancerous changes in the pancreas, may increase the clinical index of suspicion for a genetic syndrome.
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absence of germline brca1 mutations in familial Pancreatic Cancer patients
Cancer Biology & Therapy, 2009Co-Authors: Jennifer E Axilbund, Kieran Brune, Ralph H Hruban, Michael Goggins, Mihoko Kamiyama, Michael Borges, Pedram Argani, Emily Palmisano, Marian Raben, Alison P KleinAbstract:Recent studies have suggested that germ line mutations in the BRCA1 gene may confer an increased risk of developing Pancreatic Cancer. To determine if BRCA1 mutations explain a significant proportion of familial Pancreatic Cancer, we sequenced the BRCA1 gene in a large series of well-characterized patients with familial Pancreatic Cancer and we evaluated the pathology of breast neoplasms that developed in relatives of Pancreatic Cancer patients. The BRCA1 gene was fully sequenced in 66 Pancreatic Cancer patients enrolled in the National Familial Pancreas Tumor Registry who had at least two additional relatives with Pancreatic Cancer. None of the 66 (0/66: 97.5% one-side CI 0-0.054%) familial Pancreatic Cancer patients were found to have a deleterious mutation in the BRCA1 gene. While patients were not selected based upon their family history of breast and ovarian Cancer, over half of the patients whose samples were sequenced reported a family history of breast and/or ovarian Cancer. Our findings suggest that mutations in the BRCA1 gene are not highly, or even moderately, prevalent in families with a clustering of Pancreatic Cancer, including Pancreatic Cancer families who report a family history of breast and/or ovarian Cancer.
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familial Pancreatic Cancer
Cancer Journal, 2008Co-Authors: Alison P Klein, Kieran Brune, Gloria M Petersen, Ralph H Hruban, Michael GogginsAbstract:Pancreatic Cancer is the fourth leading cause of Cancer death in both men and women in the United States and will be responsible for an estimated 28,900 deaths in 2001. Relatively little is known of its etiology, and the only well-established risk factor is cigarette smoking. Studies over the past 3 decades have shown that 4%-16% of patients with Pancreatic Cancer have a family history of the disease. A small fraction of this aggregation can be accounted for in inherited Cancer syndromes, including familial atypical multiple-mole melanoma, Peutz-Jeghers syndrome, hereditary breast-ovarian Cancer, hereditary pancreatitis, and hereditary nonpolyposis colorectal Cancer. These syndromes arise as a result of germline mutations in the BRCA2, pl6 (familial atypical multiple-mole melanoma), mismatch repair (hereditary nonpolyposis colorectal Cancer), and STK11 (Peutz-Jeghers syndrome) genes. In addition, hereditary plays a role in predisposing certain patients with apparently sporadic Pancreatic Cancer. Many patients with Pancreatic Cancers caused by a germline mutation in a Cancer-causing gene do not have a pedigree that is suggestive of a familial Cancer syndrome. A recent prospective analysis of the pedigrees in the National Familial Pancreatic Tumor Registry found that individuals with a family history of Pancreatic Cancer in multiple first-degree relatives have a high risk of Pancreatic Cancer themselves. The identification of such high-risk individuals will help clinicians target screening programs and develop preventive interventions with the hope of reducing the mortality of Pancreatic Cancer in these families.
Michael Goggins - One of the best experts on this subject based on the ideXlab platform.
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update on familial Pancreatic Cancer
Advances in Surgery, 2010Co-Authors: Ralph H Hruban, Michael Goggins, Marcia I. Canto, Alison P Klein, Richard D SchulickAbstract:It has been suggested that ~10% of Pancreatic Cancer has a familial basis 1, 2. Individuals with a family history of Pancreatic Cancer have an increased risk of developing both Pancreatic and extraPancreatic malignancies, and an individual’s risk of developing Pancreatic Cancer can now be quantified based on their family Cancer history 1, 3, 4. While some of the aggregation of Pancreatic Cancer in families is due to chance, and some to shared environmental exposures such as cigarette smoking, it is now clear that much of this aggregation has a genetic basis 5. Several of the genes responsible for the familial clustering of Pancreatic Cancer have been discovered. For example, germline mutations in the BRCA2 gene cause familial breast Cancer, and individuals with germline BRCA2 gene mutations have an approximately 3.5-fold increased risk of Pancreatic Cancer 6–12. Germline mutations in the p16/CDKN2A gene cause the Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, and these individuals have a 13 to 37-fold increased risk of Pancreatic Cancer 10, 13–23. Inherited mutations in the STK11 gene cause the Peutz-Jeghers syndrome, and individuals with Peutz-Jeghers have a 130-fold increased risk of Pancreatic Cancer 24–30. The discovery of these familial Pancreatic Cancer genes has helped identify cellular pathways important for the development of Pancreatic Cancer, it has provided a basis for genetic counseling of individuals with a family history of Pancreatic Cancer, and it has established a foundation for prioritizing patients for screening for early pre-invasive disease 21, 29, 31–33. In addition, the discovery of familial Pancreatic Cancer genes has also lead to the development of gene-specific therapies as demonstrated by the remarkable sensitivity of Pancreatic Cancers harboring mutations in the BRCA2 gene to Poly[ADP-ribose] polymerase (PARP) inhibitors and to mitomycin C 34–41. The field of familial Pancreatic Cancer is getting even more exciting as we enter the era of whole genome sequencing. For example, this year the PALB2 gene was discovered to be a familial Pancreatic Cancer susceptibility gene through complete, unbiased, sequencing of all of the protein-coding genes in a single patient’s Cancer 42, 43. As the speed of “next generation” sequencing technologies rises and the costs fall, we can foresee the discovery of a number of new familial Pancreatic Cancer genes in the coming years. The known genetic syndromes account for less than 20% of the observed familial aggregation of Pancreatic Cancer, and the discovery of additional familial Pancreatic Cancer genes remains one of the most exciting opportunities in Pancreatic Cancer research 1, 2. As these genes are discovered, the challenge will be to use these scientific breakthroughs to improve clinical care.
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absence of germline brca1 mutations in familial Pancreatic Cancer patients
Cancer Biology & Therapy, 2009Co-Authors: Jennifer E Axilbund, Kieran Brune, Ralph H Hruban, Michael Goggins, Mihoko Kamiyama, Michael Borges, Pedram Argani, Emily Palmisano, Marian Raben, Alison P KleinAbstract:Recent studies have suggested that germ line mutations in the BRCA1 gene may confer an increased risk of developing Pancreatic Cancer. To determine if BRCA1 mutations explain a significant proportion of familial Pancreatic Cancer, we sequenced the BRCA1 gene in a large series of well-characterized patients with familial Pancreatic Cancer and we evaluated the pathology of breast neoplasms that developed in relatives of Pancreatic Cancer patients. The BRCA1 gene was fully sequenced in 66 Pancreatic Cancer patients enrolled in the National Familial Pancreas Tumor Registry who had at least two additional relatives with Pancreatic Cancer. None of the 66 (0/66: 97.5% one-side CI 0-0.054%) familial Pancreatic Cancer patients were found to have a deleterious mutation in the BRCA1 gene. While patients were not selected based upon their family history of breast and ovarian Cancer, over half of the patients whose samples were sequenced reported a family history of breast and/or ovarian Cancer. Our findings suggest that mutations in the BRCA1 gene are not highly, or even moderately, prevalent in families with a clustering of Pancreatic Cancer, including Pancreatic Cancer families who report a family history of breast and/or ovarian Cancer.
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familial Pancreatic Cancer
Cancer Journal, 2008Co-Authors: Alison P Klein, Kieran Brune, Gloria M Petersen, Ralph H Hruban, Michael GogginsAbstract:Pancreatic Cancer is the fourth leading cause of Cancer death in both men and women in the United States and will be responsible for an estimated 28,900 deaths in 2001. Relatively little is known of its etiology, and the only well-established risk factor is cigarette smoking. Studies over the past 3 decades have shown that 4%-16% of patients with Pancreatic Cancer have a family history of the disease. A small fraction of this aggregation can be accounted for in inherited Cancer syndromes, including familial atypical multiple-mole melanoma, Peutz-Jeghers syndrome, hereditary breast-ovarian Cancer, hereditary pancreatitis, and hereditary nonpolyposis colorectal Cancer. These syndromes arise as a result of germline mutations in the BRCA2, pl6 (familial atypical multiple-mole melanoma), mismatch repair (hereditary nonpolyposis colorectal Cancer), and STK11 (Peutz-Jeghers syndrome) genes. In addition, hereditary plays a role in predisposing certain patients with apparently sporadic Pancreatic Cancer. Many patients with Pancreatic Cancers caused by a germline mutation in a Cancer-causing gene do not have a pedigree that is suggestive of a familial Cancer syndrome. A recent prospective analysis of the pedigrees in the National Familial Pancreatic Tumor Registry found that individuals with a family history of Pancreatic Cancer in multiple first-degree relatives have a high risk of Pancreatic Cancer themselves. The identification of such high-risk individuals will help clinicians target screening programs and develop preventive interventions with the hope of reducing the mortality of Pancreatic Cancer in these families.
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the prevalence of brca2 mutations in familial Pancreatic Cancer
Cancer Epidemiology Biomarkers & Prevention, 2007Co-Authors: Fergus J Couch, Kieran Brune, Mariza De Andrade, Steven Gallinger, Kari G Rabe, Michael Goggins, Alison P Klein, Michele Johnson, Heidi Rothenmund, Gloria M PetersenAbstract:Mutations in the BRCA2 gene have been implicated in Pancreatic Cancer susceptibility through studies of high-risk breast and ovarian Cancer families. To determine the contribution of mutations in BRCA2 to familial Pancreatic Cancer, we screened affected probands from 151 high-risk families identified through Pancreatic Cancer clinics for germ-line BRCA2 mutations. Of these families, 118 had two or more first- and second-degree relatives with Pancreatic Cancer, and an additional 33 had two or more affected second-degree relatives. The average age of onset for Pancreatic Cancer was 62.8 years. Five BRCA2 truncating mutations were identified, three in families with two or more first- and second-degree relatives with Pancreatic Cancer. Three of the families with mutations had a history of breast Cancer but not ovarian Cancer. Four of five families with mutations were identified through probands with early-onset (<55 years) Pancreatic Cancer. The results of this study were combined with those from a BRCA2 mutation study of 29 other families from the same Johns Hopkins University National Familial Pancreatic Tumor Registry to estimate the frequency of BRCA2 mutations. A total of 10 carriers from 180 families were identified, suggesting that BRCA2 mutations account for 6% of moderate and high-risk Pancreatic Cancer families.
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Pancreatic Cancer genetic epidemiology consortium
Cancer Epidemiology Biomarkers & Prevention, 2006Co-Authors: Gloria M Petersen, Sapna Syngal, Jeannette F. Korczak, Mariza De Andrade, Steven Gallinger, Melissa L Bondy, Ralph H Hruban, Michael Goggins, Henry T. Lynch, Kari G RabeAbstract:We have organized the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in familial Pancreatic Cancer (FPC). The Consortium comprises seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core. We recruit kindreds containing two or more affected blood relatives ascertained through incident Pancreatic adenocarcinoma cases, physician referrals, and/or through Internet recruitment. Accrual to a database containing core clinical, demographic, lifestyle, and family history information from questionnaires is ongoing, along with biospecimen collection. To date, 13,147 patients have been screened for family history, of whom 476 (50% male) probands and 1,912 of their adult (99% unaffected) relatives have been enrolled. Of these, 379 kindreds meet criteria for FPC, having at least two first-degree relatives with Pancreatic Cancer. Cumulative incidence curves using available age of diagnosis (onset) among and affected relatives were compared with those for incident Pancreatic Cancer cases reported to 13 U.S. Surveillance Epidemiology and End Results (SEER) sites from 1973 to 2000 ( N = 72,700). The mean age ± SD at diagnosis among 466 PACGENE probands and 670 affected relatives was 64.1 ± 11.8 and was 65.4 ± 11.6 for the subset of 369 FPC probands and 429 relatives. Both samples were significantly younger than the mean age at diagnosis in the SEER population (70.0 ± 12.1 years; differences in curves versus SEER, P < 0.001). Age at diagnosis (excluding probands) in FPC kindreds does not decrease with increasing number of affected individuals. In our sample, younger age at diagnosis was observed whether we grouped probands by recruitment sites that predominantly recruited through high-risk referrals, or through screening all Pancreatic Cancer patients for family history. Linkage studies are ongoing. The PACGENE Consortium will be a valuable family-based resource that will greatly enhance genetic epidemiology research in Pancreatic Cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(4):704–10)
Detlef K. Bartsch - One of the best experts on this subject based on the ideXlab platform.
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familial Pancreatic Cancer current knowledge
Nature Reviews Gastroenterology & Hepatology, 2012Co-Authors: Detlef K. Bartsch, Thomas M Gress, Peter LangerAbstract:Familial Pancreatic Cancer (FPC) describes families with at least two first-degree relatives with confirmed exocrine Pancreatic Cancer that do not fulfil the criteria of other inherited tumour syndromes with increased risks of Pancreatic Cancer, such as Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary breast and ovarian Cancer. The inheritance of FPC is mostly autosomal dominant and with a heterogeneous phenotype. The major gene defect is yet to be identified, although germline mutations in BRCA2, PALB2 and ATM are causative in some FPC families. Expert consensus conferences considered it appropriate to screen for Pancreatic Cancer in high-risk individuals using a multidisciplinary approach under research protocol conditions. However, neither biomarkers nor reliable imaging modalities for the detection of high-grade precursor lesions are yet available. Most screening programmes are currently based on findings from endoscopic ultrasonography and MRI, and data has demonstrated that precursor lesions of Pancreatic Cancer can be identified. No consensus exists regarding the age to initiate or stop screening and the optimal intervals for follow-up. Timing and extent of surgery as a treatment for FPC are debated. This Review focuses on the clinical phenotype of FPC, its histopathological characteristics, known underlying genetic changes and associated genetic counselling and screening.
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familial Pancreatic Cancer syndromes
Endocrinology and Metabolism Clinics of North America, 2006Co-Authors: Nils Habbe, Peter Langer, Mercedes Sinafrey, Detlef K. BartschAbstract:Hereditary Pancreatic Cancer (PC) is rare and extremely heterogeneous, and it accounts for approximately 2% of all PC cases. The major component of hereditary PC is the familial Pancreatic Cancer syndrome. Although up to 20% of hereditary PC cases are associated with germline mutations in the BRCA2, CDKN2A, PRSS1,STKI1, or MMR genes, the major underlying gene defect(s) is still unknown. Although hereditary PC is rare, the data on PC families that have been collected by various study groups worldwide provide a unique opportunity to evaluate the natural history, causative gene alterations, new diagnosis and chemoprevention strategies as well as treatment modalities.
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anticipation in familial Pancreatic Cancer
Gut, 2006Co-Authors: Christopher Mcfaul, Harald Rieder, Ralf Kress, Stephan A. Hahn, John P. Neoptolemos, William Greenhalf, Mercedes Sinafrey, Julie Earl, Nathan Howes, Detlef K. BartschAbstract:Background: Previous studies of anticipation in familial Pancreatic Cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families. Patients and methods: A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated. Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1. Results: With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from Pancreatic Cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively. These indications of anticipation could be the result of bias. Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p = 0.002 and p Conclusion: This study provides the first strong evidence for anticipation in familial Pancreatic Cancer and must be considered in genetic counselling and the commencement of secondary screening for Pancreatic Cancer.
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prevalence of familial Pancreatic Cancer in germany
International Journal of Cancer, 2004Co-Authors: Detlef K. Bartsch, Ralf Kress, Mercedes Sinafrey, B Gerdes, Robert Grutzmann, Christian Pilarsky, Joachim W Heise, Klausmartin Schulte, Mario Colombobenkmann, Cristina SchleicherAbstract:Based on several case-control studies, it has been estimated that familial aggregation and genetic susceptibility play a role in up to 10% of patients with Pancreatic Cancer, although conclusive epidemiologic data are still lacking. Therefore, we evaluated the prevalence of familial Pancreatic Cancer and differences to its sporadic form in a prospective multicenter trial. A total of 479 consecutive patients with newly diagnosed, histologically confirmed adenocarcinoma of the pancreas were prospectively evaluated regarding medical and family history, treatment and pathology of the tumour. A family history for Pancreatic Cancer was confirmed whenever possible by reviewing the tumour specimens and medical reports. Statistical analysis was performed by calculating odds ratios, regression analysis with a logit-model and the Kaplan-Meier method. Twenty-three of 479 (prevalence 4.8%, 95% CI 3.1-7.1) patients reported at least 1 first-degree relative with Pancreatic Cancer. The familial aggregation could be confirmed by histology in 5 of 23 patients (1.1%, 95% CI 0.3-2.4), by medical records in 9 of 23 patients (1.9%, 95% CI 0.9-3.5) and by standardized interviews of first-degree relatives in 17 of 23 patients (3.5%, 95% CI 2.1-5.6), respectively. There were no statistical significant differences between familial and sporadic Pancreatic Cancer cases regarding sex ratio, age of onset, presence of diabetes mellitus and pancreatitis, tumour histology and stage, prognosis after palliative or curative treatment as well as associated tumours in index patients and families, respectively. The prevalence of familial Pancreatic Cancer in Germany is at most 3.5% (range 1.1-3.5%) depending on the mode of confirmation of the Pancreatic carcinoma in relatives. This prevalence is lower than so far postulated in the literature. There were no significant clinical differences between the familial and sporadic form of Pancreatic Cancer.
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cdkn2a germline mutations in familial Pancreatic Cancer
Annals of Surgery, 2002Co-Authors: Detlef K. Bartsch, Ralf Kress, Mercedes Sinafrey, B Gerdes, Robert Grutzmann, Mario Colombobenkmann, Sven A Lang, Anja Wild, Peter J Barth, Andreas ZieglerAbstract:In Germany about 11,000 patients develop ductal Pancreatic adenocarcinoma each year, making it the fifth most common cause of Cancer death. 1 The prognosis is dismal, with an overall 5-year survival rate of less than 5%; only 20% of patients have potentially curative resectable tumors at diagnosis. However, in patients with early-stage tumors, 5-year survival rates of up to 40% can be achieved. 2 Thus, the identification of patients at risk for this disease is an important goal to reduce mortality. It has been estimated that about 3% to 10% of patients with Pancreatic Cancer have an inherited predisposition for this tumor, although conclusive epidemiologic data are still lacking. 3–5 Based on clinical criteria, patients with inherited Pancreatic Cancer can be separated in two groups. 6,7 One group includes families with an accumulation of PC only (familial Pancreatic Cancer [FPC]). The underlying gene defect in these families is unknown. The other group consists of families with inherited tumor syndromes or diseases predisposing them to various degrees to Pancreatic Cancer. These syndromes include hereditary pancreatitis, 8 Peutz-Jeghers syndrome, 9 ataxia-teleangiectasia, 10 hereditary nonpolyposis colon Cancer (HNPCC or Lynch II-syndrome 11), Li-Fraumeni syndrome, 12 Gardner syndrome, 13 hereditary breast and ovarian Cancer, 14 and familial atypical multiple mole melanoma (FAMMM). 15 The cumulative risk for the development of Pancreatic Cancer until the age of 70 years in these syndromes varies between 3% and 40%. The CDKNA gene localized at chromosome 9p21 encodes the cyclin-dependent kinase inhibitor p16INK4a (MTS1) and the p53 activator p14ARF. Both gene products have an independent first exon (exon 1-alpha and exon 1-beta, respectively) but share exons 2 and 3 and are translated in different reading frames. The genes are involved in the negative control of cell proliferation. p16INK4a produces a G1 cell-cycle arrest by inhibiting phosphorylation of the retinoblastoma protein, and p14ARF acts both at G1/S and G2/M phases in a p53-dependent manner via binding and inhibition of the protein MDM2. 16,17 p16INK4 is inactivated in 95% of sporadic Pancreatic Cancers, 18 indicating its important role in the tumorigenesis of this disease. It has also been shown that p16INK4a germline mutations contribute to the familial accumulation of Pancreatic Cancer and melanoma. In 1995 Whelan et al 19 identified a p16INK4a germline mutation in a family with an excess of Pancreatic Cancer and malignant melanoma. FAMMM is an autosomal dominant inherited disorder associated with p16INK4a germline mutations; it predisposes mutation carriers to multiple atypical nevi and multiple malignant melanomas. In some FAMMM kindreds a high prevalence of Pancreatic Cancer has been observed. Goldstein et al 20 suggested dividing FAMMM kindreds in two groups with respect to their mutation status of the p16INK4a tumor suppressor gene: p16INK4a mutation negative kindreds, without the occurrence of Pancreatic Cancer, and p16INK4a mutation positive kindreds, with a significant excess of Pancreatic Cancer. It was estimated that p16INK4a mutation-associated FAMMM family members have an 22-fold risk for the development of Pancreatic Cancer. 20 Moreover, Moskaluk et al recently identified a p16INK4a germline mutation in a family having two first-degree relatives with Pancreatic Cancer, not showing the FAMMM phenotype. 21 Recently, a germline CDKN2a mutation involving p14ARF was identified in an individual with multiple primary melanomas, 22 but the incidence of p14ARF germline mutations in FPC is not known. Due to the few available data, the role of p16INK4a and p14ARF mutations in the setting of FPC is still not well defined. Therefore, we analyzed FPC families and families with an accumulation of Pancreatic Cancer and malignant melanoma from the German National Case Collection for Familial Pancreatic Cancer of the Deutsche Krebshilfe (FaPaCa) for the presence of CDKN2A germline mutations including p16INK4a and p14ARF.
