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Detlef K. Bartsch - One of the best experts on this subject based on the ideXlab platform.
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progress report Familial Pancreatic Cancer
Familial Cancer, 2019Co-Authors: Ioannis Mintziras, Detlef K. BartschAbstract:A hereditary predisposition to Pancreatic ductal adenocarcinoma (PDAC) is reported in approximately 5% of patients. Familial Pancreatic Cancer (FPC) accounts for the vast majority of hereditary PDAC cases. FPC defines families with two or more affected first-degree relatives with PDAC that do not fulfil the criteria of any other inherited tumor syndrome or families with PDAC in three or more relatives of any degree. The current progress report focuses on the knowledge of FPC with regard to molecular pathogenesis, clinical and molecular diagnosis, surveillance and novel treatment options reported in the last 5 years.
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german national case collection for Familial Pancreatic Cancer fapaca acceptance and psychological aspects of a Pancreatic Cancer screening program
Hereditary Cancer in Clinical Practice, 2018Co-Authors: Frederike S Franke, Emily P. Slater, Elvira Matthai, Christoph Schicker, Johannes Kruse, Detlef K. BartschAbstract:Pancreatic Cancer screening is recommended to individuals at risk (IAR) of Familial Pancreatic Cancer (FPC) families, but little is known about the acceptance of such screening programs. Thus, the acceptance and psychological aspects of a controlled FPC screening program was evaluated. IAR of FPC families underwent comprehensive counseling by a geneticist and pancreatologist prior to the proposed screening. Participating IAR, IAR who discontinued screening and IAR who never participated in the screening program were invited to complete questionnaires to assess the motivation for participating in surveillance, Cancer worries, structural distress and experiences with participation. Questionnaires were completed anonymously to receive most accurate answers. Of 286 IAR to whom Pancreatic ductal adenocarcinoma (PDAC) screening was recommended, 139 (48.6%) IAR regularly participated (group 1), 49 (17.1%) IAR (group 2) discontinued screening after median 1 (1–10) screening visits and 98 (34.2%) IAR (group 3) never underwent screening. The overall response rate of questionnaires was 67% (189/286) with rates of 100% (139 of 139 IAR), 49% (29 of 49 IAR) and 23.4% (23 of 98 IAR) for groups 1, 2 and 3, respectively. At least 93% of IAR felt adequately informed about the screening program after initial counseling. However, only 38.8% received knowledge of or the recommendation for PDAC screening by physicians. The reported Cancer-related distress and the fear of investigations were highest in group 1, but acceptably low in all three groups. The main reasons to discontinue or not to participate in screening were the time efforts and travel costs (groups 2 and 3 48,7%). Less than 50% of IAR regularly participate in a proposed PDAC screening program, although the associated psychological burden is quite low. Physicians should be educated about high risk PDAC groups and screening recommendations. Time and travel efforts must be reduced to encourage more IAR to participate in a recommended screening.
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The Combination of MiRNA-196b, LCN2, and TIMP1 is a Potential Set of Circulating Biomarkers for Screening Individuals at Risk for Familial Pancreatic Cancer
Journal of clinical medicine, 2018Co-Authors: Detlef K. Bartsch, Elvira Matthai, Konstantin Strauch, Norman Gercke, Susanne Rospleszcz, Frederike S Franke, Ronja Wieboldt, Vinona Wagner, Agnes Schäfer, Ioannis MintzirasAbstract:Individuals at risk (IAR) of Familial Pancreatic Cancer (FPC) are good candidates for screening. Unfortunately, neither reliable imaging modalities nor biomarkers are available to detect high-grade precursor lesions or early Cancer. Circulating levels of candidate biomarkers LCN2, TIMP1, Glypican-1, RNU2-1f, and miRNA-196b were analyzed in 218 individuals with sporadic Pancreatic ductal adenocarcinoma (PDAC, n = 50), FPC (n = 20), chronic pancreatitis (n = 10), IAR with relevant precursor lesions (n = 11) or non-relevant lesions (n = 5), 20 controls, and IAR with (n = 51) or without (n = 51) lesions on Pancreatic imaging. In addition, corresponding duodenal juice samples were analyzed for Glypican-1 (n = 144) enrichment and KRAS mutations (n = 123). The panel miR-196b/LCN2/TIMP1 could distinguish high-grade lesions and stage I PDAC from controls with absolute specificity and sensitivity. In contrast, Glypican-1 enrichment in serum exosomes and duodenal juice was not diagnostic. KRAS mutations in duodenal juice were detected in 9 of 12 patients with PDAC and only 4 of 9 IAR with relevant precursor lesions. IAR with lesions on imaging had elevated miR-196b/LCN2/TIMP1 levels (p = 0.0007) and KRAS mutations in duodenal juice (p = 0.0004) significantly more often than IAR without imaging lesions. The combination miR-196b/LCN2/TIMP1 might be a promising biomarker set for the detection of high-grade PDAC precursor lesions in IAR of FPC families.
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German National Case Collection for Familial Pancreatic Cancer (FaPaCa) - acceptance and psychological aspects of a Pancreatic Cancer screening program
'Springer Science and Business Media LLC', 2018Co-Authors: Frederike S Franke, Emily P. Slater, Elvira Matthai, Christoph Schicker, Johannes Kruse, Detlef K. BartschAbstract:Abstract Background Pancreatic Cancer screening is recommended to individuals at risk (IAR) of Familial Pancreatic Cancer (FPC) families, but little is known about the acceptance of such screening programs. Thus, the acceptance and psychological aspects of a controlled FPC screening program was evaluated. Methods IAR of FPC families underwent comprehensive counseling by a geneticist and pancreatologist prior to the proposed screening. Participating IAR, IAR who discontinued screening and IAR who never participated in the screening program were invited to complete questionnaires to assess the motivation for participating in surveillance, Cancer worries, structural distress and experiences with participation. Questionnaires were completed anonymously to receive most accurate answers. Results Of 286 IAR to whom Pancreatic ductal adenocarcinoma (PDAC) screening was recommended, 139 (48.6%) IAR regularly participated (group 1), 49 (17.1%) IAR (group 2) discontinued screening after median 1 (1–10) screening visits and 98 (34.2%) IAR (group 3) never underwent screening. The overall response rate of questionnaires was 67% (189/286) with rates of 100% (139 of 139 IAR), 49% (29 of 49 IAR) and 23.4% (23 of 98 IAR) for groups 1, 2 and 3, respectively. At least 93% of IAR felt adequately informed about the screening program after initial counseling. However, only 38.8% received knowledge of or the recommendation for PDAC screening by physicians. The reported Cancer-related distress and the fear of investigations were highest in group 1, but acceptably low in all three groups. The main reasons to discontinue or not to participate in screening were the time efforts and travel costs (groups 2 and 3 48,7%). Conclusion Less than 50% of IAR regularly participate in a proposed PDAC screening program, although the associated psychological burden is quite low. Physicians should be educated about high risk PDAC groups and screening recommendations. Time and travel efforts must be reduced to encourage more IAR to participate in a recommended screening
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refinement of screening for Familial Pancreatic Cancer
Gut, 2016Co-Authors: Detlef K. Bartsch, Emily P. Slater, Elvira Matthai, Julie Earl, Alfredo Carrato, Isaura S Ibrahim, C Guillenponce, Hans F A Vasen, F S Jendryschek, Jens FigielAbstract:Objective Surveillance programmes are recommended for individuals at risk (IAR) of Familial Pancreatic Cancer (FPC) to detect early Pancreatic Cancer (Pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. Methods IAR from non- CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. Results 253 IAR with a median age of 48 (25–81) years underwent screening with a median of 3 (1–11) screening visits during a median follow-up of 28 (1–152) months. 134 (53%) IAR revealed Pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, Pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at ≥24 months intervals (n=30). Conclusions It appears safe to start screening for PDAC in IAR of non- CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient.
Ralph H Hruban - One of the best experts on this subject based on the ideXlab platform.
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germline mutations in japanese Familial Pancreatic Cancer patients
Oncotarget, 2016Co-Authors: Erina Takai, Ralph H Hruban, Shinichi Yachida, Kyoko Shimizu, Junji Furuse, Emi Kubo, Akihiro Ohmoto, Masami Suzuki, Takuji Okusaka, Chigusa MorizaneAbstract:// Erina Takai 1, * , Shinichi Yachida 1, * , Kyoko Shimizu 2 , Junji Furuse 3 , Emi Kubo 4 , Akihiro Ohmoto 1 , Masami Suzuki 1 , Ralph H. Hruban 5 , Takuji Okusaka 4 , Chigusa Morizane 4 , Toru Furukawa 6 1 Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan 2 Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan 3 Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan 4 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Department of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 6 Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Toru Furukawa, email: furukawa.toru@twmu.ac.jp Keywords: Pancreatic Cancer, Familial predisposition, BRCA2, ATM, PALB2 Received: July 10, 2016 Accepted: September 29, 2016 Published: October 6, 2016 ABSTRACT Clinicopathologic and genetic features of Familial Pancreatic Cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with Pancreatic ductal adenocarcinoma (PDAC).We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any Cancer except PDAC, and personal history of smoking, other Cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for Pancreatic, breast and ovarian Cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2 , PALB2 , ATM , or MLH1 . These results indicate that a significant fraction of patients with PDAC in Japan have a family history of Pancreatic Cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.
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brca1 brca2 palb2 and cdkn2a mutations in Familial Pancreatic Cancer a pacgene study
Genetics in Medicine, 2015Co-Authors: David B Zhen, Ralph H Hruban, Michael Goggins, Kari G Rabe, Steven Gallinger, Sapna Syngal, Ann G Schwartz, Michele L Cote, Robert R Mcwilliams, Nicholas J RobertsAbstract:BRCA1 , BRCA2 , PALB2 , and CDKN2A mutations in Familial Pancreatic Cancer: a PACGENE study
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Clinical importance of Familial Pancreatic Cancer Registry in Japan: a report from kick-off meeting at International Symposium on Pancreas Cancer 2012
Journal of Hepato-Biliary-Pancreatic Sciences, 2013Co-Authors: Keita Wada, Ralph H Hruban, Teresa A Brentnall, Kyoichi Takaori, L. William Traverso, Toru Furukawa, Takashi Hatori, Keiji Sano, Tadahiro Takada, Yoshiyuki MajimaAbstract:Pancreatic Cancer is still a highly lethal disease with a 5-year survival rate of approximately 5 %. Early detection offers one of the best hopes for improving survival. Previous cohort studies and case–control studies showed that 4–10 % of Pancreatic Cancers have a hereditary basis, and individuals with a family history have an increased risk of developing Pancreatic and extra-Pancreatic malignancies. Since individuals with a family history of Pancreatic Cancer and those with a known genetic syndrome that predisposes to Pancreatic Cancer will be the first to benefit from early detection tests as they become available, Familial Pancreatic Cancer (FPC) registries have been established in the US and Europe, but not yet in Japan. Such registries form the basis for epidemiological studies, clinical trials, and basic research on Familial Pancreatic Cancer. There is a need for FPC registries in Japan as Cancer risk varies among different populations and discoveries made in Western populations may not translate to the Japanese population. These registries in Japan will align with ongoing international efforts and add to a better understanding of the natural history, risk factors, screening strategies, and responsible genes, for improving survival of this dismal disease.
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update on Familial Pancreatic Cancer
Advances in Surgery, 2010Co-Authors: Ralph H Hruban, Michael Goggins, Alison P Klein, Marcia Irene Canto, 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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increased prevalence of precursor lesions in Familial Pancreatic Cancer patients
Clinical Cancer Research, 2009Co-Authors: Chanjuan Shi, Michael Goggins, Marcia I. Canto, Alison P Klein, Richard D Schulick, Emily Palmisano, Anirban Maitra, Syed Z Ali, Ralph H HrubanAbstract:PURPOSE: Histologic findings in 51 pancreata resected from patients with a strong family history of Pancreatic Cancer were compared with the findings in 40 pancreata resected from patients with sporadic Pancreatic Cancer. None of the patients in the Familial group had a known inherited syndrome other than Familial Pancreatic Cancer. EXPERIMENTAL DESIGN: Precursor lesions, including Pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and incipient IPMN, were quantified. Invasive Cancers were classified using established histologic criteria. RESULTS: The individual precursor lesions identified in both groups were histologically similar. Precursor lesions were more common in the Familial cases than in the sporadic cases. The relative rate of PanINs per square centimeter was 2.75-fold higher (95% confidence interval, 2.05-3.70; adjusted for age) in Familial compared with sporadic cases. PanIN-3 lesions were more common in Familial versus sporadic Pancreatic Cancer patients (relative rate, 4.20; 95% confidence interval, 2.22-7.93; adjusted for age). High-grade incipient IPMNs were only observed in the Familial cases. Nine of the 51 (18%) Familial Pancreatic Cancers and 4 of the 40 (10%) sporadic Cancers arose in association with an IPMN. No significant differences were found in the types of invasive Cancers. CONCLUSIONS: Noninvasive precursor lesions are more common in patients with a strong family history of Pancreatic Cancer than in patients with sporadic disease, and precursor lesions are of a higher grade in patients with a strong family history of Pancreatic Cancer. These findings can form a basis for the design of screening tests for the early detection of Pancreatic neoplasia. (Clin Cancer Res 2009;15(24):7737-43).
Alison P Klein - One of the best experts on this subject based on the ideXlab platform.
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Familial Pancreatic Cancer who should be considered for genetic testing
Irish Journal of Medical Science, 2021Co-Authors: Kinyas Kartal, Alison P Klein, Zoe Guan, Rong Tang, Molly Griffin, Yan Wang, Danielle Braun, Kevin S HughesAbstract:Determining how many female patients who underwent breast imaging meet the eligibility criteria for genetic testing for Familial Pancreatic Cancer (FPC). A total of 42,904 patients seen at the Newton-Wellesley Hospital between 2007 and 2009 were retrospectively reviewed. The first four categories were based on Pancreatic Cancer-associated syndromes: (1) hereditary breast and ovarian Cancer (HBOC), (2) Lynch syndrome (LS), (3) Familial atypical multiple mole melanoma (FAMMM), and (4) family history of FPC (FH-FPC). PancPRO (5) and MelaPRO (6) categories were based on risk scores from Mendelian risk prediction tool. Exactly 4445 of 42,904 patients were found to be in at least one of the six risk categories. About 5.7% of patients were classified as being at high risk for HBOC, 2.3% as being at high risk for LS, 0.1% as being at high risk for FAMMM, 0.1% as being at high risk for FH-FPC, 2.7% as being at high risk based on PancPRO, and 0.2% as being at high risk based on MelaPRO. About 10.4% of the female patients were classified as being at high risk for FPC. This finding emphasizes the importance of applying criteria to the general population, in order to ensure that individuals with high risk are identified early.
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genome wide sequencing to identify the cause of hereditary Cancer syndromes with examples from Familial Pancreatic Cancer
Cancer Letters, 2013Co-Authors: Nicholas J Roberts, Alison P KleinAbstract:Advances in our understanding of the human genome and next-generation technologies have facilitated the use of genome-wide sequencing to decipher the genetic basis of Mendelian disease and hereditary Cancer syndromes. However, the application of genome-wide sequencing in hereditary Cancer syndromes has had mixed success, in part, due to complex nature of the underlying genetic architecture. In this review we discuss the use of genome-wide sequencing in both Mendelian diseases and hereditary Cancer syndromes, highlighting the potential and challenges of this approach using Familial Pancreatic Cancer as an example.
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risk factors of Familial Pancreatic Cancer in japan current smoking and recent onset of diabetes
Pancreas, 2011Co-Authors: Hiroyuki Matsubayashi, Atsuyuki Maeda, Hideyuki Kanemoto, Katsuhiko Uesaka, Kentaro Yamazaki, Shuichi Hironaka, Yuji Miyagi, Hisatomo Ikehara, Hiroyuki Ono, Alison P KleinAbstract:OBJECTIVES In western countries, 7% to 10% of patients with Pancreatic Cancer (PC) have a Familial predisposition to their disease. The aim of this study was to determine the Familial susceptibility to PC in Japan. METHODS Five hundred seventy-seven patients with PC and 577 age- and gender-matched controls were analyzed for Cancer history in their first-degree relative(s) (FDRs) and demographic factors. RESULTS The patients with PC were more likely to have an FDR with PC (6.9%) than the controls (2.9%; odds ratio [OR], 2.5; P = 0.02). Three patients (0.5%), but none of the controls, had a family history of PC in multiple FDRs. Smoking, especially current smoking (OR, 1.5; P = 0.005), and diabetes mellitus (OR: 1.7, P = 0.001) were also associated with PC. The odds increased up to 10-fold if the patients were positive for these 3 factors. The patients with Familial PC were more likely to be current smokers (40%) and to have diabetes mellitus (32.5%) than the sporadic cases (30.1% and 20.1%; OR, 1.6 and 1.9). CONCLUSIONS A family history of PC is a risk of PC in Japan (6.9%) as is a personal history of diabetes and smoking. It is prudent to inform the kindred of patients with familiar PC of the risk of smoking and to follow carefully if they develop diabetes.
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update on Familial Pancreatic Cancer
Advances in Surgery, 2010Co-Authors: Ralph H Hruban, Michael Goggins, Alison P Klein, Marcia Irene Canto, 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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increased prevalence of precursor lesions in Familial Pancreatic Cancer patients
Clinical Cancer Research, 2009Co-Authors: Chanjuan Shi, Michael Goggins, Marcia I. Canto, Alison P Klein, Richard D Schulick, Emily Palmisano, Anirban Maitra, Syed Z Ali, Ralph H HrubanAbstract:PURPOSE: Histologic findings in 51 pancreata resected from patients with a strong family history of Pancreatic Cancer were compared with the findings in 40 pancreata resected from patients with sporadic Pancreatic Cancer. None of the patients in the Familial group had a known inherited syndrome other than Familial Pancreatic Cancer. EXPERIMENTAL DESIGN: Precursor lesions, including Pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and incipient IPMN, were quantified. Invasive Cancers were classified using established histologic criteria. RESULTS: The individual precursor lesions identified in both groups were histologically similar. Precursor lesions were more common in the Familial cases than in the sporadic cases. The relative rate of PanINs per square centimeter was 2.75-fold higher (95% confidence interval, 2.05-3.70; adjusted for age) in Familial compared with sporadic cases. PanIN-3 lesions were more common in Familial versus sporadic Pancreatic Cancer patients (relative rate, 4.20; 95% confidence interval, 2.22-7.93; adjusted for age). High-grade incipient IPMNs were only observed in the Familial cases. Nine of the 51 (18%) Familial Pancreatic Cancers and 4 of the 40 (10%) sporadic Cancers arose in association with an IPMN. No significant differences were found in the types of invasive Cancers. CONCLUSIONS: Noninvasive precursor lesions are more common in patients with a strong family history of Pancreatic Cancer than in patients with sporadic disease, and precursor lesions are of a higher grade in patients with a strong family history of Pancreatic Cancer. These findings can form a basis for the design of screening tests for the early detection of Pancreatic neoplasia. (Clin Cancer Res 2009;15(24):7737-43).
Michael Goggins - One of the best experts on this subject based on the ideXlab platform.
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brca1 brca2 palb2 and cdkn2a mutations in Familial Pancreatic Cancer a pacgene study
Genetics in Medicine, 2015Co-Authors: David B Zhen, Ralph H Hruban, Michael Goggins, Kari G Rabe, Steven Gallinger, Sapna Syngal, Ann G Schwartz, Michele L Cote, Robert R Mcwilliams, Nicholas J RobertsAbstract:BRCA1 , BRCA2 , PALB2 , and CDKN2A mutations in Familial Pancreatic Cancer: a PACGENE study
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update on Familial Pancreatic Cancer
Advances in Surgery, 2010Co-Authors: Ralph H Hruban, Michael Goggins, Alison P Klein, Marcia Irene Canto, 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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increased prevalence of precursor lesions in Familial Pancreatic Cancer patients
Clinical Cancer Research, 2009Co-Authors: Chanjuan Shi, Michael Goggins, Marcia I. Canto, Alison P Klein, Richard D Schulick, Emily Palmisano, Anirban Maitra, Syed Z Ali, Ralph H HrubanAbstract:PURPOSE: Histologic findings in 51 pancreata resected from patients with a strong family history of Pancreatic Cancer were compared with the findings in 40 pancreata resected from patients with sporadic Pancreatic Cancer. None of the patients in the Familial group had a known inherited syndrome other than Familial Pancreatic Cancer. EXPERIMENTAL DESIGN: Precursor lesions, including Pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and incipient IPMN, were quantified. Invasive Cancers were classified using established histologic criteria. RESULTS: The individual precursor lesions identified in both groups were histologically similar. Precursor lesions were more common in the Familial cases than in the sporadic cases. The relative rate of PanINs per square centimeter was 2.75-fold higher (95% confidence interval, 2.05-3.70; adjusted for age) in Familial compared with sporadic cases. PanIN-3 lesions were more common in Familial versus sporadic Pancreatic Cancer patients (relative rate, 4.20; 95% confidence interval, 2.22-7.93; adjusted for age). High-grade incipient IPMNs were only observed in the Familial cases. Nine of the 51 (18%) Familial Pancreatic Cancers and 4 of the 40 (10%) sporadic Cancers arose in association with an IPMN. No significant differences were found in the types of invasive Cancers. CONCLUSIONS: Noninvasive precursor lesions are more common in patients with a strong family history of Pancreatic Cancer than in patients with sporadic disease, and precursor lesions are of a higher grade in patients with a strong family history of Pancreatic Cancer. These findings can form a basis for the design of screening tests for the early detection of Pancreatic neoplasia. (Clin Cancer Res 2009;15(24):7737-43).
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s2012 prevalence of high grade neoplasia hgn in Familial Pancreatic Cancer pc precursors a case control study
Gastroenterology, 2009Co-Authors: Marcia I. Canto, Kieran Brune, Charles J Yeo, Michael Goggins, Richard D Schulick, John L Cameron, Ralph H HrubanAbstract:min) groups and tumor volumes were measured in every 4 days. Metformin (given intraperitoneally, once/day, 250 mg/kg, for 25-41 days), significantly decreased (p<0.005) the growth of MiaPaca-2 and Panc-1 xenografts. At the end of the experiments the MiaPaCa-2 xenograft tumor volumes were 1075 ± 207mm3 (control) and 414 ± 116mm3 (metformin), and in the Panc-1 xenografts 1198 ± 134 mm3(control) and 412 ±122 mm3 (metformin). Conclusion: Metformin significantly inhibits the growth of Pancreatic Cancer cells In Vitro and in subcutaneous xenografts in mice. Thus, metformin could be a potential candidate in novel strategies for treatment of human Pancreatic Cancer.
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absence of deleterious palladin mutations in patients with Familial Pancreatic Cancer
Cancer Epidemiology Biomarkers & Prevention, 2009Co-Authors: Alison P Klein, Kieran Brune, Ralph H Hruban, Michael Borges, Margaret Griffith, Seungmo Hong, Noriyuki Omura, Michael GogginsAbstract:It has been reported that germline mutations in the palladin gene (PALLD) cause the Familial aggregation of Pancreatic Cancer, but the evidence is weak and controversial. We sequenced the coding regions of PALLD in 48 individuals with Familial Pancreatic Cancer. We did not find any deleterious mutations and find no evidence to implicate mutations in PALLD as a cause of Familial Pancreatic Cancer.
Emily P. Slater - One of the best experts on this subject based on the ideXlab platform.
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combinations of low frequency genetic variants might predispose to Familial Pancreatic Cancer
Journal of Personalized Medicine, 2021Co-Authors: Emily P. Slater, Elvira Matthai, Lisa M Wilke, Lutz Benedikt Bohm, Konstantin Strauch, Manuel Lutz, Norman Gercke, Kari HemminkiAbstract:Familial Pancreatic Cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of Pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with Pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with Pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.
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german national case collection for Familial Pancreatic Cancer fapaca acceptance and psychological aspects of a Pancreatic Cancer screening program
Hereditary Cancer in Clinical Practice, 2018Co-Authors: Frederike S Franke, Emily P. Slater, Elvira Matthai, Christoph Schicker, Johannes Kruse, Detlef K. BartschAbstract:Pancreatic Cancer screening is recommended to individuals at risk (IAR) of Familial Pancreatic Cancer (FPC) families, but little is known about the acceptance of such screening programs. Thus, the acceptance and psychological aspects of a controlled FPC screening program was evaluated. IAR of FPC families underwent comprehensive counseling by a geneticist and pancreatologist prior to the proposed screening. Participating IAR, IAR who discontinued screening and IAR who never participated in the screening program were invited to complete questionnaires to assess the motivation for participating in surveillance, Cancer worries, structural distress and experiences with participation. Questionnaires were completed anonymously to receive most accurate answers. Of 286 IAR to whom Pancreatic ductal adenocarcinoma (PDAC) screening was recommended, 139 (48.6%) IAR regularly participated (group 1), 49 (17.1%) IAR (group 2) discontinued screening after median 1 (1–10) screening visits and 98 (34.2%) IAR (group 3) never underwent screening. The overall response rate of questionnaires was 67% (189/286) with rates of 100% (139 of 139 IAR), 49% (29 of 49 IAR) and 23.4% (23 of 98 IAR) for groups 1, 2 and 3, respectively. At least 93% of IAR felt adequately informed about the screening program after initial counseling. However, only 38.8% received knowledge of or the recommendation for PDAC screening by physicians. The reported Cancer-related distress and the fear of investigations were highest in group 1, but acceptably low in all three groups. The main reasons to discontinue or not to participate in screening were the time efforts and travel costs (groups 2 and 3 48,7%). Less than 50% of IAR regularly participate in a proposed PDAC screening program, although the associated psychological burden is quite low. Physicians should be educated about high risk PDAC groups and screening recommendations. Time and travel efforts must be reduced to encourage more IAR to participate in a recommended screening.
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German National Case Collection for Familial Pancreatic Cancer (FaPaCa) - acceptance and psychological aspects of a Pancreatic Cancer screening program
'Springer Science and Business Media LLC', 2018Co-Authors: Frederike S Franke, Emily P. Slater, Elvira Matthai, Christoph Schicker, Johannes Kruse, Detlef K. BartschAbstract:Abstract Background Pancreatic Cancer screening is recommended to individuals at risk (IAR) of Familial Pancreatic Cancer (FPC) families, but little is known about the acceptance of such screening programs. Thus, the acceptance and psychological aspects of a controlled FPC screening program was evaluated. Methods IAR of FPC families underwent comprehensive counseling by a geneticist and pancreatologist prior to the proposed screening. Participating IAR, IAR who discontinued screening and IAR who never participated in the screening program were invited to complete questionnaires to assess the motivation for participating in surveillance, Cancer worries, structural distress and experiences with participation. Questionnaires were completed anonymously to receive most accurate answers. Results Of 286 IAR to whom Pancreatic ductal adenocarcinoma (PDAC) screening was recommended, 139 (48.6%) IAR regularly participated (group 1), 49 (17.1%) IAR (group 2) discontinued screening after median 1 (1–10) screening visits and 98 (34.2%) IAR (group 3) never underwent screening. The overall response rate of questionnaires was 67% (189/286) with rates of 100% (139 of 139 IAR), 49% (29 of 49 IAR) and 23.4% (23 of 98 IAR) for groups 1, 2 and 3, respectively. At least 93% of IAR felt adequately informed about the screening program after initial counseling. However, only 38.8% received knowledge of or the recommendation for PDAC screening by physicians. The reported Cancer-related distress and the fear of investigations were highest in group 1, but acceptably low in all three groups. The main reasons to discontinue or not to participate in screening were the time efforts and travel costs (groups 2 and 3 48,7%). Conclusion Less than 50% of IAR regularly participate in a proposed PDAC screening program, although the associated psychological burden is quite low. Physicians should be educated about high risk PDAC groups and screening recommendations. Time and travel efforts must be reduced to encourage more IAR to participate in a recommended screening
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refinement of screening for Familial Pancreatic Cancer
Gut, 2016Co-Authors: Detlef K. Bartsch, Emily P. Slater, Elvira Matthai, Julie Earl, Alfredo Carrato, Isaura S Ibrahim, C Guillenponce, Hans F A Vasen, F S Jendryschek, Jens FigielAbstract:Objective Surveillance programmes are recommended for individuals at risk (IAR) of Familial Pancreatic Cancer (FPC) to detect early Pancreatic Cancer (Pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. Methods IAR from non- CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. Results 253 IAR with a median age of 48 (25–81) years underwent screening with a median of 3 (1–11) screening visits during a median follow-up of 28 (1–152) months. 134 (53%) IAR revealed Pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p<0.0001). In 21 IAR who underwent surgery, no significant lesions (PDAC, Pancreatic intraepithelial neoplasia (PanIN) 3 lesions, high-grade intraductal papillary mucinous neoplasia (IPMN)) were detected before the age of 50 years. Potentially relevant lesions (multifocal PanIN2 lesions, low/moderate-grade branch-duct IPMNs) occurred also significantly more often after the age of 50 years (13 vs 2, p<0.0004). The diagnostic yield of potentially relevant lesions was not different between screening protocols using annual MRI with EUS (n=98) or annual MRI with EUS every 3rd year (n=198) and between IAR screened at intervals of 12 months (n=180) or IAR that decided to be screened at ≥24 months intervals (n=30). Conclusions It appears safe to start screening for PDAC in IAR of non- CDKN2a FPC families at the age of 50 years. MRI-based screening supplemented by EUS at baseline and every 3rd year or when changes in MRI occur appears to be efficient.
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microrna 196a and 196b as potential biomarkers for the early detection of Familial Pancreatic Cancer
Translational Oncology, 2014Co-Authors: Emily P. Slater, Volker Fendrich, Elvira Matthai, Irene Esposito, Konstantin Strauch, Susanne Rospleszcz, Annette Ramaswamy, Gunter Kloppel, Kristin Heeger, P LangerAbstract:Screening programs are recommended for individuals at risk (IAR) from families with Familial Pancreatic Cancer (FPC). However, reliable imaging methods or biomarkers for early diagnosis of Pancreatic ductal adenocarcinoma (PC) or its precursor lesions are still lacking. The ability of circulating microRNAs (miRNAs) to discriminate multifocal high-grade precursor lesions or PC from normal was examined. The presence of miRNA-21, -155, -196a, -196b and -210 was analyzed in the serum of transgenic KPC mice to test their ability to distinguish mice with different grades of Pancreatic intraepithelial neoplasia (mPanIN1–3) or PC from control mice. Serum levels of miR-196a and -196b were significantly higher in mice with PanIN2/3 lesions (n = 10) or PC (n = 8) as compared to control mice (n = 10) or mice with PanIN1 lesions (n = 10; P = .01). In humans, miR-196a and -196b were also diagnostic. Patients with PC, sporadic (n = 9) or hereditary (n = 10), and IAR with multifocal PanIN2/3 lesions (n = 5) had significantly higher serum levels than patients with neuroendocrine Pancreatic tumors (n = 10) or chronic pancreatitis (n = 10), IAR with PanIN1 or no PanIN lesions (n = 5), and healthy controls (n = 10). The combination of both miR-196a and -196b reached a sensitivity of 1 and specificity of 0.9 (area under the curve = 0.99) to diagnose PC or high-grade PanIN lesions. In addition, preoperative elevated serum levels of miR-196a and -196b in patients with PC or multifocal PanIN2/3 lesions dropped to normal after potential curative resection. The combination of miR-196a and -196b may be a promising biomarker test for the screening of IAR for FPC.
