Familial Pancreatic Ductal Adenocarcinoma
2018; Elsevier BV; Volume: 189; Issue: 1 Linguagem: Inglês
10.1016/j.ajpath.2018.06.026
ISSN1525-2191
AutoresKelly E. Diaz, Aimee L. Lucas,
Tópico(s)Genetic factors in colorectal cancer
ResumoPancreatic ductal adenocarcinoma (PDAC), although a rare disease, has a poor prognosis. With 5-year overall survival of 8%, there is a critical need to detect PDAC early or at a premalignant stage. Current screening methods are largely imaging based, but a more focused screening approach based on modifiable and nonmodifiable risk factors may improve the efficacy and likely outcomes of screening. In addition, the pathologic mechanisms that lead to the development of PDAC are discussed in an effort to further understand the targets of pancreatic cancer screening. The focus of this article will be inherited pancreatic cancer syndromes and familial pancreatic cancer, which together compose up to 10% of PDAC. Understanding the methods and targets of PDAC screening in high-risk individuals may translate to improved morbidity and mortality. Pancreatic ductal adenocarcinoma (PDAC), although a rare disease, has a poor prognosis. With 5-year overall survival of 8%, there is a critical need to detect PDAC early or at a premalignant stage. Current screening methods are largely imaging based, but a more focused screening approach based on modifiable and nonmodifiable risk factors may improve the efficacy and likely outcomes of screening. In addition, the pathologic mechanisms that lead to the development of PDAC are discussed in an effort to further understand the targets of pancreatic cancer screening. The focus of this article will be inherited pancreatic cancer syndromes and familial pancreatic cancer, which together compose up to 10% of PDAC. Understanding the methods and targets of PDAC screening in high-risk individuals may translate to improved morbidity and mortality. Pancreatic cancer (PC) affected 2.4% of the world in 2012 and has a high morbidity and mortality.1Ferlay J. Soerjomataram I. Dikshit R. Eser S. Mathers C. Rebelo M. Parkin D.M. Forman D. Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015; 136: E359-E386Crossref PubMed Scopus (21236) Google Scholar It is the fourth most common cause of cancer death in the United States, with an estimated 43,090 deaths in 2017,1Ferlay J. Soerjomataram I. Dikshit R. Eser S. Mathers C. Rebelo M. Parkin D.M. Forman D. Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015; 136: E359-E386Crossref PubMed Scopus (21236) Google Scholar, 2Vege S.S. Ziring B. Jain R. Moayyedi P. Clinical Guidelines CommitteeAmerican Gastroenterology AssociationAmerican Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.Gastroenterology. 2015; 148: 819-822Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar and has been projected to be the second leading cause of cancer death in 2020.3Rahib L. Smith B.D. Aizenberg R. Rosenzweig A.B. Fleshman J.M. Matrisian L.M. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (4226) Google Scholar Of the cases of PC, 94% are pancreatic ductal adenocarcinoma (PDAC) that develop in the exocrine tissue of the pancreas.2Vege S.S. Ziring B. Jain R. Moayyedi P. Clinical Guidelines CommitteeAmerican Gastroenterology AssociationAmerican Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.Gastroenterology. 2015; 148: 819-822Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar PDAC arises in the sporadic setting, associated with a known inherited cancer syndrome, or in familial PC (FPC)4Welinsky S. Lucas A.L. Familial pancreatic cancer and the future of directed screening.Gut Liver. 2017; 11: 761-770Crossref PubMed Scopus (17) Google Scholar; this article will focus on the latter two categories. Approximately 10% of PDACs have a hereditary component, and of the cases of familial PDAC, 20% have an identifiable germline mutation.5Bartsch D.K. Gress T.M. Langer P. Familial pancreatic cancer: current knowledge.Nat Rev Gastroenterol Hepatol. 2012; 9: 445-453Crossref PubMed Scopus (116) Google Scholar, 6Hruban R.H. Canto M.I. Goggins M. Schulick R. Klein A.P. Update on familial pancreatic cancer.Adv Surg. 2010; 44: 293-311Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar Because of low prevalence in the general population, population-based screening programs for PDAC do not exist. However, certain risk factors may increase the utility and outcome of screening methods. With 29% 1-year survival and 7% 5-year survival rates across all stages, strategies to safely and effectively screen for PDAC in high-risk individuals are increasingly important.7American Cancer SocietyCancer Facts and Figures 2016. American Cancer Society, Atlanta, GA2016Google Scholar The survival rate significantly decreases as tumor size increases, reinforcing the need for early effective screening methods.8Hur C. Tramontano A.C. Dowling E.C. Brooks G.A. Jeon A. Brugge W.R. Gazelle G.S. Kong C.Y. Pandharipande P.V. Early pancreatic ductal adenocarcinoma survival is dependent on size: positive implications for future targeted screening.Pancreas. 2016; 45: 1062-1066Crossref PubMed Scopus (25) Google Scholar We will focus on the risk factors, pathology, screening methods, and intervention for PDAC in inherited cancer syndromes and FPC. Inherited cancer syndromes, in order of highest to lowest increased risk of PDAC, include Peutz-Jeghers syndrome (PJS), hereditary pancreatitis (HP), familial atypical multiple mole melanoma syndrome, Lynch syndrome (hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis, hereditary breast and ovarian cancer syndrome, and ataxia telangiectasia (Table 1).9van Lier M.G. Wagner A. Mathus-Vliegen E.M. Kuipers E.J. Steyerberg E.W. van Leerdam M.E. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.Am J Gastroenterol. 2010; 105: 1258-1264Crossref PubMed Scopus (360) Google Scholar, 10de Snoo F.A. Bishop D.T. Bergman W. van Leeuwen I. van der Drift C. van Nieuwpoort F.A. Out-Luiting C.J. Vasen H.F. ter Huurne J.A. Frants R.R. Willemze R. Breuning M.H. Gruis N.A. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families.Clin Cancer Res. 2008; 14: 7151-7157Crossref PubMed Scopus (135) Google Scholar, 11Brose M.S. Rebbeck T.R. Calzone K.A. Stopfer J.E. Nathanson K.L. Weber B.L. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.J Natl Cancer Inst. 2002; 94: 1358-1365Crossref PubMed Google Scholar However, a germline mutation is not identified in most PDACs that appear to have a hereditary component.Table 1Cancer Syndromes and PDAC RiskCancer syndromeGene mutationIncreased PDAC riskPDAC lifetime risk, %Age to initiate surveillance, yearsFamilial pancreatic cancer2 FDR3+ FDRUnknownSIR, 6.4SIR, 32.050 (or 10 years younger than youngest diagnosed age of PDAC)Peutz-Jeghers syndromeSTK11 (LKB1)132%11–3230–35Hereditary pancreatitisPRSS1RR, 6925–4040Familial atypical multiple mole melanoma syndromeP16INK4A/CDKN2ARR, 461750 (or 10 years younger than youngest diagnosed age of PDAC)Lynch syndrome (HNPCC)MLH1, MSH2, MSH6, PMS2, EPCAM8.650 (or 10 years younger than youngest diagnosed age of PDAC)FAPAPC1.750 (or 10 years younger than youngest diagnosed age of PDAC)Cystic fibrosisCFTR5.3-fold increased risk<550 (or 10 years younger than youngest diagnosed age of PDAC)HBOC syndromeBRCA1, BRCA2/FANCD1, PALB2/FANCN, FANCC, FANCGBRCA2: 4.6-fold increased riskBRCA1: 2-3-fold increased risk3–850 (or 10 years younger than youngest diagnosed age of PDAC)Ataxia telangiectasiaATMTwofold increased risk50 (or 10 years younger than youngest diagnosed age of PDAC)FAP, familial adenomatous polyposis; FDR, first degree relative; HBOC, hereditary breast and ovarian cancer; HNPCC, hereditary nonpolyposis colorectal cancer; PDAC, pancreatic ductal adenocarcinoma; RR, relative risk; SIR, standardized incidence ratio. Open table in a new tab FAP, familial adenomatous polyposis; FDR, first degree relative; HBOC, hereditary breast and ovarian cancer; HNPCC, hereditary nonpolyposis colorectal cancer; PDAC, pancreatic ductal adenocarcinoma; RR, relative risk; SIR, standardized incidence ratio. FPC is defined by consensus as families with at least two first-degree relatives with PDAC who do not meet criteria for a known PDAC-associated hereditary syndrome.12Syngal S. Brand R.E. Church J.M. Giardiello F.M. Hampel H.L. Burt R.W. American College of GastroenterologyACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110: 223-262Crossref PubMed Scopus (914) Google Scholar, 13Hruban R.H. Petersen G.M. Goggins M. Tersmetter A.C. Offerhaus G.J.A. Falatko F. Yeo C.J. Kern S.E. Famiilal pancreatic cancer.Ann Oncol. 1999; 10: S69-S73Abstract Full Text PDF PubMed Scopus (114) Google Scholar, 14Brand R.E. Lerch M.M. Rubinstein W.S. Neoptolemos J.P. Whitcomb D.C. Hruban R.H. Brentnall T.A. Lynch H.T. Canto M.I. Participants of the Fourth International Symposium of Inherited Diseases of the PancreasAdvances in counselling and surveillance of patients at risk for pancreatic cancer.Gut. 2007; 56: 1460-1469Crossref PubMed Scopus (244) Google Scholar In individuals with two first-degree relatives with pancreatic cancer, the relative risk and lifetime risk are 6.4% and 9% to 18%, respectively. Furthermore, individuals with three affected first-degree relatives have a relative risk and lifetime risk of 32% and 38%, respectively.15Klein A.P. Brune K.A. Petersen G.M. Goggins M. Tersmette A.C. Offerhaus G.J.A. Griffin C. Cameron J.L. Yeo C.J. Kern S.E. Hruban R.H. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.Cancer Res. 2004; 64: 2634-2638Crossref PubMed Scopus (514) Google Scholar The gene mutation causing FPC, likely functioning in an autosomal dominant manner with reduced penetrance, has not yet been determined.16Klein A.P. Beaty T.H. Bailey-Wilson J.E. Brune K.A. Hruban R.H. Petersen G.M. Evidence for major gene influencing risk of pancreatic cancer.Genet Epidemiol. 2002; 55: 252-258Google Scholar PJS, a result of a germline mutation in the STK11 (LKB1) gene, is associated with hamartomatous polyps throughout the gastrointestinal tract and characteristic mucocutaneous pigmentation often found on the perioral or buccal mucosa.17Jeghers H. McKusick V.A. Katz K.H. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips, and digits: a syndrome of diagnostic significance.N Engl J Med. 1949; 241: 1031-1036Crossref PubMed Scopus (315) Google Scholar STK11 is a tumor suppressor gene; when a second somatic mutation in the STK11 allele is acquired, disease manifestations are noted.18Jenne D.E. Reimann H. Nezu J. Friedel W. Loff S. Jeschke R. Müller O. Back W. Zimmer M. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.Nat Genet. 1998; 18: 38-43Crossref PubMed Scopus (978) Google Scholar PJS is associated with a significantly increased risk of many extraintestinal cancers (ie, breast, ovarian, and cervical) and gastrointestinal cancers, including a 132% increased risk and 11% to 36% lifetime risk of developing PDAC.9van Lier M.G. Wagner A. Mathus-Vliegen E.M. Kuipers E.J. Steyerberg E.W. van Leerdam M.E. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.Am J Gastroenterol. 2010; 105: 1258-1264Crossref PubMed Scopus (360) Google Scholar, 19Giardiello F.M. Brensinger J.D. Tersmette A.C. Goodman S.N. Petersen G.M. Booker S.V. Cruz-Correa M. Offerhaus J.A. Very high risk of cancer in familial Peutz-Jeghers syndrome.Gastroenterology. 2000; 119: 1447-1453Abstract Full Text Full Text PDF PubMed Scopus (1065) Google Scholar Given this increased risk, National Comprehensive Cancer Network Guidelines recommend screening for pancreatic cancer in individuals with PJS starting at the age of 30 to 35 years.12Syngal S. Brand R.E. Church J.M. Giardiello F.M. Hampel H.L. Burt R.W. American College of GastroenterologyACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110: 223-262Crossref PubMed Scopus (914) Google Scholar Mutations in both PRSS1 and SPINK1 can cause HP. However, mutations in PRSS1 lead to an autosomal dominant form of inheritance. They are present in 80% of patients with HP.20Howes N. Lerch M.M. Greenhalf W. Stocken D.D. Ellis I. Simon P. Truninger K. Ammann R. Cavallini G. Charnley R.M. Uomo G. Delhaye M. Spicak J. Drumm B. Jansen J. Mountford R. Whitcomb D.C. Neoptolemos J.P. European Registry of Hereditary Pancreatitis and Pancreatic CancerClinical and genetic characteristics of hereditary pancreatitis in Europe.Clin Gastroenterol Hepatol. 2004; 2: 252-261Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar SPINK1 mutations are inherited in complex inheritance patterns, and <1% of patients with these mutations develop pancreatitis.6Hruban R.H. Canto M.I. Goggins M. Schulick R. Klein A.P. Update on familial pancreatic cancer.Adv Surg. 2010; 44: 293-311Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar HP is characterized by recurrent episodes of acute pancreatitis in adolescents, leading to chronic pancreatitis by early adulthood.20Howes N. Lerch M.M. Greenhalf W. Stocken D.D. Ellis I. Simon P. Truninger K. Ammann R. Cavallini G. Charnley R.M. Uomo G. Delhaye M. Spicak J. Drumm B. Jansen J. Mountford R. Whitcomb D.C. Neoptolemos J.P. European Registry of Hereditary Pancreatitis and Pancreatic CancerClinical and genetic characteristics of hereditary pancreatitis in Europe.Clin Gastroenterol Hepatol. 2004; 2: 252-261Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar PRSS1 encodes trypsinogen, which is cleaved to its active form in the small intestine. With this mutation, there is premature activation of pancreatic enzymes within the pancreas that are thought to cause the recurrent inflammatory responses in acute pancreatitis. Although the relative risk of PDAC in HP was 69%, the risk was noted to be higher in patients who had additional modifiable risk factors, like tobacco use and diabetes, as discussed below.21Raimondi S. Lowenfels A.B. Morselli-Labate A.M. Maisonneuve P. Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection.Best Pract Res Clin Gastroenterol. 2010; 24: 349-358Crossref PubMed Scopus (423) Google Scholar Familial atypical multiple mole melanoma syndrome is associated with a mutation in CDKN2A/p16INK4A and is characterized by a history of malignant melanoma in one or more first-degree relatives and multiple atypical melanocytic nevi.22Eckerle Mize D. Bishop M. Reese E. Sluzevich J. Familial atypical multiple mole melanoma syndrome. Cancer Syndromes [Internet].in: Riegert-Johnson D.L. Boardman L.A. Hefferon T. Roberts M. National Center for Biotechnology Information (US), Bethesda, MD2009Google Scholar Mutations in the CDKN2A gene disrupt the p16INK4 protein, allowing cells to inappropriately progress from the G1 to the S phase with uncontrolled cell growth. There is a 47% relative risk of PDAC in this population.10de Snoo F.A. Bishop D.T. Bergman W. van Leeuwen I. van der Drift C. van Nieuwpoort F.A. Out-Luiting C.J. Vasen H.F. ter Huurne J.A. Frants R.R. Willemze R. Breuning M.H. Gruis N.A. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families.Clin Cancer Res. 2008; 14: 7151-7157Crossref PubMed Scopus (135) Google Scholar Lynch syndrome, or hereditary nonpolyposis colon cancer, is caused by a germline mutation in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2, or EPCAM.23Kastrinos F. Stoffel E.M. History, genetics, and strategies for cancer prevention in Lynch syndrome.Clin Gastroenterol Hepatol. 2014; 12: 715-727Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar These patients are at increased risk of multiple types of cancers: colorectal, endometrial, ovarian, stomach, small intestine, hepatobiliary system, urinary tract, brain, and pancreatic cancer. The lifetime risk of PDAC in hereditary nonpolyposis colorectal cancer has been estimated as high as 8.6%; however, other studies have found that mismatch repair genes have a lifetime risk of 3.7% of developing PDAC.24Kastrinos F. Mukherjee B. Tayob N. Wang F. Sparr J. Raymond V.M. Bandipalliam P. Stoffel E.M. Gruber S.B. Syngal S. Risk of pancreatic cancer in families with Lynch syndrome.JAMA. 2009; 302: 1790-1795Crossref PubMed Scopus (358) Google Scholar, 25Win A.K. Young J.P. Lindor N.M. Tucker K.M. Ahnen D.J. Young G.P. Buchanan D.D. Clendenning M. Giles G.G. Winship I. Macrae F.A. Goldblatt J. Southey M.C. Arnold J. Thibodeau S.N. Gunawardena S.R. Bapat B. Baron J.A. Casey G. Gallinger S. Le Marchand L. Newcomb P.A. Haile R.W. Hopper J.L. Jenkins M.A. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.J Clin Oncol. 2012; 30: 958-964Crossref PubMed Scopus (252) Google Scholar Familial adenomatous polyposis is characterized by multiple colorectal adenomatous polyps and involves a germline inactivating mutation in the tumor suppressor APC gene. In addition to an increased risk of pancreatic cancer, these patients are at increased risk of extracolonic tumors, such as desmoid, duodenal, ampullary, thyroid, hepatoblastoma, and brain.12Syngal S. Brand R.E. Church J.M. Giardiello F.M. Hampel H.L. Burt R.W. American College of GastroenterologyACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110: 223-262Crossref PubMed Scopus (914) Google Scholar The APC gene encodes β-catenin, which interacts with E-cadherin. When the APC gene is mutated, the cell division process is unchecked and cells cannot suppress overgrowth, leading to malignancy. Mutation in the APC gene can also cause altered cell migration and chromosomal instability, predisposing the cell to mutations in other genes leading to tumor progression and proliferation. Even after colectomy, these patients remain at increased risk of cancer in the anal transition zone, the ileal pouch, and other gastrointestinal organs.12Syngal S. Brand R.E. Church J.M. Giardiello F.M. Hampel H.L. Burt R.W. American College of GastroenterologyACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110: 223-262Crossref PubMed Scopus (914) Google Scholar There is a 4.5% increased risk of developing PDAC and a lifetime risk of 1.7%.26Galiatsatos P. Foulkes W.D. Familial adenomatous polyposis.Am J Gastroenterol. 2006; 101: 385-398Crossref PubMed Scopus (455) Google Scholar Cystic fibrosis is an autosomal recessive disease resulting from a mutation in the CFTR gene. In cystic fibrosis, it is thought that the pancreatic exocrine dysfunction predisposes patients to chronic pancreatitis, and this chronic inflammation leads to the development of PDAC.27Cohn J.A. Mitchell R.M. Jowell P.S. The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis.Clin Lab Med. 2005; 25: 79-100Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In patients with cystic fibrosis, there is a 5.3-fold increased relative risk of PDAC.28Maisonneuve P. Marshall B.C. Lowenfels A.B. Risk of pancreatic cancer in patients with cystic fibrosis.Gut. 2007; 56: 1327-1328Crossref PubMed Scopus (71) Google Scholar Individuals with cystic fibrosis are at increased risk of many other cancers as well: colon cancer, small-bowel cancer, and lymphoid leukemia.29Maisonneuve P. Marshall B.C. Knapp E.A. Lowenfels A.B. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States.J Natl Cancer Inst. 2013; 105: 122-129Crossref PubMed Scopus (200) Google Scholar These individuals may also be at increased risk of gastrointestinal cancer after organ transplant. Hereditary breast and ovarian cancer syndrome and other Fanconi anemia genes involve mutations in BRCA1, BRCA2/FANCD1, PALB2/FANCN, FANCC, and FANCG. BRCA1 and BRCA2 encode proteins involved in repairing double-stranded DNA breaks. Fanconi anemia genes are similarly involved in multiple DNA repair mechanisms, including the BRCA1/BRCA2 pathway. Hereditary breast and ovarian cancer syndrome presents with early-onset breast and ovarian cancers. Although BRCA2 mutations are associated with a fourfold to sixfold increased risk of PDAC, the association of BRCA1 mutations is less well defined, with some finding a twofold to threefold increased risk and others finding no association.11Brose M.S. Rebbeck T.R. Calzone K.A. Stopfer J.E. Nathanson K.L. Weber B.L. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.J Natl Cancer Inst. 2002; 94: 1358-1365Crossref PubMed Google Scholar, 30Risch H.A. McLaughlin J.R. Cole D.E. Rosen B. Bradley L. Fan I. Tang J. 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Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.Mol Cell. 2006; 22: 719-729Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar PALB2 mutations are known to increase susceptibility to PDAC, a relatively new disease association. In patients with familial pancreatic cancer, the prevalence of the PALB2 mutation is between 1% and 4%.37Tischkowitz M.D. Sabbaghian N. Hamel N. Borgida A. Rosner C. Taherian N. Srivastava A. Holter S. Rothenmund H. Ghadirian P. Foulkes W.D. Gallinger S. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer.Gastroenterology. 2009; 137: 1183-1186Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 38Hofstatter E.W. Domchek S.M. Miron A. Garber J. Wang M. Componeschi K. Boghossian L. Miron P.L. Nathanson K.L. Tung N. PALB2 mutations in familial breast and pancreatic cancer.Fam Cancer. 2011; 10: 225-231Crossref PubMed Scopus (89) Google Scholar Ataxia telangiectasia is an autosomal recessive disorder attributable to a homozygous mutation in the ATM gene and is characterized by cerebellar ataxia, oculocutaneous telangiectasias, abnormal eye movements, and immunodeficiency. However, monoallelic carriers of ATM mutations are at increased risk of breast, pancreatic, lymphoid, and central nervous system cancers. There is a twofold increased risk of PDAC.39Roberts N.J. Jiao Y. Yu J. Kopelovich L. Petersen G.M. Bondy M.L. Gallinger S. Schwartz A.G. Syngal S. Cote M.L. Axilbund J. Schulick R. Ali S.Z. Eshleman J.R. Velculescu V.E. Goggins M. Vogelstein B. Papadopoulos N. Hruban R.H. Kinzler K.W. Klein A.P. ATM mutations in patients with hereditary pancreatic cancer.Cancer Discov. 2012; 2: 41-46Crossref PubMed Scopus (372) Google Scholar Interestingly, the incidental discovery of the association of ATM gene and PDAC was made with unbiased genome-wide sequencing.39Roberts N.J. Jiao Y. Yu J. Kopelovich L. Petersen G.M. Bondy M.L. Gallinger S. Schwartz A.G. Syngal S. Cote M.L. Axilbund J. Schulick R. Ali S.Z. Eshleman J.R. Velculescu V.E. Goggins M. Vogelstein B. Papadopoulos N. Hruban R.H. Kinzler K.W. Klein A.P. ATM mutations in patients with hereditary pancreatic cancer.Cancer Discov. 2012; 2: 41-46Crossref PubMed Scopus (372) Google Scholar In addition to multiple genetic risk factors, modifiable risk factors may also be important in prevention of PDAC. Tobacco use doubles the risk of pancreatic cancer relative to the general population and may accelerate the onset of illness.40Bosetti C. Lucenteforte E. Silverman D.T. Petersen G. Bracci P.M. Ji B.T. Negri E. Li D. Risch H.A. Olson S.H. Gallinger S. Miller A.B. Bueno-de-Mesquita H.B. Talamini R. Polesel J. Ghadirian P. Baghurst P.A. Zatonski W. Fontham E. Bamlet W.R. Holly E.A. Bertuccio P. Gao Y.T. Hassan M. Yu H. Kurtz R.C. Cotterchio M. Su J. Maisonneuve P. Duell E.J. Boffetta P. La Vecchia C. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4).Ann Oncol. 2012; 23: 1880-1888Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 41Rulyak S.J. Lowenfels A.B. Maisonneuve P. Brentnall T.A. 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