PanGen-Fam: Spanish registry of hereditary pancreatic cancer
Introduction
In Spain, each year, 6.9 men and 4.3 women per 100,000 people are diagnosed with pancreatic ductal adenocarcinoma (PDAC) (http://www-dep.iarc.fr/) and these rates are predicted to increase [1]. PDAC has a dismal prognosis, with 5-year survival <5%, making mortality and incidence rates almost identical [2]. This makes PDAC a priority in research and prevention. Because of the low incidence of the disease, the current screening is directed only to individuals at high risk of PDAC [3]; these are members of families with tumour-predisposing syndromes known to increase PDAC risk. The majority of these subjects are familial pancreatic cancer (FPC) cases (⩾2 first-degree relatives with PDAC [4]); in these families, PDAC risk increases with the number of cases (6.4- and 32-fold in individuals with 2 and ⩾3 affected first-degree relatives, respectively [5]) and younger age of diagnosis [6]. At present few 3 genes, all involved in DNA repair, have been identified as responsible for FPC; however germline mutations in these genes explain only ∼ 25% of the cases: BRCA2 (15–17%) [7], [8], PALB2 (3%) [9], [10], [11].
Other syndromes increasing PDAC risk are Peutz–Jeghers syndrome (PJS; ∼132-fold increased risk [12]), hereditary pancreatitis (HP; 50–60-fold increased risk [13]), familial-atypical multiple mole melanoma (FAMMM; ∼17-fold increased risk [14]), Lynch syndrome (LS, 8.6-fold increased risk [15]), hereditary breast and ovarian cancer (HBOC; BRCA1 and BRCA2 mutation carriers have a ∼4- and 6-fold increased risk, respectively [16]) and cystic fibrosis (CF; 5.3-fold increased risk [17]).
There is a general consensus that PDAC screening based on endoscopic ultrasonography (EUS) and high-resolution magnetic resonance imaging (MRI) is able to detect small potentially curable tumours and premalignant lesions such as Pancreatic Intraepithelial Neoplasia (PanIN) and Intraductal Papillary Mucinous Neoplasms (IPMN) [3]. EUS allows performing Fine Needle Aspiration (FNA) of the pancreatic lesions, increasing the accuracy (92%) in the diagnosis and staging of pancreatic malignancies [18].
The PanGen-Fam registry was established in Spain in 2009 to collect families with high PDAC risk. Besides, PanGen-Fam offers an individualised screening programme for early tumour detection in high-risk subjects. The study is combined with an up-to-date genomic research programme to identify new genetic determinants for the families for which the genetic cause is unknown.
Here we describe the objectives of PanGen-Fam and present the screening strategy adopted as well as preliminary findings. Currently we are testing the workflow of the study in the Ramon y Cajal genetic counseling unit (GCU), as a pilot project, before including the other 15 participating centres.
Section snippets
Patients and methods
PanGen-Fam is coordinated by the Ramón y Cajal University Hospital (HRC) and the Spanish National Cancer Research Centre (CNIO); To date, 16 centres from Spain have joined the project.
The eligibility criteria for families being recruited are: ⩾2 PDACs; Lynch syndrome and 1 PDAC; melanoma and 1 PDAC; Peutz–Jeghers syndrome and hereditary pancreatitis. We also recruited families with one early onset PDAC (⩽50 years). Families with Lynch syndrome are proposed to undergo genetic testing but no
PanGenEU cases
We analysed 577 index cases with PDAC and 4,034 first-degree relatives, recruited in Spain, PanGenEU. On average, men were diagnosed 3.8 years younger than women (64.8 years versus 68.6 years, P = 3.4e−04). Smokers were diagnosed 9 years earlier than non-smokers (62.6 years versus 71.6 years respectively, P = 2.2e−16). Among index cases, 33.6% were affected with diabetes before developing PDAC and were diagnosed 4 years later than non-diabetic cases (69 versus 65, respectively, P = 1e−04). Overall, the mean
Discussion
PanGen-Fam represents the first registry in Spain collecting families with hereditary pancreatic cancer syndromes.
These preliminary results show heterogeneity in FPC cases; actually few cases were “pure”, with PDAC as the only cancer site, whereas the majority showed PDAC clustering with other cancers making the classification of the family into a specific syndrome difficult. The most common cancers in FPC families were breast (54%), colon (36%) and lung (28%); the same cancer sites were
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by two research grants PI09/02221, PI12/01635 and the RTICC (RD12/0036/0034 and RD12/0036/0073) from the Institute of Health Carlos III, ISCIII, in Spain. The authors also acknowledge the contribution of the following investigators: Ana Custodio, Hospital Universitario La Paz in Madrid; Iván Márquez Rodas, Hospital Universitario Gregorio Marañón in Madrid; José María Mesa, Hospital Universitario Príncipe de Asturias in Alcalá de Henares (Madrid); María José Molina
References (31)
European cancer mortality predictions for the year 2014
Ann Oncol
(2014)Update on familial pancreatic cancer
Adv Surg
(2010)Very high risk of cancer in familial Peutz–Jeghers syndrome
Gastroenterology
(2000)- et al.
Risk factors for cancer in hereditary pancreatitis. International Hereditary Pancreatitis Study Group
Med Clin North Am
(2000) Genetics of pancreatic cancer. From genes to families
Surg Oncol Clin N Am
(1998)Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds
Gastroenterology
(2003)Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study
Clin Gastroenterol Hepatol
(2006)Familial pancreatic cancer in Italy. Risk assessment, screening programs and clinical approach: a position paper from the Italian Registry
Dig Liver Dis
(2010)- et al.
Carcinogenesis of pancreatic cancer: challenges, collaborations, progress
Mol Carcinog
(2012) International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer
Gut
(2013)
Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds
Cancer Res
Importance of age of onset in pancreatic cancer kindreds
J Natl Cancer Inst
Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families
Fam Cancer
The prevalence of BRCA2 mutations in familial pancreatic cancer
Cancer Epidemiol Biomarkers Prev
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene
Science
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2020, EBioMedicineCitation Excerpt :One of the keys to improving patient prognosis is early diagnosis and FPC is a known high risk population that would benefit from early detection strategies. The Spanish familial pancreatic cancer registry (Pan-Gen-FAM) was established in 2009 in Spain with the principal objective to characterise the phenotypic and genetic background of FPC [19]. The registry currently includes over 200 individuals representing some 88 families presenting with pancreatic cancer alone or in combination with known cancer syndromes.
Chronic pancreatitis changes in high-risk individuals for pancreatic ductal adenocarcinoma
2019, Gastrointestinal EndoscopyCitation Excerpt :These findings suggest that HRIs with CP changes are at higher risk for PDAC and may require closer monitoring. CP changes on EUS in HRIs have been previously reported, as summarized in Table 6.6,10-15,17,22,25 In agreement with our findings, Canto et al22 and Mizrahi et al10 reported these changes more frequently in HRIs when compared with control subjects.
Supported by grants from the Institute of Health Carlos III, ISCIII, in Spain (PI09/02221 and PI12/01635) and the Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD12/0036/0034 and RD12/0036/0073).
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Both authors have equally contributed to this study.