Elsevier

European Journal of Cancer

Volume 51, Issue 14, September 2015, Pages 1911-1917
European Journal of Cancer

PanGen-Fam: Spanish registry of hereditary pancreatic cancer

https://doi.org/10.1016/j.ejca.2015.07.004Get rights and content

Abstract

Purpose

To describe the organisation of the registry and the preliminary results in terms of characteristics of high-risk pancreatic ductal adenocarcinoma (PDAC) families recruited to date and findings of the screening programme. To compare early onset sporadic cases (⩽50 years), sporadic cases (>50 years) and cases with family history of cancer, for PDAC possible risk factors.

Methods/patients

Families with hereditary cancer syndromes predisposing to PDAC were recruited from two main sources: Spanish hospitals participating in PanGenEU, a pan-European multicentre case–control study, and their genetic counseling unit. Individuals at high-risk of PDAC were enrolled into a screening programme, consisting of Endoscopic ultrasound, computerised tomography, magnetic resonance imaging. Genetic testing of candidate genes was offered according to each patient’s risk.

Results

Among 577 consecutive PDAC cases, recruited via PanGenEU, 36 (6%) had ⩾2 first-degree relative with PDAC: Familial pancreatic cancer (FPC). So far PanGen-Fam has recruited 42 high-risk PDAC families; 25 (60%) had FPC. Five index cases with cancer were positive for BRCA2 and one for BRCA1 germline mutations. In the second year of prospective PDAC screening, one neuroendocrine tumour and a high-grade dysplasia lesion suspicious of carcinoma were diagnosed among 41 high-risk individuals. Furthermore EUS detected chronic-pancreatitis-like parenchymal changes in 15 patients.

Concluding statement

The identification and recruitment of PDAC high-risk families into the PanGen-Fam registry provides an opportunity to detect early onset cancer and precursor pancreatic cancer lesions at a potentially curative stage and to increase the knowledge of the natural history of the disease.

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

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