Factors which influence penetrance in Familial Pancreatic Cancer

Butler, JV (2016) Factors which influence penetrance in Familial Pancreatic Cancer. Doctor of Medicine thesis, University of Liverpool.

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Abstract

Introduction Pancreatic cancer (PDAC) confers a high mortality rate as it often presents at an advanced stage. Screening could improve early detection and survival. However, the prevalence of the disease and absence of specific screening tools mean that screening of the general population would result in many false positive tests. This may mean unnecessary overtreatment including surgery with considerable morbidity. Current screening techniques have associated risks including exposure to radiation and induction of pancreatitis. It is therefore essential to identify high risk screening populations and improve both specificity and safety of the screening modality. The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) was established to identify individuals with a genetic predisposition for PDAC to offer secondary screening. Thesis Aims The aims of this thesis were to identify subpopulations of high risk families who are at the greatest risk of pancreatic cancer in order to undertake targeted screening. Furthermore, to minimise the risks and complications to individuals participating in the EUROPAC secondary screening study for early PDAC. Materials and Methods Familial Pancreatic Cancer (FPC) was defined as autosomal dominant predisposition for PDAC. Hereditary Pancreatitis (HP) is an autosomal dominant predisposition for pancreatitis associated with an approximately 40% life time risk of PDAC. Families with other recognised cancer syndromes conferring a predisposition to PDAC were also recruited. At recruitment, blood samples for DNA storage and cell lines were obtained for the analysis of potential candidate genes implicated in FPC. Individual and familial demographic, lifestyle and disease related data were collected to facilitate analysis of possible risk factors which could influence penetrance in these high risk groups. On confirmation of a familial predisposition, eligible individuals were invited to participate in the EUROPAC secondary screening study for early pancreatic cancer. The screening protocol comprised blood tests and imaging techniques along with analysis of molecular markers in pancreatic juice. Results 273 potential FPC kindreds were identified and recruited; 89 had 3 or more affected family members. In FPC, age is a major risk factor but the pattern of age related risk is the same as in the general population. However, this is consistently 100 fold greater in FPC. No evidence was found for earlier age of onset in FPC contrary to other reports. Selection bias based on proband is proposed as an explanation for the apparent differences seen in the literature. Reporting bias could also explain the relationship of smoking and PDAC in FPC kindreds. No further causative mutations were found during the preparation of this thesis but a PALB2 mutation was found in three families (possibly associated with breast cancer). A model for risk was proposed, but in this thesis only secondary screening based on previous estimates is described. The methodology involved Endoscopic Retrograde Cholangiopancreatography (ERCP) and 7 cases of pancreatitis resulted. Consequently, stenting and use of diclofenac was introduced resulting in a significant reduction in ERCP associated pancreatitis (3 of 31 screens). Use of secretin to allow sampling of pancreatic juice from the duodenum was also piloted to further improve safety. This thesis provides data to support risk stratification in FPC and an improved screening modality. A total of 212 HP kindreds were identified. A variable clinical picture and cancer risk was found in the HP families with p.R122H, p.N29I and p.A16V all conferring a significantly increased lifetime risk for the development of pancreatic cancer, in addition to the earlier age of onset of exocrine and endocrine failure. Cancer risk was shown to be increased with smoking and diabetes. Risk of PDAC increases with age equally for HP and the general population but was 28 fold higher in each age group with HP. Conclusion My thesis has identified specific lifestyle and disease derived risk factors which may influence risk for the development of PDAC in high risk groups. As a direct result of this thesis, amendments made to the screening protocol have improved safety and minimised harm to those individuals undertaking screening for early pancreatic cancer under the auspices of EUROPAC.

Item Type:	Thesis (Doctor of Medicine)
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	02 Aug 2016 09:55
Last Modified:	19 Jan 2023 07:37
DOI:	10.17638/03000838
Supervisors:	Greenhalf, W Neoptolemos, J
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3000838