Short summary

Pancreatic cancer is among the deadliest cancer diagnoses worldwide - with an estimated 1-year mortality about 60% in western populations. The greatest challenge in the treatment of pancreatic cancer is early diagnosis of the disease, enabling timely surgical resection with complete removal of the malignant lesion. An estimated fraction of up to 10% of all pancreatic cancers is attributed to familial pancreatic cancer (FPC) with a heritability estimate of 36%. To date, no genetic mutations with strong associations to FPC are known. Proper identification of strong genetic markers associated with FPC would enable systematic genetic testing in relevant populations (e.g. patients with two or more cases of pancreatic cancer in first-degree relatives) - identifying high-risk individuals that can benefit from regular screening for pancreatic cancer in order for timely intervention. 

Rationale

Pancreatic cancer is among the deadliest cancer diagnoses worldwide - with an estimated 1-year mortality of about 60% in western populations. Surgical resection is the only curative treatment, as chemotherapy has only little effect on overall survival. The greatest challenge in the treatment of pancreatic cancer is early diagnosis of the disease, enabling timely surgical resection with complete removal of the malignant lesion. An estimated fraction of up to 10% of all pancreatic cancers is attributed to familial pancreatic cancer (FPC) with a heritability estimate of 36%. To date, no genetic mutations with strong associations to FPC are known. 

Proper identification of strong genetic markers associated with FPC would enable systematic genetic testing in relevant populations (e.g. patients with two or more cases of pancreatic cancer in first-degree relatives) - identifying high-risk individuals that can benefit from regular screening for pancreatic cancer in order for timely intervention. 

In addition to the identification of genetic mutations associated with FPC, pathological changes in the pancreatic tissue are also of great clinical value for the early screening and diagnostics of potential malignant lesions - as pancreatic core needle biopsies can help identify pre-malignant stages of pancreatic neoplasms.

Another high-risk group for the development of pancreatic cancer is patients with hereditary pancreatitis (HP). While genetic mutations in the PRSS1 gene are strongly associated with the occurrence of HP, 20% of patients with PRSS1 mutations do not develop HP, and conversely 20% of patients with HP do not have a known mutation. By high-throughput genomic analysis using deep sequencing technique, we hope to identify novel genetic variants for the observed variations in the expression of HP - potentially identifying pharmacological and therapeutic molecular targets for the use of targeted therapy in individuals with predisposition for HP.

Genomics, transcriptomics and personalized medicine are ever increasingly important approaches for improved early diagnostics and individualized treatment of hereditary diseases. Further basic understanding of genetic mutations and gene activity associated with FPC and HP would be of great clinical value for early diagnostics and timely intervention of pancreatic cancer in early stages, as well as targeted therapy for hereditary pancreatitis.

Using a large collection of blood samples for genomic analysis, as well as pancreatic tissue samples for transcriptomic analysis, the aims of this study are:

1. To identify genetic mutations strongly associated with Familial Pancreatic Cancer.

2. To examine the histopathological stages between pre-malignant to malignant lesions in pancreatic tissue, using both gene expression microarray and exome sequencing technology for marker discovery, thus enabling early diagnosis of prospective pancreatic cancers.

3. To verify and assess known genetic markers of Hereditary Pancreatitis, as well as potential other genetic mutations associated with the occurrence or inhibition of pancreatitis in predisposed families.

This project combines sequencing technique with the efficient family-based association design to identify novel genetic variants for FPC and HP in the Danish population. Results from this study will help to stratify which first-degree relatives of patients with FPC and HP it will be relevant to offer surveillance to detect PDAC early, and hopefully we will learn more about the progression from pre-malignant to malignant conditions at a tissue level. All this is with the aim of individualized prevention and treatment of familial pancreatic cancer and hereditary pancreatitis.

Description of the cohort

This study will primarily be carried out as a family-based association study with the inclusion of family members from 16 pre-identified families with Familial Pancreatic Cancer (FPC) and another 16 families with Hereditary Pancreatitis (HP), all currently followed at the Department of Medical Gastroenterology S, OUH.

Inclusion criteria for the FPC group are: 1) At least two first-degree family members with PDAC, with at least one of them being <50 years old at the time of diagnosis, or 2) At least three first-degree relatives with known PDAC.

Inclusion for the HP group are: 1) First degree relatives aged ?18 years, to patients known with HP, and 2) The patient being operable by total pancreatectomy.

Data and biological material

Aim 1) and 3):

Blood samples from around 100 individual family members from the 16 families with FPC, and blood samples from 100 individuals from the 16 families with HP (in total 2 x 100 patients), are expected to be collected for genetic analyses (through whole exome sequencing).

Aim 2): 

Histopathological analyses of pancreatic tissue in FPC will be performed on tissue from patients with known FPC who underwent total pancreatectomy at OUH because of pancreatic ductal adenocarcinoma (PDAC). These specimens will be analyzed using gene expression microarray and whole exome sequencing.

For all patients, the following data will be collected through the medical records and patient interview: patient characteristics, clinical parameters, blood samples and data on comorbidities.

Collaborating researchers and departments

Department of Medical Gastrointestinal Diseases, Odense University Hospital

• Consultant, Associate Professor Maiken Thyregod Jørgensen, MD, PhD (Main supervisor)
• Consultant, Professor, Head of Research Ove B. Schaffalitzky de Muckadell, MD, DMSci (co-supervisor)

Department of Clinical Genetics, Odense University Hospital

• Molecular biologist, Associate Professor Klaus Brusgaard, MSc, PhD

Department of Pathology, Odense University Hospital

• Consultant, Associate Professor Sönke Detlefsen, MD, PhD