Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk.

/pdf/a-region-based-gene-association-study-combined-with-a-leave-5qi9sdsivh.pdf

A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene.

BACKGROUND
Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance.


METHODS
A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months.


RESULTS
Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. One patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole-genome sequencing of this patient's PC and of a second patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the malignant transformation of an underlying BD-IPMN in <6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN that harbored polyclonal KRAS mutations.


CONCLUSIONS
PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.

Is Biannual Surveillance for Pancreatic Cancer Sufficient in Individuals With Genetic Syndromes or Familial Pancreatic Cancer?

Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer

// Qing Li 1, * , Hao Wang 2, * , George Zogopoulos 3, 4 , Qin Shao 5 , Kun Dong 6 , Fudong Lv 6 , Karam Nwilati 1 , Xian-yong Gui 7 , Adeline Cuggia 4 , Jun-Li Liu 1 , Zu-hua Gao 5 1 Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada 2 Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China 3 Department of Surgery, McGill University Health Centre, Montreal, QC, Canada 4 Quebec Pancreas Cancer Study, McGill University Health Centre, Montreal, QC, Canada 5 Department of Pathology, McGill University Health Centre, Montreal, QC, Canada 6 Department of Pathology, You An Hospital, Capital Medical University, Beijing, China 7 Department of Pathology, University of Calgary, Calgary, AB, Canada * These authors have contributed equally Correspondence to: Zu-hua Gao, email: zu-hua.gao@mcgill.ca Jun-Li Liu, email: jun-li.liu@mcgill.ca Keywords: Reg family proteins, pancreatic ductal adenocarcinoma, acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia, cholangiocarcinoma Received: March 01, 2016     Accepted: October 13, 2016     Published: October 24, 2016 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry. In the 3-dimensional culture of mouse acinar cells, Reg3A promoted ADM formation with concurrent activation of mitogen-acitvated protein kinase. Upregulation of Reg1A and Reg1B levels was observed as benign ductal epithelium progresses from PanIN to invasive PDAC. Patients with PDAC showed significantly higher serum levels of Reg1A and Reg1B than matching healthy subjects. These results were further validated by the quantification of Reg 1A and 1B mRNA levels in the microdissected tissues (22- and 6-fold increases vs. non-tumor tissues). Interestingly, patients with higher levels of Reg1A and 1B exhibited improved survival rate than those with lower levels. Furthermore, tissue expressions of Reg1A, Reg1B, and Reg4 could differentiate metastatic PDAC in the liver from intrahepatic cholangiocarcinoma with 92% sensitivity and 95% specificity. Overall, our results demonstrate the upregulation of Reg proteins during PDAC development. If validated in larger scale, Reg1A and Reg1B could become clinical markers for detecting early stages of PDAC, monitoring therapeutic response, and/or predicting patient’s prognosis.

Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma

Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673

Background Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies. Methods Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk. Results The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germline mutations in hereditary diseases. Conclusions Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.

https://www.mdpi.com/1718-7729/22/2/2300/pdf

Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec.

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Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec.