Familial Pancreatic Cancer Research Articles

Familial pancreatic cancer: Concept, management and issues.

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, “anticipation” is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

Prevalence and Progression of Pancreatic Cystic Precursor Lesions Differ Between Groups at High Risk of Developing Pancreatic Cancer.

The aim of this study was to compare the prevalence of cystic pancreatic lesions and their natural behavior in 2 distinct high-risk groups for developing pancreatic ductal adenocarcinoma (PDAC): (1) carriers of a mutation that predisposes to PDAC and (2) individuals without a known gene mutation but with a family history of PDAC (familial pancreatic cancer [FPC]). Pancreatic surveillance by annual magnetic resonance imaging and endoscopic ultrasound was performed in individuals with an estimated lifetime risk of developing PDAC of 10% or greater. Progression of a lesion was defined as growth 4 mm or greater or the development of worrisome features. We included 186 individuals: 98 mutation carriers and 88 FPC individuals (mean follow-up, 51 months). Individuals with FPC were significantly more likely than mutation carriers to have a pancreatic cyst 10 mm or greater (16% vs 5%, P = 0.045). Pancreatic cysts detected in mutation carriers, however, were significantly more likely to progress than those in FPC individuals (16% vs 2%, P = 0.050). This study provides evidence that the prevalence and growth characteristics of pancreatic cysts differ between distinct high-risk groups: individuals with FPC have a higher prevalence of pancreatic cysts 10 mm or greater, whereas cysts in mutation carriers are more likely to progress. These observations may help to develop more optimally tailored surveillance strategies in specific high-risk populations.

Screening for Subsequent Pancreatic Cancer in Childhood Cancer Survivors is Needed. A Case Report

Introduction: The survival of children with cancer has improved considerably over the last decades which have led to a growing number of long term survivors. One of the most serious adverse outcomes in this population is subsequent primary neoplasms with the risk as high as six-fold over expected. The relative risk for subsequent pancreatic cancer in childhood cancer survivors is high, especially after subdiafragmatic radiotherapy and/or chemotherapy with alkylating agents. The survival of patient with advanced pancreatic cancer is very low, and early diagnosis is of vital importance. Case report: We present a female patient, treated for Ewing sarcoma of thoracic wall with multimodal treatment at the age of 5. She received chemotherapy containing a high dose of Cyclophosphamide and postoperative radiotherapy to the left hemithorax with the dose of 15 Gy followed by local boost to the tumour bed. She had regular follow-ups at the Late-effect clinic at the Institute of Oncology in Ljubljana. Well differentiated papillary cancer of thyroid with nodal metastases was diagnosed during a regular neck ultrasound 26 years after the completion of cancer treatment. Two years later, at the age of 33, she presented with abdominal distension, inappetence and diffuse liver metastases with ascites were found by abdominal ultrasound. Tumour marker CA 19-9 was high, but pancreas was morphologically normal on the ultrasound and on abdominal helical CT. Cytological test of ascites and hepatic metastases showed poorly differentiated adenocarcinoma. The disease progressed very fast and she died a month after the appearance of the first symptom. The autopsy revealed poorly differentiated adenocarcinoma of the pancreatic head and body with multiple metastases in abdominal organs and lungs. Conclusion: It would be reasonable to introduce the same guidelines for screening of subsequent pancreatic cancer in childhood cancer survivors at high risk for subsequent pancreas cancer as proposed for patients with increased risk for familial pancreatic cancer.

2．膵癌早期発見に向けた家族性膵癌登録

家族性膵癌家系の定義は「膵癌に罹患した一対（2名）以上の第一度近親者がいる家系」であり，家族性膵癌家系に属する個人は膵癌の発症リスクが高いことが報告されている．米国Johns Hopkins大学で1994年に家族性膵癌登録制度（NFPTR）が発足し各分野で研究実績を残している．日本でも2014年に家族性膵癌登録制度（JFPCR）が発足，登録が進んでいる．JFPCRを基盤として膵癌の早期発見，発癌の原因遺伝子の検索，治療法開発など，様々な研究開発が期待されるが，中でも膵癌の早期発見は医療ニーズが高い．膵癌発症の高リスク群である家族性膵癌家系が登録，フォローアップされていくJFPCRは膵癌の早期発見を目指した研究開発を行うのに適したプラットフォームといえ，今後の研究開発が期待されている．

Abstract A02: Assessment of germline cancer predisposition genes in 392 unselected pancreatic cancer patients

Abstract Aim: To determine the prevalence of pathogenic germline mutations in known pancreatic cancer (PC) predisposition genes in an unselected PC cohort; identify clinico-pathological characteristics associated with gene carrier status; and analyse somatic genomic data for evidence of biallelic inactivation. Methods: Whole-genome (n = 184) and exome (n = 208) sequencing was performed on matched tumor-normal DNA pairs from 392 predominantly sporadic cases of PC. Pathogenic mutations were assessed in 13 cancer predisposition genes associated with PC risk (APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, TP53. Results: A total of 377 unique high confidence germline variants were observed in the 13 PC predisposition genes. 22 were classified as pathogenic and identified in 23/392 (5.9%) PC patients. The mutations occurred in BRCA2 (n=9), ATM (n=4), BRCA1 (n=3), PALB2 (n=3), CDKN2A (n=2) and one each in PMS2 and STK11. Truncating BRCA2 and PALB2 mutations were detected in 2 cases classified as familial PC. There was no significant difference in average age at diagnosis (67.9 vs 66.6, P = 0.5468), post-resection survival (20.3 vs 20.5 months, P = 0.9788), family history of malignancy (55.6% vs 40.5%, P = 0.2249) or personal history of malignancy (31.8% vs 15.0%, P = 0.0642) between those with and those without a pathogenic germline PC risk mutation. Patients harboring BRCA1, BRCA2 or PALB2 mutations were associated with an increased family history of breast or ovarian cancer (27.3% vs 6.3%, P = 0.0348). The second-hit mechanism could be assessed in tumors with &amp;gt;30% cellularity (n=16), of which 75% (7 BRCA2, 4 ATM, 1 BRCA1) showed evidence of biallelic inactivation. Conclusion: 5.9% of PC patients with predominantly sporadic disease have a pathogenic germline mutation in cancer predisposition genes associated with PC risk. However, carrier status did not significantly affect age at diagnosis, survival, personal or family history of malignancy in this cohort. Second hit mechanisms were identified in 12 (52.2%) cases, supporting a potential role in pancreatic tumorgenesis. An expanded analysis of the germline data is required to further understand the genetic basis of both sporadic and familial PC. Citation Format: Skye McKay, Jeremy Humphris, Amber Johns, Mark Pinese, Ann-Marie Patch, Katia Nones, Australian Pancreatic Cancer Genome Initiative (APGI), Sean Grimmond, Andrew Biankin, Nicola Waddell.{Authors}. Assessment of germline cancer predisposition genes in 392 unselected pancreatic cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A02.

Abstract IA03: Genetic and non-genetic risk factors of pancreatic cancer

Abstract In the United States, incidence and mortality rates of pancreatic cancer (PC) have remained largely unchanged since 1973. During 2005-2009, the incidence rate for Whites was 11.6/105 and for African-Americans, 15.2/105. Mortality rates were 10.7/105 for Whites and 13.8/105 for African-Americans. The 5-year survival has been 4-7% for decades. The absolute number of new cases and deaths due to PC has been increasing steadily since 2004 due to the baby-boomer generation reaching the risk window (where median age at diagnosis is 71 years). By 2030, PC will be the second most common cause of cancer mortality, after lung cancer. Already, in 2016 it is estimated to be the third leading cause of cancer death, surpassing deaths from breast cancer. Though the etiology of PC remains to be fully understood, we have learned much in the past decade in a variety of case-control and cohort studies on non-genetic and genetic risk factors. Non genetic factors: Host and lifestyle factors such as cigarette smoking, high body mass index, and heavy alcohol use, and long-standing type II diabetes mellitus and chronic pancreatitis, are associated with increased risk. The range of increased risks among these factors are two- to three fold increased risk over the general population. Other epidemiological investigations have implicated environmental exposures such as pesticides, asbestos, benzene and chlorinated hydrocarbons, with odds ratios in the range of 1.2 to 1.7. Protective effects of factors have been observed with diets rich in fruits and vegetables, dietary fiber, aspirin use, and history of allergies. Genetic factors account for ~10% of all PC cases. The genetic risk factors for PC have been pursued along two lines of inquiry. The first line of inquiry involves studies of high risk families, particularly those kindreds meeting criteria for familial pancreatic cancer (FPC) by containing at least two affected first degree relatives. Family-based studies and new methods for gene discovery, including next generation sequencing, have significantly increased our understanding of low frequency predisposition mutations, and the proportion of patients who carry mutations in genes such as BRCA1, BRCA2, CDKN2A, PALB2, ATM, mismatch repair genes (Lynch syndrome), and PRSS1 and SPINK2 (hereditary pancreatitis). Novel predisposition genes, among them a host of DNA repair genes, continue to be identified and emphasize the genetic heterogeneity of PC. As sporadic case series are being screened for mutations, we are finding that family history of PC is not a necessary requirement to be a PC mutation carrier. Predisposition genetic testing for individuals in FPC kindreds is feasible, and evolving, but typically will consist of sequencing a panel of multiple genes. The second line of inquiry involves large series of sporadic cases and non-cancer controls who are screened agnostically with thousands of single nucleotide polymorphisms (SNPs) that are studied in genome wide association studies (GWAS). Through this approach, numerous low penetrance but common variants have been implicated as contributing to PC risk, including SNPs in genes or regions such as ABO, NR5A2, CLPTMIL-TERT, LINC-PINT, BCAR1/CTRB1/CTRB2, PDX1, ZNRF3, LINC00673, SUGCT, TP63, and ETAA1. In general, these findings have helped generate new lines of inquiry for further understanding of PC etiology. Ongoing research continues to identify new risk factors and gene-environment interactions. Improvements in risk assessment and preventive interventions are increasingly becoming plausible. Citation Format: Gloria M. Petersen.{Authors}. Genetic and non-genetic risk factors of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA03.

A current picture of genetic counseling for familial pancreatic cancer

Introduction: Genetic testing for hereditary cancer syndromes, including those with an increased risk for pancreatic cancer, has become more routine for patients and families with a personal and/or...

Germline mutations in Japanese familial pancreatic cancer patients.

Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with pancreatic ductal adenocarcinoma (PDAC). We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any cancer except PDAC, and personal history of smoking, other cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2, PALB2, ATM, or MLH1. These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.

EUS and MRI/MRCP Findings in Pancreatic Cancer Screening for Individuals Who Harbor a BRCA2 Deleterious Germline Mutation

Introduction: Individuals with BRCA2 gene mutations have up to a 7% lifetime risk for developing pancreatic cancer (PC). In addition, these mutations account for the highest percentage of inherited causes of PC. In 2012 the International Cancer of the Pancreas Screening (CAPS) Consortium developed statements on screening, surveillance and management of patients with increased risk for familial PC. Our aim was to describe longitudinal endoscopic ultrasound (EUS) findings in patients undergoing PC screening who harbor a mutation in BRCA2 and to correlate EUS and MRI/MRCP findings. Methods: Patients with BRCA2 mutations were identified through the University of Michigan Breast and Ovarian Cancer Risk Evaluation Program Registry. Demographic information and descriptive analysis of screening tests were obtained from a prospective cohort. Results: 91 patients with BRCA2 mutations were enrolled in the registry, of which 37 (40.7%) were referred for PC screening discussion. Patients were followed for a mean of 7.5 years (+4). Demographic and clinical characteristics were similar between those who were and were not sent for PC screening (mean age 55.2±12.2y v. 54.5±11.5y; mean BMI 29.3±7.3 v. 25.8±5.5). Patients with a family history of PC (OR 9.5, 95% CI 1.1-82.5) were most likely to be referred for PC screening discussion. Of those referred, 18 (48.6%) BRCA2 mutation carriers pursued PC screening. All had EUS performed with 9 (50%) having both EUS and MRI. An average of 2.52 EUS and 1.75 MRI exams were performed. A normal exam on EUS or MRI was present in 12 (66.7%) and 7 (77.8%) patients, respectively. No solid lesions were identified on any surveillance exam. Two patients (11.1%) had a cystic lesion identified on initial EUS consistent with branch-duct (BD) IPMN. An additional 2 patients (11.1%) developed cystic lesions consistent with BD-IPMN after an average of 5 years. Other EUS findings included diffuse echogenicity suggestive of fatty infiltration of the pancreas in 2 (11.1%) patients and changes indeterminate or suggestive of chronic pancreatitis based on Rosemont criteria in 3 (16.7%) patients. Conclusion: In individuals with BRCA2 mutations, less than ½ pursued PC screening. The majority of patients were found to have normal screening examinations. Overtime, 22.2% of patients had findings consistent with BD-IPMNs. Further studies should be performed to determine appropriate screening recommendations and intervals.

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers.

Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation.

Value of EUS screening in patients with high risk factors for pancreatic cancer (focus on familial pancreatic cancer)

Value of EUS screening in patients with high risk factors for pancreatic cancer (focus on familial pancreatic cancer)

A report of Japanese familial pancreatic cancer

A report of Japanese familial pancreatic cancer

Japanese familial pancreatic cancer registry by Japan Pancreas Society

Japanese familial pancreatic cancer registry by Japan Pancreas Society

Expert consensus on surveillance methods for early detection of familial pancreatic cancer in Japan

Expert consensus on surveillance methods for early detection of familial pancreatic cancer in Japan

The Prevalence of Founder Mutations among Individuals from Families with Familial Pancreatic Cancer Syndrome.

PurposeFamilial pancreatic cancer describes families with at least two first-degree relatives with pancreatic cancer that do not fulfil the criteria of other inherited tumor syndromes with increased risks of pancreatic cancer. Although much has been learned regarding the aggregation of pancreatic cancer in some families, the genetic basis for this familial aggregation is poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among individuals from families with diagnosed familial pancreatic cancer syndrome and assessed their possible association with the familial pancreatic cancer (FPC) risk in Poland.Materials and MethodsIn this study, 400 FPC individuals and 4,000 control subjects were genotyped for founder mutations in BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), NBS1 (657del5), and PALB2 (509_510delGA, 172_175delTTGT) genes.ResultsA statistically significant association was observed between the 172_175delTTGT mutation of the PALB2 gene and an increased risk of FPC syndrome (odds ratio [OR], 10.05; p=0.048). In addition, an increased risk of cancer was observed in the FPC family members with a BRCA1 mutation (OR, 6.72; p=0.006). Novel associations were found between the FPC family members with cancer and CHEK2 mutations (OR, 2.26; p=0.008) with a noticeable contribution of the missense variant, I157T of CHEK2 (OR, 2.17; p=0.026).ConclusionThe founder mutations in the genes, BRCA1, PALB2, and CHEK2, cause a small percentage of familial pancreatic cancer syndrome in the Polish population. Following confirmation in larger studies, these mutations can be added to the panel of genes to be tested in families with a diagnosis of FPC syndrome.

Early pancreatic carcinogenesis – risk factors, early symptoms, and the impact of antidiabetic drugs

Risk factors (long-term diabetes, obesity) and early symptoms (new-onset diabetes, loss of weight, or persistent low body mass) are the initial symptoms of pancreatic carcinogenesis. They may be influenced by antidiabetic drugs and their correct evaluation is a prerequisite for early diagnosis of pancreatic cancer (PC). We review the risk factors, early symptoms, and the impact of antidiabetic drugs on early pancreatic carcinogenesis. The main source of data was the database Medline/PubMed and abstracts of international congresses (DDW, UEGW). The risk factors and early symptoms are integral components of the familial PC surveillance and sporadic PC screening. Preventive programs should always be include multistep and multidisciplinary procedures. The correct evaluation of antidiabetic drugs and their interactions with other components of pancreatic carcinogenesis may influence the early diagnosis of PC.

Association of Common Susceptibility Variants of Pancreatic Cancer in Higher-Risk Patients: A PACGENE Study.

Individuals from pancreatic cancer families are at increased risk, not only of pancreatic cancer, but also of melanoma, breast, ovarian, and colon cancers. While some of the increased risk may be due to mutations in high-penetrance genes (i.e., BRCA2, PALB2, ATM, p16/CDKN2A or DNA mismatch repair genes), common genetic variants may also be involved. In a high-risk population of cases with either a family history of pancreatic cancer or early-onset pancreatic cancer (diagnosis before the age of 50 years), we examined the role of genetic variants previously associated with risk of pancreatic, breast, ovarian, or prostate cancer. We genotyped 985 cases (79 early-onset cases, 906 cases with a family history of pancreatic cancer) and 877 controls for 215,389 SNPs using the iSelect Collaborative Oncological Gene-Environment Study (iCOGS) array with custom content. Logistic regression was performed using a log-linear additive model. We replicated several previously reported pancreatic cancer susceptibility loci, including recently identified variants on 2p13.3 and 7p13 (2p13.3, rs1486134: OR = 1.36; 95% CI, 1.13-1.63; P = 9.29 × 10(-4); 7p13, rs17688601: OR = 0.76; 95% CI, 0.63-0.93; P = 6.59 × 10(-3)). For the replicated loci, the magnitude of association observed in these high-risk patients was similar to that observed in studies of unselected patients. In addition to the established pancreatic cancer loci, we also found suggestive evidence of association (P < 5 × 10(-5)) to pancreatic cancer for SNPs at HDAC9 (7p21.1) and COL6A2 (21q22.3). Even in high-risk populations, common variants influence pancreatic cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 25(7); 1185-91. ©2016 AACR.

High risk factors of pancreatic carcinoma.

Over the past decades, cancer has become one of the toughest challenges for health professionals. The epidemiologists are increasingly directing their research efforts on various malignant tumor worldwide. Of note, incidence of cancers is on the rise more quickly in developed countries. Indeed, great endeavors have to be made in the control of the life-threatening disease. As we know it, pancreatic cancer (PC) is a malignant disease with the worst prognosis. While little is known about the etiology of the PC and measures to prevent the condition, so far, a number of risk factors have been identified. Genetic factors, pre-malignant lesions, predisposing diseases and exogenous factors have been found to be linked to PC. Genetic susceptibility was observed in 10% of PC cases, including inherited PC syndromes and familial PC. However, in the remaining 90%, their PC might be caused by genetic factors in combination with environmental factors. Nonetheless, the exact mechanism of the two kinds of factors, endogenous and exogenous, working together to cause PC remains poorly understood. The fact that most pancreatic neoplasms are diagnosed at an incurable stage of the disease highlights the need to identify risk factors and to understand their contribution to carcinogenesis. This article reviews the high risk factors contributing to the development of PC, to provide information for clinicians and epidemiologists.

The Spanish national familial pancreatic cancer registry Pan-Gen-FAM: Screening of high-risk individuals for the early detection of a pancreatic tumor

The Spanish national familial pancreatic cancer registry Pan-Gen-FAM: Screening of high-risk individuals for the early detection of a pancreatic tumor

Circulating free tumor DNA (cftDNA) as a novel biomarker for the early detection of cancer in familial pancreatic cancer families

Circulating free tumor DNA (cftDNA) as a novel biomarker for the early detection of cancer in familial pancreatic cancer families