Familial Pancreatic Cancer Cases Research Articles

A novel germline mutation of the <i>PALB</i> gene in a young Yakut breast cancer woman

Background. Breast cancer (BC) is the most common female malignancy worldwide. partner and localizer of BRCA2 gene (PALB2) is directly involved in DNA damage response. germline mutation in PALB2 has been identified in breast cancer and familial pancreatic cancer cases, accounting for approximately 1–2% and 3–4%, respectively. the goal of this report was to describe new PALB2 mutation in a young Yakut breast cancer patient with family history of cancer. Material and methods. Genomic DNA were isolated from blood samples and used to prepare libraries using a capture-based target enrichment kit, Hereditary Cancer Solution™ (SOPHIA GENETICS, Switzerland), covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). paired-end sequencing (2 × 150 bp) was conducted using NextSeq 500 system (Illumina, USA). Results. Here we describe a case of a never-before-reported mutation in the PALB gene that led to the early onset breast cancer. We report the case of a 39-year-old breast cancer Yakut woman with a family history of pancreatic cancer. Bioinformatics analysis of the NGS data revealed the presence of the new PALB2 gene germinal frameshift deletion (NM_024675:exon1:c.47dela:p.K16fs). in accordance with dbPubMed ClinVar, new mutation is located in codon of the PALB2 gene, where the likely pathogenic donor splice site mutation (NM_024675.3:c.48+1delG) associated with hereditary cancer-predisposing syndrome has been earlier described. Conclusion. We found a new never-before-reported mutation in PALB2 gene, which probably associated with early onset breast cancer in Yakut indigenous women with a family history of pancreatic cancer.

Germline and somatic mutation profiling in familial pancreatic cancer cases identifies clinically actionable variants

Germline and somatic mutation profiling in familial pancreatic cancer cases identifies clinically actionable variants

KRAS negativity and a longer overall survival in hereditary and familial pancreatic cancer cases

KRAS negativity and a longer overall survival in hereditary and familial pancreatic cancer cases

Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. KRAS mutations occur in up to 95% of cases and render the tumor resistant to many types of therapy. Therefore, these patients are treated with traditional cytotoxic agents, according to guidelines. The familial or hereditary form of the disease accounts for up to 10–15% of cases. We hypothesized that hereditary and Familial Pancreatic Cancer cases (H/FPC) have a distinct tumor specific mutation profile due to the presence of pathogenic germline mutations and we used circulating free DNA (cfDNA) in plasma to assess this hypothesis. H/FPC cases were mainly KRAS mutation negative and harbored tumor specific mutations that are potential treatment targets in the clinic. Thus, we conclude that cases with a hereditary or familial background can be treated with newer and more effective agents that may ultimately improve their overall survival.Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10–15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a KRAS somatic mutation. In addition, KRAS mutation negative cases harbor somatic mutations in potentially druggable genes such as KIT, PDGFR, MET, BRAF, and PIK3CA that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.

Prognostic significance of familial pancreatic cancer after surgery.

772 Background: Familial pancreatic cancer (FPC) is defined as two first-degree relatives with pancreatic cancer. It is known that the risk of developing pancreatic cancer increases in those who have a family history of pancreatic cancer in first-degree relatives. However, prognostic significance of FPC after surgery is not fully understood. Methods: Patients who underwent pancreatectomy for pancreatic ductal carcinoma between January 2008 and December 2016 were retrospectively reviewed. The prognostic significance of FPC was analyzed. Results: A total of 423 patients underwent pancreatectomy for pancreatic ductal carcinoma. FPC was identified in 32 (7.6%) patients. Recurrence occurred in 72% of all resected cases and in 88% of resected FPC cases. Multivariate analysis revealed FPC (hazard ratio [HR] 1.60; P=0.026), CA19-9 ≥300 U/ml (HR 1.54; P=0.001), lymph node metastasis (HR 2.10; P<0.001), microscopic venous invasion (HR 1.64; P<0.001), nerve plexus invasion (HR 1.39; P=0.010), R1 resection (HR 1.65; P=0.010), and lack of adjuvant chemotherapy (HR 2.27; P<0.001) as independent predictors for recurrence-free survival (RFS). The univariate analysis revealed that FPC is significantly associated with worse overall survival (OS) (P=0.018). The multivariate analysis showed that FPC was not an independent predictor of OS. This cohort was divided into 314 patients (FPC: 18 patients, non-FPC: 296 patients) who received adjuvant chemotherapy (AC group) and 109 patients (FPC: 14 patients, non-FPC: 95 patients) received no adjuvant chemotherapy (no AC group). In AC group, FPC is an independent predictor for RFS (HR 3.03; P<0.001) and OS (HR 2.23; P=0.018). In no AC group, FPC is not a predictor for RFS and OS. Conclusions: This study may show that FPC has a significant impact on RFS and OS after resection in patients who received adjuvant chemotherapy.

Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.

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.

Abstract B102: A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation

Abstract Background: Despite the recent progress made with front-line treatment for advanced pancreatic cancer (PC), most patients (pts) will either relapse or be refractory to treatment. Others may not even be eligible due to the toxicity profile of the available options or due to clinical deterioration. Once the disease progresses following front-line treatment, there is no accepted standard of care. Treatment options are clearly needed for patients with refractory disease. Approximately 5% of unselected PC pts, 10% of PC patients of Ashkenazi Jewish descent, and up to 19% of familial PC cases, harbor a germline BRCA mutation. Though less well characterized to date, somatic BRCA mutations also appear to play a significant role in PC. Clinical data have shown that pts with BRCA-mutant (BRCAmut) tumors, including those with PC, respond to treatment with a PARP inhibitor (PARPi). Early data suggest that other genomic characteristics may be surrogate biomarkers of homologous recombination deficiency (HRD) and define a larger group of responders than just BRCA mutation(s) alone. Rucaparib, an oral PARPi, is being developed for treatment of cancers associated with HRD due to a BRCA mutation or other homologous recombination pathway defect. Rucaparib has a desirable PK profile, is well tolerated, and has demonstrated clinical activity (RECIST and/or CA-125 responses) in patients with BRCAmut pancreatic, ovarian, or breast cancer in an ongoing Phase 1/2 study (NCT01482715). Three studies are currently ongoing in ovarian cancer and a trial in BRCAmut pancreatic cancer is now planned. The clinical activity of PARPi, including rucaparib, in BRCAmut PC, combined with the paucity of active 2nd-line therapies, support evaluation of rucaparib in PC pts with a BRCA mutation. Methods: Study CO-338-023 (NCT02042378) is a single-arm, open-label Phase 2 trial of continuous monotherapy rucaparib in up to 100 pts with pancreatic ductal adenocarcinoma (or related subtype) who are known to harbor a deleterious BRCA mutation (germline or somatic). Pts must have received at least 1, but no more than 2, prior regimens for locally advanced or metastatic disease and have relapsed / progressive disease confirmed by radiologic assessment, or are no longer able to tolerate chemotherapy due to toxicity, and radiologic assessment confirms stable or progressive disease. Other key inclusion criteria include measurable disease, ECOG Performance Status 0 or 1, and adequate organ function. Pts with endocrine tumors or who received prior PARPi treatment are excluded. Pts will take 600 mg BID rucaparib continuously and be evaluated for safety every 2–4 wks, disease status (CT scans, CA19–9) every 4–8 wks until disease progression, and then for survival every 4 wks. Blood and archival tumor tissue (if available) will be collected from all pts. The primary endpoint is ORR by RECIST v1.1. Key secondary endpoints include duration of response, PFS, OS, and safety. Exploratory analyses include gene sequence and structural rearrangements of tumor DNA and evaluation of circulating tumor DNA. A group sequential interim monitoring plan will be implemented to stop the study early for either superior efficacy or futility. Interim analyses will occur after every 10th patient enrolled has sufficient disease assessment data available. If robust activity is observed in the BRCAmut PC population, the trial may be broadened to include PC pts with HRD due to other than a BRCA mutation. The trial will be open to enrollment at clinical sites in the US and Israel in 2Q 2014. Citation Format: Susan M. Domchek, Robert McWilliams, Andrew Hendifar, Rachna T. Shroff, Lawrence Leichman, Ron Epelbaum, Ravit Geva, George Kim, Steven R. Alberts, Robert A. Wolff, Andrew Allen, Heidi Giordano, Mitch Raponi, Jeff Isaacson, Lindsey Rolfe, Andrew Biankin, Robert H. Vonderheide. A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B102.

294 Higher Prevalence of Cystic Lesions of the Pancreas in First Degree Relatives of Familial Pancreatic Cancer Cases Than in Carriers of Pancreatic Cancer-Prone Gene Mutations

G A A b st ra ct s disease, and current in vitro systems do not lend to studying metastasis either. Hence, in this abstract, we demonstrate the development of a new model, called Tumor in a Dish or TiD. Methods: Epithelial cells and fibroblasts from the colon and lung, as well as human vascular endothelial cells were used to develop a colon and lung organoid, respectively. For mismatch repair [MMR] proficient and defective cells, we used HCT-116 and DLD-1, and SW480 and LS174T cells, respectively. In addition, we used freshly resected colon cancer samples. For therapeutic interventions, we used 5-fluouracil (5FU), oxaloplatin (OX), irinotecan (IRI) and SN38, the active metabolite of irinotecan. Results: In the multi-cell type organoid system, cancer cells were grown in a 3-dimensional (3D) culture containing normal epithelial cells, fibroblasts and endothelial cells, which took approximately 10 days to form. The model resembles in vivo tumor microenvironments, including cell-cell contact, tumor architecture, and the influence of different cell types. To study colon cancer, we developed both primary TiD (priTiD) and metastatic TiD (metTiD). In the priTiD, we used normal colon epithelial cells and fibroblasts to develop a primary colon organoid and included colon cancer cells to develop a colon tumor. For metTiD, we similarly developed a lung organoid in which we added colon cancer cells and demonstrate colonization. We next determined the efficacy of standard colon cancer treatment agents. We observed differential activity of 5FU in cells with MMR defects in both priand metTiD system when compared to standard 2D cultures. Another surprising result we found was with freshly resected patient samples. Without knowing the genetic characteristics of the cancer tissue, the TiD method was able to identify cells that were resistant to oxaloplatin. Moreover, using this method, we have developed novel drugs that target cancer cells while not affecting the normal tissue. Conclusion: We have developed a novel method for identifying the appropriate therapeutic agent that specifically target tumor tissues, especially with mismatch repair defects. More importantly, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects.

Molecular pathology of pancreatic cancer

By genomic and epigenomic screening techniques, substantial progress has been made in our understanding of pancreatic cancer. The comprehensive studies of the pancreatic cancer genome have revealed that most genetic alterations are identified to be associated with specific core signaling pathways including high-frequency mutated genes such as KRAS, CDKN2A, TP53, and SMAD4 along with several low-frequency mutated genes. Three types of histological precursors of pancreatic cancer: pancreatic intraepithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm, had been recognized by morphological studies and the recent genomic screening techniques revealed that each of these precursor lesions were associated with specific molecular alterations. In the familial pancreatic cancer cases, several responsible genes were discovered. Epigenetic changes also play an important role in the progression of pancreatic cancer. Several tumor suppressor genes were silenced due to aberrant promoter CpG island hypermethylation. Several genetically engineered mouse models, based on the Kras mutation, were created, and provided reliable tools to identify the key molecules responsible for the development or progression of pancreatic cancer.

Familial pancreatic cancer: genetic advances

Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.

Spanish national hereditary pancreatic cancer registry (PanFAM).

e12033 Background: Inherited predisposition to Pancreatic Cancer (PC) corresponds 10% of all cases and includes members of families affected with hereditary cancer syndromes as Familial Pancreatic Cancer (FPC), Peutz-Jeghers, familial melanoma, hereditary breast and ovarian cancer, hereditary pancreatitis. An inherited predisposition in early onset PC (≤ 50 years) has also been suggested. We report preliminary data on PanFAM patients and screening of high risk individuals. Methods: PamFAM is a part of the European PANGEN PC case/control study of hereditary PC, co-ordinated by the Ramón y Cajal (RC) hospital and the Spanish National Cancer Research Center, with 16 participating hospitals. All families with clinical evidence of an inherited PC syndrome were recruited and multi-generational pedigrees were constructed. Cancer diagnoses were confirmed, when possible, by review of medical records. Blood samples and epidemiological data were collected for all participating family members. A screening program for early detection of PC, based on endoscopic ultrasound (EUS), CT and circulating tumour cells (CTCs) was offered to high risk individuals. Results: Of 505 Spanish PCs collected by PANGEN, 31 (~6%) were FPC cases; 18 (58%) revealed only PC and the remaining showed clustering with other tumor types, gastric cancer was the most common (13%). Among FPC families, 3 had 3 cases of PC and the remaining had 2 cases. The mean age of diagnosis was 67 years (range 47-85), 20 male and 11 female. Four FPCs were previously diagnosed with cancer (Hodgkin lymphoma, breast and prostate cancer) and 3 with acute pancreatitis. 37 PCs with no family history of cancer were diagnosed at the age of 50 years or earlier (mean 45, range 30-50), 18 male and 19 female. Other 27 eligible families were recruited by RyC hospital, 8 (30%) with FPC and 3 (11%) with PC ≤ 50 years. A cohort of 61 high risk individuals participes in the screening study: 3 had abnormal EUS, 1 a benign pancreatic node and 1 a renal angiolipoma; one young man had 2 CTCs. Conclusions: PanFAM is the first registry in Spain collecting hereditary PC cases and it represents an important resource to identify underlying gene defects and to the development of screening methods precursor lesions detection in high risk individuals.

PALB2 mutations in familial breast and pancreatic cancer

PALB2 (Partner And Localizer of BRCA2) binds to and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1-2% of familial breast cancer and 3-4% of familial pancreatic cancer cases. The goal of this study was to evaluate the prevalence of PALB2 mutations in women with breast cancer without BRCA1/2 mutations who also had a personal or family history of pancreatic cancer. PALB2 mutation analysis was performed in 94 non-BRCA1/2 breast cancer patients with a personal or family history of pancreatic cancer. Two truncating PALB2 mutations, c.3549C>CA and c.2962C>CT, were identified resulting in a mutation prevalence of 2.1%. The proband found to carry the c.3549C>CA PALB2 mutation had a mother diagnosed with both breast and pancreatic cancer; this relative was subsequently confirmed to carry the identical mutation. The proband with the c.2962C>CT mutation had a father and paternal aunt diagnosed with pancreatic cancer; neither relative was available for testing. Two novel PALB2 missense variants were also found, one of which was deemed potentially deleterious. The prevalence rate of PALB2 mutations in a non-BRCA1/2 breast cancer population specifically selected for a family history of pancreatic cancer does not appear to be significantly increased compared to that observed in other breast cancer populations studied thus far. Further evaluation is needed to determine the prevalence of PALB2 mutations and the clinical utility of such testing in those individuals affected with both breast and pancreatic cancers.

The NOD2 3020insC Mutation and The Risk of Familial Pancreatic Cancer?

Dear Sirs, Pancreatic cancer is an aggressive disease with a poor prognosis but despite much investigation little is known about genetic susceptibilities to this cancer [1-4]. There are several studies showing pancreatic abnormalities in patients with Crohn's disease, a chronic inflammatory condition of the digestive tract. It has been suggested that pancreatitis could be an extrahepatic manifestation of inflammatory bowel disease, since its incidence in this disease is greater than that in the general population and in many cases no aetiological factor has been found [5]. It has been recently identified in Japan that over 6% of Crohn's disease patients had morphological abnormalities of the pancreas [6]. There is also a notion that Crohn's-associated pancreatitis could be a premalignant state for cystadenocarcinoma of the pancreas [7]. Recently in patients with Crohn's disease mutations in CARD15/NOD2 have been found. NOD2 encodes a protein involved in bacterial recognition by monocytes. The NOD2 gene is localized to chromosome 16 and is comprised of 12 exons that encode a protein of 1040 amino acids [8]. Several mutations have been identified in the NOD2 gene, which appear with a significantly higher frequency in patients with Crohn's disease. One such mutation (3020insC) is believed to be clearly causative because it is the only common variant which results in a prematurely truncated protein predicted to reduce its functional efficiency. It has been recognized recently that the presence of this particular NOD2 mutation increases the risk of developing colorectal cancer characterized by a later average age of disease diagnosis [9]. Since the risk of cancers at various sites has been characteristic among patients with Crohn's disease, it was considered justified to study the relationship between the 3020insC mutation and other cancer risks. Here, we report the analyses of the 3020insC mutation in the NOD2 gene in patients with pancreatic cancer. Initially, we have examined the frequency of the 3020insC mutation in a series of 158 patients divided into 3 groups: 1. 127 consecutive pancreatic cancers; 2. 4 familial cases - pancreatic cancer patients from families with at least two pancreatic cancers on the one side of the family; 3. 27 healthy children of pancreatic cancer patients from families with at least two pancreatic cancer cases where DNA samples from affected individuals were not available. Individuals from the last group were younger than 46 years. In the consecutive group peripheral blood samples were available from 58 cases. DNA from the remaining patients was isolated from paraffin embedded tissues. In all familial cases and the group of healthy children DNA samples were obtained from the peripheral blood lymphocytes. The control group consisted of 300 consecutive newborns from the clinical hospitals of Szczecin. DNA samples were obtained from umbilical cord blood. The method described by Ogura et al [8] was used to identify the 3020insC mutation. The sequence of the PCR products was confirmed by DNA sequencing. The frequency of the 3020insC mutation in the control group was 7%. In the group of consecutive cases six C-insertion mutations were identified (4.7%). In the four independent familial pancreatic cancer patients no mutation was found, but four changes (14.8%; 4/27) were detected in the group of healthy children of pancreatic cancer patients derived from families with aggregations of these tumours (Fig. ​(Fig.11). Figure 1 Pedigree of the family with 3020insC mutation. Since our results indicated that there was an increased frequency of the 3020insC mutation in familial pancreatic cancer cases we decided to enlarge this group. 30 additional histologically confirmed familial pancreatic cancer patients of independent families from the German National Case Collection for Familial Pancreatic Cancer of the Deutsche Krebshilfe (FaPaCa) were included in this study [10]. The frequency of the mutant allele in this group did not confirm our initial result since only two changes were found (6.7%; 2/30). However, even if Polish and German familial cases are combined it is still an open question whether 3020insC is related to a predisposition to familial pancreatic cancer. Further investigations on a larger number of cases are needed. In summary we cannot conclude that NOD2 is not involved in familial pancreatic cancer but it appears not to be associated with sporadic cases of disease.