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Background: Early-onset pancreatic cancer (EOPC) represents 5–10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. Methods: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. Results: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69–5.04, P = 1.44 × 10−4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41–65.50, P = 3.58 × 10−4). Conclusion: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in this study. We conducted a multi-phase study analysing 7,745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14,666 PDAC cases and 221,897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR=1.11, 95%CI=1.07-1.15, P=5.25×10-9 ). CDKN2B-AS1/ANRIL is a long non-coding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases. This article is protected by copyright. All rights reserved.

Bei den malignen soliden pseudopapillaren Neoplasien (SPN) handelt es sich um eine seltene Tumorentitat des Pankreas. Die Prognose der SPN ist generell exzellent, allerdings haben einige Tumoren ein malignes Potenzial und neigen zur Metastasierung bzw. zum Rezidiv. Untersucht werden soll, ob es histopathologische oder operationstechnische Risikofaktoren gibt, die das biologische Potenzial von SPN einschatzen lassen. Das Patientenkollektiv aus 2 grosen deutschen Pankreaszentren aus den Jahren 2009 bis 2018 wird in Bezug auf das Vorkommen von SPN, das chirurgische Management, histopathologische Tumorcharakteristika und das postoperative Outcome evaluiert. Es wurden 22 Patienten (17 Frauen, 5 Manner) mit SPN operiert. Das Alter der Patienten lag im Median bei 37 Jahren (Range 19–69 Jahre). Zum Zeitpunkt der Resektion zeigten 20 Patienten ein auf das Pankreas begrenztes Tumorwachstum. Eine Patientin mit Rezidiv einer auswarts resezierten SPN wies einen Lymphknotenbefall auf. Eine weitere Patientin hatte ein hepatisch metastasiertes Rezidiv (Union Internationale contre Cancer (UICC)-Stadium IV) einer auswartig resezierten SPN. Wahrend samtliche Patienten im Rahmen des Follow-ups rezidivfrei uberlebten, entwickelte diese Patientin erneut Leberfiliae. Die Uberlebensrate bis zum Ende des Follow-ups (Median 43 Monate; Range 1–132 Monate) dieser Studie lag bei 100 %. Es mangelt an Kenntnissen bezuglich moglicher Parameter, die das biologische Verhalten von SPN vorhersagen lassen. Auser einer erhohten Rezidivwahrscheinlichkeit nach Resektion eines SPN-Rezidives liesen sich am untersuchten Patientenkollektiv keine klaren Risikofaktoren ausmachen, die auf ein gesteigertes malignes Potenzial und ein moglicherweise schlechteres Outcome hinweisen konnten. Nur eine radikale operative Resektion mit Lymphadenektomie ermoglicht eine sichere Abschatzung des Tumorstadiums und eine Entfernung moglicherweise betroffener Lymphknoten, die beim Belassen Ursache eines Rezidivs sein konnten.

Malignant solid pseudopapillary neoplasms (SPN) are rare tumor entities of the pancreas. The prognosis for SPN is generally excellent, although some tumors have malignant potential and tend to metastasize or relapse.The aim was to investigate whether there are histopathological or surgical risk factors that enable the biological potential of SPN to be estimated.Data from patients with SPN treated in two large German pancreas centers from 2009 to 2018 were evaluated with respect to the occurrence of SPN, surgical management, histopathological tumor characteristics and the postoperative outcome.A total of 22 patients with SPN (17 women, 5 men) were operated on. The median age of the patients was 37 years (range 19-69 years). At the time of surgery 20 patients showed tumor growth limited to the pancreas. A female patient with recurrence of an externally resected SPN had lymph node involvement. Another female patient had a hepatic metastatic recurrence (Union Internationale contre Cancer (UICC) stage IV) of an externally resected SPN. Although all patients survived recurrence-free during the follow-up, this patient developed liver metastases again. The survival rate up to the end of the follow-up (median 43 months; range 1-132 months) of this study was 100%.There is a lack of knowledge of the possible parameters that can be used to predict the biological behavior of SPN. Apart from an increased likelihood of recurrence after resection of an SPN recurrence, no clear risk factors could be identified in the examined patient collective that could indicate an increased malignant potential and a possibly poorer outcome. Only a radical surgical resection with lymphadenectomy enables a reliable assessment of the tumor stage and the removal of possibly affected lymph nodes, which could be the cause of a recurrence if left intact.HINTERGRUND: Bei den malignen soliden pseudopapillären Neoplasien (SPN) handelt es sich um eine seltene Tumorentität des Pankreas. Die Prognose der SPN ist generell exzellent, allerdings haben einige Tumoren ein malignes Potenzial und neigen zur Metastasierung bzw. zum Rezidiv.Untersucht werden soll, ob es histopathologische oder operationstechnische Risikofaktoren gibt, die das biologische Potenzial von SPN einschätzen lassen.Das Patientenkollektiv aus 2 großen deutschen Pankreaszentren aus den Jahren 2009 bis 2018 wird in Bezug auf das Vorkommen von SPN, das chirurgische Management, histopathologische Tumorcharakteristika und das postoperative Outcome evaluiert.Es wurden 22 Patienten (17 Frauen, 5 Männer) mit SPN operiert. Das Alter der Patienten lag im Median bei 37 Jahren (Range 19–69 Jahre). Zum Zeitpunkt der Resektion zeigten 20 Patienten ein auf das Pankreas begrenztes Tumorwachstum. Eine Patientin mit Rezidiv einer auswärts resezierten SPN wies einen Lymphknotenbefall auf. Eine weitere Patientin hatte ein hepatisch metastasiertes Rezidiv (Union Internationale contre Cancer (UICC)-Stadium IV) einer auswärtig resezierten SPN. Während sämtliche Patienten im Rahmen des Follow-ups rezidivfrei überlebten, entwickelte diese Patientin erneut Leberfiliae. Die Überlebensrate bis zum Ende des Follow-ups (Median 43 Monate; Range 1–132 Monate) dieser Studie lag bei 100 %.Es mangelt an Kenntnissen bezüglich möglicher Parameter, die das biologische Verhalten von SPN vorhersagen lassen. Außer einer erhöhten Rezidivwahrscheinlichkeit nach Resektion eines SPN-Rezidives ließen sich am untersuchten Patientenkollektiv keine klaren Risikofaktoren ausmachen, die auf ein gesteigertes malignes Potenzial und ein möglicherweise schlechteres Outcome hinweisen könnten. Nur eine radikale operative Resektion mit Lymphadenektomie ermöglicht eine sichere Abschätzung des Tumorstadiums und eine Entfernung möglicherweise betroffener Lymphknoten, die beim Belassen Ursache eines Rezidivs sein könnten.

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10−5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.