The Evolving (Epi)Genetic Landscape of Pancreatic Neuroendocrine Tumours
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26 9 Endocrine-Related C P Pipinikas et al. Evolution of PanNET genomics 26:9 R519–R544 Cancer REVIEW The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours Christodoulos P Pipinikas1, Alison M Berner1, Teresa Sposito1 and Christina Thirlwell1,2 1Medical Genomics Laboratory, University College London Cancer Institute, London, UK 2Neuroendocrine Tumour Unit and Department of Oncology, Royal Free Hospital, London, UK Correspondence should be addressed to C Thirlwell: [email protected] Abstract Neuroendocrine neoplasms (NENs) are a relatively rare group of heterogeneous tumours Key Words originating from neuroendocrine cells found throughout the body. Pancreatic NENs f pancreatic neuroendocrine (PanNENs) are the second most common pancreatic malignancy accounting for 1–3% of tumour all neoplasms developing in the pancreas. Despite having a low background mutation f MEN1 rate, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes (PTEN, TSC1/2) are f DAXX implicated in disease development and progression. Their increased incidence coupled f ATRX with advances in sequencing technologies has reignited the interest in PanNEN research f mTOR and has accelerated the acquisition of molecular data. Studies utilising such technological f MUTYH advances have further enriched our knowledge of PanNENs’ biology through novel f BRCA2 findings, including higher-than-expected presence of germline mutations in 17% of f CHEK2 sporadic tumours of no familial background, identification of novel mutational signatures f alternative lengthening of telomeres and complex chromosomal rearrangements and a dysregulated epigenetic machinery. f chromatin remodelling. Integrated genomic studies have progressed the field by identifying the synergistic action between different molecular mechanisms, while holding the promise for deciphering disease heterogeneity. Although our understanding is far from being complete, these novel findings have provided the optimism of shaping the future of PanNEN research, ultimately leading to an era of precision medicine for NETs. Here, we recapitulate the existing knowledge on pancreatic neuroendocrine tumours (PanNETs) and discuss how recent, novel findings have furthered our understanding of these complex tumours. Endocrine-Related Cancer (2019) 26, R519–R544 Introduction Neuroendocrine neoplasms (NENs) develop from cells of NENs are rare tumours previously described as ‘orphan’ neuroendocrine differentiation distributed throughout cancers (Kawasaki et al. 2018). However, this rarity may be the body, most commonly in the small intestine, lung due to variation in disease coding/nomenclature between and pancreas (PanNENs) (Dasari et al. 2017). PanNENs (inter)national cancer registries leading to inaccurate were originally called ‘islet cell tumours’ due to the belief incidence and prevalence rates (IR and PR, respectively) that they arise from islet cells. More recently, it has been (Niederle et al. 2010, Genus et al. 2017). Recent population- suggested that they may originate from pluripotent stem based studies indicate higher IRs than previously cells of the ductal-acinar system (Vortmeyer et al. 2004, described (Fraenkel et al. 2015) with a 3- to 5-fold increase Klöppel et al. 2007). during the last 3–4 decades both worldwide and in the https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-19-0175 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 06:30:47AM via free access -19-0175 Endocrine-Related C P Pipinikas et al. Evolution of PanNET genomics 26:9 R520 Cancer United Kingdom (Halfdanarson et al. 2008, Yao et al. 2008, neuroendocrine carcinomas (PanNECs). While G1/G2 Dasari et al. 2017, Genus et al. 2017). Increased detection NETs can be either functional or non-functional, G3 rates are attributed to several factors including use of NECs are mainly non-functional due to loss of hormone more sensitive imaging/diagnostic modalities, refined secretion-associated genes (Sadanandam et al. 2015). This markers of neuroendocrine differentiation (for example, distinction in histological/morphological characteristics chromogranin A, synaptophysin, neuron-specific enolase, and clinical outcomes is also reflected in the molecular/ pancreatic polypeptide), establishment of accurate records, genetic landscape between the two entities (Yachida et al. improvements in training and increased awareness both 2012, Girardi et al. 2017). While TP53 and RB1 recurrent in the clinical field and the general population. mutations are found in NECs, they are rarely seen in NETs. The IR of PanNENs is currently 0.43/100,000 having However, reports indicate that 35–50% of G3 PanNECs been 0.17 in 1973–1977 (2003–2007 SEER) (Lawrence are well differentiated with similar clinical course and et al. 2011). Due to the indolent nature of some NENs the molecular profiles to G2 PanNETs Vélayoudom-Céphise( PR is higher than any other upper gastrointestinal or liver et al. 2013, Sorbye et al. 2014, Basturk et al. 2015, Tang et al. cancer, second only to colorectal cancer when considering 2016). The WHO classification criteria have been recently gastrointestinal malignancies (Yao et al. 2008, Dasari updated (Lloyd et al. 2017) to address this heterogeneity et al. 2017). PanNENs account for 1–3% of all pancreatic by further sub-dividing tumours into WD G3 PanNETs neoplasms and are the 2nd most common pancreatic and PD G3 PanNECs. malignancy (Bosman et al. 2010). Autopsy studies have PanNENs are highly heterogeneous and complex demonstrated that up to 10% of PanNENs remain tumours, which demonstrate diverse clinical behaviours clinically undetected, an observation that may impact (rate of development and progression, metastatic the reported IR/PR (Kimura et al. 1991, Halfdanarson et al. potential, treatment response/resistance and survival 2008, Fraenkel et al. 2012). Survival rates vary depending rates) that ultimately define tumour fate. Although various on grade and stage at diagnosis (Yao et al. 2008) with prognostic indicators and classification systems evolved 5-year survival rates post resection for well-differentiated over time have been clinically useful, they have their tumours of around 65% (de Wilde et al. 2012a). In own inherent limitations and, most importantly, they patients with distant unresectable disease (stage IV), most do not reflect the biological and clinical heterogeneity commonly liver metastases, 5-year survival is 16–46% of PanNETs. Such heterogeneity is more pronounced in (Mignon et al. 2000, Viúdez et al. 2016, Batukbhai et al. G1 and G2 tumours that, unlike the predictable lethality 2019) (Fig. 1A). of G3 NECs, have a variable clinical course ranging from Functionally, PanNENs are divided into functional and indolent to aggressive (Lloyd et al. 2017). non-functional tumours (F-PanNENs and NF-PanNENs, In this review, we provide an update on the evolving respectively). F-PanNENs are associated with various genomic and epigenomic landscape of G1/G2 PanNET clinical syndromes leading to earlier diagnosis due to development and progression and discuss recent novel clinical manifestation of hormone secretion-associated findings. As PD G3 NECs represent a separate tumour symptoms (Fig. 1A). In contrast, NF-PanNENs pose a entity, they are not discussed further. significant early-diagnostic challenge since symptoms only become evident later on in the disease course due to the growing tumour mass. At initial diagnosis, Genetic landscape of PanNETs approximately 60–80% of cases are detected with locally Cancer-predisposition syndromes advanced or metastatic disease (Baur et al. 2016, Viúdez et al. 2016), resulting in a worse prognosis. Although PanNETs are most commonly sporadic, they Classification of PanNENs, according to World Health also arise in the familial setting due to inherited germline Organization (WHO) criteria, is based on the degree mutations in tumour suppressor genes (TSG) that increase of cellular differentiation and fraction of proliferating organ susceptibility to cancer development. These cancer- neoplastic cells as a measure of tumour grade (determined predisposition syndromes (Fig. 1A) account for <10% by the mitotic count and the Ki-67 labelling index). of PanNETs (Marx et al. 2005) and are discussed below. PanNENs are classified into well-differentiated (WD), Recently, germline mutations in DNA damage repair genes, low-to-intermediate-grade (G1 and G2, respectively) such as CHEK2 and MUTYH, have been identified in 17% pancreatic neuroendocrine tumours (WD-PanNETs, >90%) of sporadic cases of apparently no familial background and poorly differentiated (PD), high-grade, G3 pancreatic (Scarpa et al. 2017). https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-19-0175 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 06:30:47AM via free access Endocrine-Related C P Pipinikas et al. Evolution of PanNET genomics 26:9 R521 Cancer A B Figure 1 Overview of the multi-layered pancreatic neuroendocrine tumours (PanNET) complexity. (A) Discrimination of PanNENs into those associated with a familial syndrome, due to germline mutations in tumour suppressor genes, and sporadic tumours further sub-divided into functional and non-functional. Epidemiological and survival rates (orange box) and tumour classification according to the WHO 2017 criteria (yellow boxes) are also shown. (B) Involvement of major molecular