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Shockley, K.E.; To, B.; Chen, W.; Lozanski, G.; Cruz-Monserrate, Z.; Krishna, S.G. Genetic Alterations in Intraductal Papillary Mucinous Neoplasms. Encyclopedia. Available online: https://encyclopedia.pub/entry/42595 (accessed on 27 July 2024).
Shockley KE, To B, Chen W, Lozanski G, Cruz-Monserrate Z, Krishna SG. Genetic Alterations in Intraductal Papillary Mucinous Neoplasms. Encyclopedia. Available at: https://encyclopedia.pub/entry/42595. Accessed July 27, 2024.
Shockley, Kylie E., Briana To, Wei Chen, Gerard Lozanski, Zobeida Cruz-Monserrate, Somashekar G. Krishna. "Genetic Alterations in Intraductal Papillary Mucinous Neoplasms" Encyclopedia, https://encyclopedia.pub/entry/42595 (accessed July 27, 2024).
Shockley, K.E., To, B., Chen, W., Lozanski, G., Cruz-Monserrate, Z., & Krishna, S.G. (2023, March 28). Genetic Alterations in Intraductal Papillary Mucinous Neoplasms. In Encyclopedia. https://encyclopedia.pub/entry/42595
Shockley, Kylie E., et al. "Genetic Alterations in Intraductal Papillary Mucinous Neoplasms." Encyclopedia. Web. 28 March, 2023.
Genetic Alterations in Intraductal Papillary Mucinous Neoplasms
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15061722

Intraductal papillary mucinous neoplasms (IPMN) are benign pancreatic cysts found in the ducts of the pancreas that have the potential to become malignant. Identifying IPMNs that have high potential to become pancreatic cancer may help prevent unnecessary surgery which is the definitive treatment of IPMNs. Whole exome and targeted sequencing were utilized to better characterize the genetic alterations in IPMNs. The most commonly mutated gene in IPMNs is KRAS with 50–80% of IPMNs harboring a KRAS mutation.

PDAC IPMN pancreatic cyst

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC), currently the third leading cause of cancer-related mortality, is projected to be the second most common cause of death due to malignancies in the United States by 2030 [1]. This poor clinical outcome can be partly attributed to the often vague or absent clinical symptoms associated with pancreatic ductal adenocarcinoma. Thus, many patients with PDAC present with advanced stages of the disease. While early PDAC, which constitutes <15% of all new diagnoses, are surgically resectable and associated with a better outcome, the mainstay treatment of advanced pancreatic cancer is limited to chemotherapy. Despite extensive research, attempts to develop targeted therapies were largely unsuccessful [2]. A better understanding of the development of PDAC may provide insight into the discovery of new diagnostic tools and therapeutics. PDAC commonly arises from precursor lesions including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN). Among the cystic precursors, IPMN is the most prevalent.
These cysts are mucin-producing and arise from the main pancreatic or the branch duct. Main duct lesions (MD-IPMN) has a higher risk of malignancy compared to branch duct (BD-IPMN). There is a third type that shares features of MD-IPMN and BD-IPMN and is referred to as mixed type (MT-IPMN). MT-IPMN and MD-IPMN tend to be more symptomatic. Symptomatic patients tend to progress to malignancy more than those who are asymptomatic, regardless of subtype. While they all arise from cells which produce mucin, four histopathological IPMN types are distinguished by the specific mucin(s) they produce: gastric (49–63%), intestinal (18–36%), pancreaticobiliary (7–18%), and oncocytic (1–8%). Of these, gastric is the most common and rarely progresses to malignancy. While pancreaticobiliary is less common, it is commonly associated with aggressive PDAC [3]. The degree of cytological atypia and crowding of the epithelium allows for classification of the IPMNs into low, intermediate, and high grade dysplasia [4]. In addition to MD-IPMN carrying a larger risk for malignant progression, other high risk features inform malignant potential including the size of the lesion, rate of growth of the lesion, presence of solid components within the lesion, the presence of high grade dysplasia, main duct dilation on imaging, and the presence of symptoms including jaundice, new onset diabetes, or pancreatitis [3].
The primary management of IPMN is the surgical resection of high-risk lesions that can progress to malignant disease [5]. Risk stratification of these cystic lesions is largely based on imaging and clinical characteristics of the cyst including size, location, and grade of dysplasia [5]. The exact molecular mechanisms driving IPMN progression to PDAC are unclear; however, genetic, metabolic, immune, and inflammatory changes appear to play a role in this process.

2. Genetic Alterations

Whole exome and targeted sequencing were utilized to better characterize the genetic alterations in IPMNs. The most commonly mutated gene in IPMNs is KRAS with 50–80% of IPMNs harboring a KRAS mutation [6][7]. The most common location of the KRAS mutation is in codon 12, resulting in a G12D mutation. This KRAS mutation encodes a constitutively active GTP-binding protein that regulates various signaling cascades including cell growth and proliferation. Furthermore, KRAS mutations are found in >90% of PDACs and, hence, are thought to be essential and an early event for tumorigenesis [8]. Mutation in the GNAS gene is another common alteration in IPMNs and was identified in 40–70% of lesions [9]. GNAS encodes the stimulatory alpha subunit of the guanine nucleotide-binding protein which activates cyclic adenosine monophosphate (cAMP), leading to the activation of multiple effectors including protein kinase A and EPAC (Exchange Protein directly activated by cAMP). Although the relevance of these pathways in pancreatic cancer was not fully established, these pathways were implicated in other cancer types [10][11]. The GNAS mutation is predominantly located at codon 201, commonly leading to R201H or R201C alterations [9]. This is thought to be an activating mutation that results in the constitutive activation of GNAS. In contrast to KRAS, GNAS mutations are not commonly observed in non-IPMN PDACs but were found in 25–61% of IPMN- derived PDACs [7][12][13].
KRAS and/or GNAS mutations are found in >90% of IPMNs, both in those with advanced neoplasia (high-grade dysplasia or adenocarcinoma) and low-grade dysplasia [7]. The prevalence of their alteration suggests that they play an important role in IPMN development. These mutations were found to coexist, suggesting that they are not mutually exclusive. Interestingly, transgenic mouse models of IPMNs required synergistic mutation between GNAS and KRAS to generate cystic lesions that are histologically similar to human IPMNs [9][14]. Although there are no significant differences in KRAS and GNAS alterations in IPMNs with and without advanced neoplasia, a difference in mutation frequency were observed when analyzing the histological subtypes [7].
IPMNs can be divided into histological subtypes including gastric, intestinal, and pancreatobiliary. The oncocytic subtype is now considered a separate entity, i.e., “Intraductal Oncocytic Papillary Neoplasm”, by WHO’s classification of tumors, due to its different molecular and clinical features. These subtypes can give rise to different types of invasive carcinoma [15]. In general, intestinal IPMN gives rise to colloid carcinoma while tubular carcinoma can arise from gastric or pancreatobiliary subtype. Interestingly, there is a higher frequency of GNAS mutation in IPMN-associated colloid carcinoma and KRAS mutations in IPMN-associated tubular carcinoma [7]. This difference in mutational frequency may be clinically relevant, given that tubular adenocarcinoma is associated with worst clinical outcomes, and thus, it may offer prognostic value.
Inactivating mutation in the RNF43 gene is another common genetic alteration found in IPMNs, occurring in 10–75% of cystic lesions [7]. RNF43 encodes a transmembrane E3 ubiquitin ligase that negatively regulates the Wnt pathway. Thus, the loss of function of RNF43 confers Wnt pathway activation, which was shown to play a potential role in mediating PDAC progression [16][17]. Other loss of function mutations found in IPMNs include TP53, CDKN2A, and SMAD4. These genetic alterations occur at a lower rate in IPMNs with low-grade dysplasia compared to those with advanced neoplasia, suggesting that these genes may play a role in mediating progression to malignancy [7]. Furthermore, these genetic alterations are also commonly detected in invasive pancreatic cancer.
More recently, Noe et al. performed whole exome sequencing (WES) of IPMNs and MCNs and their associated invasive carcinomas to better understand the genetic alteration driving tumorigenesis in these cystic precursors [18]. WES analysis revealed the high prevalence of previously identified drivers of pancreatic tumorigenesis including KRAS, GNAS, RNF43, CDKN2A, TP53, and SMAD4. In addition, the use of WES revealed novel mutations in IPMN tumorigenesis. Somatic mutations in the ATM gene were found in 17% of lesions. ATM encodes a serine/threonine kinase that is involved in DNA double-strand break repair as well as other cellular processes including metabolism and chromatin remodeling. Moreover, individuals with germline pathogenic ATM variants appear to have an increased lifetime risk of pancreatic cancer [19][20]. In addition, loss of ATM expression in a mouse model of PDAC resulted in a greater number of proliferative precursor lesions [21]. Somatic mutation in GLI3 gene was also observed in 8% of samples. GLI3 gene encodes a transcription factor that is a member of the Hedgehog signaling pathway and is involved in normal cellular processes including tissue and immune cell development. Furthermore, studies implicated GLI3 in mediating pro-tumorigenesis pathways in various cancers, including pancreatic cancer [22][23][24].

References

  1. Rahib, L.; Wehner, M.R.; Matrisian, L.M.; Nead, K.T. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw. Open 2021, 4, e214708.
  2. Tempero, M.A.; Malafa, M.P.; Al-Hawary, M.; Behrman, S.W.; Benson, A.B.; Cardin, D.B.; Chiorean, E.G.; Chung, V.; Czito, B.; Chiaro, M.D.; et al. Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2021, 19, 439–457.
  3. Jabłońska, B.; Szmigiel, P.; Mrowiec, S. Pancreatic intraductal papillary mucinous neoplasms: Current diagnosis and management. World J. Gastrointest. Oncol. 2021, 13, 1880–1895.
  4. Venkatesh, P.G.K.; Navaneethan, U.; Vege, S.S. Intraductal papillary mucinous neoplasm and acute pancreatitis. J. Clin. Gastroenterol. 2011, 45, 755–758.
  5. Tanaka, M.; Fernández-del Castillo, C.; Kamisawa, T.; Jang, J.Y.; Levy, P.; Ohtsuka, T.; Salvia, R.; Shimizu, Y.; Tada, M.; Wolfgang, C.L. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology 2017, 17, 738–753.
  6. Amato, E.; Dal Molin, M.; Mafficini, A.; Yu, J.; Malleo, G.; Rusev, B.; Fassan, M.; Antonello, D.; Sadakari, Y.; Castelli, P.; et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J. Pathol. J Pathol 2014, 233, 217–227.
  7. Tan, M.C.; Basturk, O.; Brannon, A.R.; Bhanot, U.; Scott, S.N.; Bouvier, N.; Lafemina, J.; Jarnagin, W.R.; Berger, M.F.; Klimstra, D.; et al. GNAS and KRAS mutations define separate progression pathways in intraductal papillary mucinous neoplasm-associated carcinoma. J. Am. Coll. Surg. 2015, 220, 845–854.e1.
  8. Biankin, A.V.; Waddell, N.; Kassahn, K.S.; Gingras, M.C.; Muthuswamy, L.B.; Johns, A.L.; Miller, D.K.; Wilson, P.J.; Patch, A.M.; Wu, J.; et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012, 491, 399–405.
  9. Taki, K.; Ohmuraya, M.; Tanji, E.; Komatsu, H.; Hashimoto, D.; Semba, K.; Araki, K.; Kawaguchi, Y.; Baba, H.; Furukawa, T. GNASR201H and KrasG12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm. Oncogene 2016, 35, 2407–2412.
  10. Grandoch, M.; Rose, A.; ter Braak, M.; Jendrossek, V.; Rübben, H.; Fischer, J.; Schmidt, M.; Weber, A. Epac inhibits migration and proliferation of human prostate carcinoma cells. Br. J. Cancer 2009, 101, 2038–2042.
  11. James, M.A.; Lu, Y.; Liu, Y.; Vikis, H.G.; You, M. RGS17, an Overexpressed Gene in Human Lung and Prostate Cancer, Induces Tumor Cell Proliferation Through the Cyclic AMP-PKA-CREB Pathway. Cancer Res 2009, 69, 2108–2124.
  12. Ideno, N.; Ohtsuka, T.; Matsunaga, T.; Kimura, H.; Watanabe, Y.; Tamura, K.; Aso, T.; Aishima, S.; Miyasaka, Y.; Ohuchida, K.; et al. Clinical significance of GNAS mutation in intraductal papillary mucinous neoplasm of the pancreas with concomitant pancreatic ductal adenocarcinoma. Pancreas 2015, 44, 311–320.
  13. Ohtsuka, T.; Tomosugi, T.; Kimura, R.; Nakamura, S.; Miyasaka, Y.; Nakata, K.; Mori, Y.; Morita, M.; Torata, N.; Shindo, K.; et al. Clinical assessment of the GNAS mutation status in patients with intraductal papillary mucinous neoplasm of the pancreas. Surg. Today 2019, 49, 887–893.
  14. Ideno, N.; Yamaguchi, H.; Ghosh, B.; Gupta, S.; Okumura, T.; Steffen, D.J.; Fisher, C.G.; Wood, L.D.; Singhi, A.D.; Nakamura, M.; et al. GNASR201C Induces Pancreatic Cystic Neoplasms in Mice That Express Activated KRAS by Inhibiting YAP1 Signaling. Gastroenterology 2018, 155, 1593–1607.e12.
  15. Adsay, V.; Mino-Kenudson, M.; Furukawa, T.; Basturk, O.; Zamboni, G.; Marchegiani, G.; Bassi, C.; Salvia, R.; Malleo, G.; Paiella, S.; et al. Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: Recommendations of verona consensus meeting. Ann. Surg. 2016, 263, 162–177.
  16. Jiang, X.; Hao, H.X.; Growney, J.D.; Woolfenden, S.; Bottiglio, C.; Ng, N.; Lu, B.; Hsieh, M.H.; Bagdasarian, L.; Meyer, R.; et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl. Acad. Sci. USA 2013, 110, 12649–12654.
  17. Wu, J.; Jiao, Y.; Dal Molin, M.; Maitra, A.; De Wilde, R.F.; Wood, L.D.; Eshleman, J.R.; Goggins, M.G.; Wolfgang, C.L.; Canto, M.I.; et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc. Natl. Acad. Sci. USA 2011, 108, 21188–21193.
  18. Noë, M.; Niknafs, N.; Fischer, C.G.; Hackeng, W.M.; Beleva Guthrie, V.; Hosoda, W.; Debeljak, M.; Papp, E.; Adleff, V.; White, J.R.; et al. Genomic characterization of malignant progression in neoplastic pancreatic cysts. Nat. Commun. 2020, 11, 4085.
  19. Roberts, N.J.; Jiao, Y.; Yu, J.; Kopelovich, L.; Petersen, G.M.; Bondy, M.L.; Gallinger, S.; Schwartz, A.G.; Syngal, S.; Cote, M.L.; et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012, 2, 41–46.
  20. Hsu, F.C.; Roberts, N.J.; Childs, E.; Porter, N.; Rabe, K.G.; Borgida, A.; Ukaegbu, C.; Goggins, M.G.; Hruban, R.H.; Zogopoulos, G.; et al. Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene. JAMA Oncol. 2021, 7, 1664–1668.
  21. Russell, R.; Perkhofer, L.; Liebau, S.; Lin, Q.; Lechel, A.; Feld, F.M.; Hessmann, E.; Gaedcke, J.; Güthle, M.; Zenke, M.; et al. Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition. Nat. Commun. 2015, 6, 7677.
  22. Steg, A.; Amm, H.M.; Novak, Z.; Frost, A.R.; Johnson, M.R. Gli3 mediates cell survival and sensitivity to cyclopamine in pancreatic cancer. Cancer Biol. Ther. 2010, 10, 893–902.
  23. Lin, M.; Zhu, H.; Shen, Q.; Sun, L.Z.; Zhu, X. GLI3 and androgen receptor are mutually dependent for their malignancy-promoting activity in ovarian and breast cancer cells. Cell. Signal. 2022, 92, 110278.
  24. Matissek, S.J.; Elsawa, S.F. GLI3: A mediator of genetic diseases, development and cancer. Cell Commun. Signal. 2020, 18, 54.
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Subjects: Gastroenterology & Hepatology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Kylie E. Shockley
,
Briana To
,
Wei Chen
,
Gerard Lozanski
,
Zobeida Cruz-Monserrate
,
Somashekar G. Krishna
View Times: 398
Revisions: 2 times (View History)
Update Date: 31 Mar 2023
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