Chromothripsis is a novel biomarker for prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms

Abstract

This study aimed to identify the role of chromothripsis as a novel biomarker in the prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms (pNENs). We conducted next-generation gene sequencing in a cohort of 30 patients with high-grade (G3) pNENs. As a reference, a similar analysis was also performed on 25 patients with low-grade (G1/G2) pancreatic neuroendocrine tumors (pNETs). Chromothripsis and its relationship with clinicopathological features and prognosis were investigated. The results showed that DNA damage response and repair gene alteration and TP53 mutation were found in 29 and 11 patients, respectively. A total of 14 out of 55 patients had chromothripsis involving different chromosomes. Chromothripsis had a close relationship with TP53 alteration and higher grade. In the entire cohort, chromothripsis was associated with a higher risk of distant metastasis; both chromothripsis and metastasis (ENETS Stage IV) suggested a significantly shorter overall survival (OS). Importantly, in the high-grade pNENs group, chromothripsis was the only independent prognostic indicator significantly associated with a shorter OS, other than TP53 alteration or pathological pancreatic neuroendocrine carcinomas (pNECs) diagnosis. Chromothripsis can guide worse prognosis in pNENs, and help differentiate pNECs from high-grade (G3) pNETs.

Keywords

chromothripsis / DDR gene / differentiation diagnosis / pancreatic neuroendocrine neoplasms / prognosis / TP53

References

1	JM Guilmette, V Nosé. Neoplasms of the neuroendocrine pancreas: an update in the classification, definition, and molecular genetic advances. Adv Anat Pathol. 2019;26(1):13-30.
2	A Ohmoto, H Rokutan, S Yachida. Pancreatic neuroendocrine neoplasms: basic biology, current treatment strategies and prospects for the future. Int J Mol Sci. 2017;18(1):143.
3	SM Chai, IS Brown, MP Kumarasinghe. Gastroenteropancreatic neuroendocrine neoplasms: selected pathology review and molecular updates. Histopathology. 2018;72(1):153-167.
4	AD Singhi, DS Klimstra. Well-differentiated pancreatic neuroendocrine tumours (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs): concepts, issues and a practical diagnostic approach to high-grade (G3) cases. Histopathology. 2018;72(1):168-177.
5	FT Bosman, F Carneiro, RH Hruban et al,. WHO classification of tumours of the digestive system. International Agency for Research on Cancer (IARC). 4th ed.. 2010.
6	FL Vélayoudom-Céphise, P Duvillard, L Foucan, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer. 2013;20(5):649-657.
7	O Basturk, Z Yang, LH Tang, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39(5):683-690.
8	S Hijioka, W Hosoda, K Matsuo, et al. Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: a Japanese Multicenter Pancreatic NEN-G3 Study. Clin Cancer Res. 2017;23(16):4625-4632.
9	B Konukiewitz, AM Schlitter, M Jesinghaus, et al. Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. Mod Pathol. 2017;30(4):587-598.
10	N Raj, E Valentino, M Capanu, et al. Treatment response and outcomes of Grade 3 pancreatic neuroendocrine neoplasms based on morphology: well differentiated versus poorly differentiated. Pancreas. 2017;46(3):296-301.
11	R Coriat, T Walter, B Terris, et al. Gastroenteropancreatic well-differentiated grade 3 neuroendocrine tumors: review and position statement. Oncologist. 2016;21(10):1191-1199.
12	G Rindi, DS Klimstra, B Abedi-Ardekani, et al. Common classification framework for neuroendocrine tumors: international Cancer Research Agency (IARC) and the World WHO Expert Consensus Proposal. Modern Pathology. 2018;31:1770-1786.
13	ID Nagtegaal, RD Odze, D Klimstra, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182-188.
14	LH Tang, O Basturk, JJ Sue, et al. A practical approach to the classification of WHO grade 3 (G3) well differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192-1202.
15	H Sorbye, S Welin, SW Langer, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24(1):152-160.
16	S Yachida, E Vakiani, CM White, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36(2):173-184.
17	DM Girardi, ACB Silva, JFM Rêgo, et al. Unraveling molecular pathways of poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: a systematic review. Cancer Treat Rev. 2017;56:28-35.
18	B Konukiewitz, M Jesinghaus, K Steiger, et al. Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3. Hum Pathol. 2018;77:70-79.
19	D Hanahan, RA Weinberg. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
20	BV Chakravarthi, S Nepal, S Varambally. Genomic and epigenomic alterations in cancer. Am J Pathol. 2016;186(7):1724-1735.
21	PJ Stephens, CD Greenman, B Fu, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144(1):27-40.
22	A Rode, KK Maass, KV Willmund, et al. Chromothripsis in cancer cells: an update. Int J Cancer. 2016;138(10):2322-2333.
23	JV Forment, A Kaidi, SP Jackson. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer. 2012;12(10):663-670.
24	EM Hatch, AH Fischer, TJ Deerinck, et al. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell. 2013;154(1):47-60.
25	K Crasta, NJ Ganem, R Dagher, et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012;482(7383):53-58.
26	P Ly, DW Cleveland. Rebuilding chromosomes after catastrophe: emerging mechanisms of chromothripsis. Trends Cell Biol. 2017;27(12):917-930.
27	CZ Zhang, ML Leibowitz, D Pellman. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 2013;27(23):2513-2530.
28	K Závacká, K Plevová, M Jaro?ová, et al. Chromothripsis-extensive chromosomal rearrangements and their significance in cancer. Klin Onkol. 2019;32(2):101-108.
29	F Pellestor, V Gatinois. Chromothripsis, a credible chromosomal mechanism in evolutionary process. Chromosoma. 2019;128(1):1-6.
30	F Notta, M Chan-Seng-Yue, M Lemire, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538(7625):378-382.
31	MNH Luijten, JXT Lee, KC Crasta. Mutational game changer: chromothripsis and its emerging relevance to cancer. Mutat Res. 2018;777:29-51.
32	J Smetana, J Oppelt, M ?tork, et al. Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse. Mol Cytogenet. 2018;11:7.
33	DH McDermott, JL Gao, Q Liu, et al. Chromothriptic cure of WHIM syndrome. Cell. 2015;160(4):686-699.
34	A Scarpa, DK Chang, K Nones, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65-71.
35	S Ji, W Yang, J Liu, et al. High throughput gene sequencing reveals altered landscape in DNA damage responses and chromatin remodeling in sporadic pancreatic neuroendocrine tumors. Pancreatology. 2018;18(3):318-327.
36	A Mafficini, A Scarpa. Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium. J Endocrinol. 2018;236(3):R161-R167.
37	M Ratnaparkhe, JKL Wong, PC Wei, et al. Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. Nat Commun. 2018;9(1):4760.
38	L Nazaryan-Petersen, VA Bjerregaard, FC Nielsen, et al. Chromothripsis and DNA repair disorders. J Clin Med. 2020;9(3):613.
39	M Ratnaparkhe, M Hlevnjak, T Kolb, et al. Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis. Leukemia. 2017;31(10):2048-2056.
40	H Mokrani-Benhelli, L Gaillard, P Biasutto, et al. Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations. Hum Mutat. 2013;34(2):374-384.
41	T Rausch, DT Jones, M Zapatka, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 2012;148(1-2):59-71.
42	MC Fontana, G Marconi, JDM Feenstra, et al. Chromothripsis in acute myeloid leukemia: biological features and impact on survival. Leukemia. 2018;32(7):1609-1620.
43	SN Gr?bner, BC Worst, J Weischenfeldt, et al. The landscape of genomic alterations across childhood cancers. Nature. 2018;555(7696):321-327.
44	SL Thompson, DA Compton. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol. 2010;188(3):369-381.
45	MY Teo, K Seier, I Ostrovnaya, et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J Clin Oncol. 2018;36(17):1685-1694.
46	MY Teo, RM Bambury, EC Zabor, et al. DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma. Clin Cancer Res. 2017;23(14):3610-3618.