Longitudinal multiomics analysis of aggressive pituitary neuroendocrine tumors: comparing primary and recurrent tumors from the same patient, reveals genomic stability and heterogeneous transcriptomic profiles with alterations in metabolic pathways.

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Pituitary Neoplasms*/genetics ; Pituitary Neoplasms*/pathology ; Pituitary Neoplasms*/metabolism ; Neuroendocrine Tumors*/genetics ; Neuroendocrine Tumors*/pathology ; Neuroendocrine Tumors*/metabolism ; Neoplasm Recurrence, Local*/genetics ; Neoplasm Recurrence, Local*/pathology ; Transcriptome*; Humans ; Metabolic Networks and Pathways/genetics ; Genomic Instability ; Male ; Female ; DNA Methylation ; Middle Aged ; Multiomics

Pituitary neuroendocrine tumors (PitNET) represent the vast majority of sellar masses. Some behave aggressively, growing rapidly and invading surrounding tissues, with high rates of recurrence and resistance to therapy. Our aim was to establish patterns of genomic, transcriptomic and methylomic evolution throughout time in primary and recurrent tumors from the same patient. Therefore, we performed transcriptome- and exome-sequencing and methylome microarrays of aggressive, primary, and recurrent PitNET from the same patient. Primary and recurrent tumors showed a similar exome profile, potentially indicating a stable genome over time. In contrast, the transcriptome of primary and recurrent PitNET was dissimilar. Gonadotroph, silent corticotroph, as well as metastatic corticotroph and a somatotroph PitNET expressed genes related to fatty acid biosynthesis and metabolism, phosphatidylinositol signaling, glycerophospholipid and phospholipase D signaling, respectively. Diacylglycerol kinase gamma (DGKG), a key enzyme in glycerophospholipid metabolism and phosphatidylinositol signaling pathways, was differentially expressed between primary and recurrent PitNET. These alterations did not seem to be regulated by DNA methylation, but rather by several transcription factors. Molecular docking showed that dasatinib, a small molecule tyrosine kinase inhibitor used in the treatment of chronic lymphocytic and acute lymphoblastic leukemia, could target DGKG. Dasatinib induced apoptosis and decreased proliferation in GH3 cells. Our data indicate that pituitary tumorigenesis could be driven by transcriptomically heterogeneous clones, and we describe alternative pharmacological therapies for aggressive and recurrent PitNET.
(© 2024. The Author(s).)

Clin Cancer Res. 2005 Oct 1;11(19 Pt 1):6924-32. (PMID: 16203784)
BMC Cancer. 2013 May 30;13:267. (PMID: 23721490)
Drug Des Devel Ther. 2017 Feb 21;11:469-481. (PMID: 28260860)
J Ovarian Res. 2022 Aug 13;15(1):93. (PMID: 35964092)
Nat Rev Endocrinol. 2021 Nov;17(11):671-684. (PMID: 34493834)
Lipids Health Dis. 2020 May 28;19(1):113. (PMID: 32466765)
Cell Rep Med. 2022 Nov 15;3(11):100802. (PMID: 36334593)
J Biol Chem. 2016 Nov 18;291(47):24538-24550. (PMID: 27694442)
Front Endocrinol (Lausanne). 2018 Aug 27;9:453. (PMID: 30210447)
Trends Endocrinol Metab. 2016 Mar;27(3):119-122. (PMID: 26803729)
Nat Rev Endocrinol. 2011 May;7(5):257-66. (PMID: 21423242)
Sci Rep. 2020 Nov 9;10(1):19373. (PMID: 33168897)
Nat Rev Cancer. 2007 Nov;7(11):834-46. (PMID: 17957189)
J Clin Endocrinol Metab. 2015 Sep;100(9):E1242-54. (PMID: 26186299)
Nat Commun. 2020 Jul 30;11(1):3811. (PMID: 32732914)
Genome Med. 2021 Dec 16;13(1):189. (PMID: 34915921)
Trends Genet. 2021 Nov;37(11):1012-1027. (PMID: 34120771)
Gene. 2020 Jun 15;743:144604. (PMID: 32213297)
BMC Med Genomics. 2010 Apr 28;3:13. (PMID: 20426862)
Genet Test Mol Biomarkers. 2015 Jul;19(7):394-8. (PMID: 25938168)
Cancers (Basel). 2021 Oct 16;13(20):. (PMID: 34680338)
Front Oncol. 2021 Jan 14;10:583053. (PMID: 33520699)
J Clin Endocrinol Metab. 2021 Mar 25;106(4):1183-1194. (PMID: 33106857)
Oncogene. 2020 Oct;39(43):6633-6646. (PMID: 32943730)
BMC Med. 2009 Nov 05;7:68. (PMID: 19891767)
Oncogenesis. 2022 Aug 9;11(1):46. (PMID: 35945203)
N Engl J Med. 2020 Mar 5;382(10):937-950. (PMID: 32130815)
Cancers (Basel). 2022 Sep 21;14(19):. (PMID: 36230492)
Nutr J. 2014 Feb 14;13:17. (PMID: 24524207)
Front Med (Lausanne). 2020 Nov 30;7:612393. (PMID: 33330574)
Oncol Lett. 2019 May;17(5):4474-4486. (PMID: 30988816)
Cell Rep Med. 2023 Feb 21;4(2):100934. (PMID: 36754052)
Mol Ther Nucleic Acids. 2021 May 01;24:1033-1050. (PMID: 34141458)
Front Oncol. 2021 Dec 16;11:608748. (PMID: 34976781)
Mol Carcinog. 2017 Jul;56(7):1743-1752. (PMID: 28218473)
Brain Tumor Pathol. 2018 Apr;35(2):57-61. (PMID: 29318396)
PLoS One. 2014 Apr 11;9(4):e94554. (PMID: 24728327)
JAMA. 2017 Feb 07;317(5):516-524. (PMID: 28170483)
BMC Med Genomics. 2022 Mar 8;15(1):52. (PMID: 35260162)
Clin Cancer Res. 2015 Nov 15;21(22):5008-12. (PMID: 26420856)
Biomed Pharmacother. 2020 Jul;127:110069. (PMID: 32294597)
Nat Commun. 2019 Mar 22;10(1):1326. (PMID: 30902980)
Clin Cancer Res. 2022 Mar 01;28(5):1038-1052. (PMID: 34965946)
Nat Rev Cancer. 2019 Nov;19(11):611-624. (PMID: 31511663)
Front Immunol. 2013 Jul 04;4:178. (PMID: 23847619)
Cancer Res. 2017 Aug 1;77(15):3965-3981. (PMID: 28701486)
Front Endocrinol (Lausanne). 2021 Feb 26;12:624112. (PMID: 33716977)
Am J Transl Res. 2020 Jun 15;12(6):2538-2553. (PMID: 32655789)
Exp Mol Med. 2021 Jan;53(1):8-18. (PMID: 33462379)
Curr Opin Biotechnol. 2015 Feb;31:122-9. (PMID: 25123841)
Cancer Gene Ther. 2022 Dec;29(12):1866-1877. (PMID: 35788171)
PLoS One. 2016 Dec 28;11(12):e0168984. (PMID: 28030620)
Nat Commun. 2021 Jul 16;12(1):4362. (PMID: 34272396)
J Immunother Cancer. 2022 Jul;10(7):. (PMID: 35858708)
Front Endocrinol (Lausanne). 2021 Sep 30;12:748997. (PMID: 34659129)
J Neuroendocrinol. 2022 Aug;34(8):e13169. (PMID: 35979732)
Int J Mol Sci. 2022 Apr 27;23(9):. (PMID: 35563252)
Biol Direct. 2016 Aug 23;11:43. (PMID: 27550042)
J Clin Invest. 2017 Jun 1;127(6):2091-2105. (PMID: 28504653)
Gastroenterology. 2019 Dec;157(6):1630-1645.e6. (PMID: 31560893)
Br J Cancer. 2009 Nov 17;101(10):1699-708. (PMID: 19861960)
Eur J Endocrinol. 2010 Aug;163(2):193-200. (PMID: 20460423)
Br J Haematol. 2011 Apr;153(2):199-211. (PMID: 21352196)
J Clin Invest. 2003 May;111(9):1381-8. (PMID: 12727930)

R-2019-785-052 Fundación IMSS

Keywords: Aggressive; Exome; PitNET; Recurrent; Same patient; Transcriptome

Date Created: 20240831 Date Completed: 20240831 Latest Revision: 20240903

20240903

PMC11365143

10.1186/s40478-024-01796-x

39217365