# Molecular biology of pituitary neuroendocrine tumors

**Authors:** Reilly L. Kidwell, James Trippett, Manish K. Aghi

PMC · DOI: 10.1007/s11060-026-05447-0 · 2026-02-04

## TL;DR

This paper reviews the molecular biology of pituitary neuroendocrine tumors to improve diagnosis and treatment through better classification methods.

## Contribution

The paper highlights the integration of molecular data with clinical information for more accurate prediction of tumor behavior.

## Key findings

- Molecular classification of PitNETs includes genomic, transcriptomic, and epigenetic profiling.
- Tumor behavior is influenced by somatic mutations, germline genes, and signaling pathways.
- Combining molecular and clinical data improves diagnostic accuracy and treatment decisions.

## Abstract

Pituitary neuroendocrine tumors (PitNETs) represent a heterogeneous group of intracranial neoplasms arising from the anterior pituitary gland. While most tumors are benign, certain subsets can display aggressive behavior marked by invasiveness, treatment resistance, and familial clustering. The current World Health Organization (WHO) classification emphasizes the role of lineage-specific transcription factors in better identifying cell types. However, this methodology is not sufficient to ensure fully accurate prediction of tumor behavior; therefore, new, more in-depth methods are required to improve diagnostic reliability and treatment decision-making.

A narrative review was carried out to evaluate the literature on PitNET classification schemas and their molecular signatures. Attention was placed on classification research and developments that impact current clinical management.

Evidence indicates improvement in the molecular classification of PitNETs, not just from lineage-specific transcription factors, but also from advances in genomic, transcriptomic, and epigenetic profiling. These newer techniques have revealed that PitNETs are driven by a complex interplay of alterations, including somatic mutations, germline predisposition genes, copy number variations, and poorly regulated signaling pathways. Each of these general findings plays a role in influencing tumor behavior, controlling lineage differentiation, and determining response to therapy. These findings indicate the need for integrating molecular characteristics with clinical data to improve risk stratification and guide personalized treatment.

Clinical data combined with molecular classification systems is redefining our understanding of PitNET behavior and improving clinical decision-making by increasing our diagnostic accuracy and advancing our knowledge of individualized patient tumor biology. Continued research and development of comprehensive predictive approaches are necessary to achieve reliable outcome prediction and improve therapeutic decision-making for all patients.

## Full-text entities

- **Genes:** CHGA (chromogranin A) [NCBI Gene 1113] {aka CGA, PHE5, PHES}, PTTG1 (PTTG1 regulator of sister chromatid separation, securin) [NCBI Gene 9232] {aka EAP1, ECRAR, HPTTG, PTTG, TUTR1}, PRL (prolactin) [NCBI Gene 5617] {aka GHA1, pPRL}, Aatf (apoptosis antagonizing transcription factor) [NCBI Gene 56321] {aka 4933415H02Rik, 5830465M17Rik, Che-1, Trb}, F3 (coagulation factor III, tissue factor) [NCBI Gene 2152] {aka CD142, TF, TFA}, Egfr (epidermal growth factor receptor) [NCBI Gene 13649] {aka 9030024J15Rik, Erbb, Errb1, Errp, Wa5, wa-2}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], SST (somatostatin) [NCBI Gene 6750] {aka SMST, SST1}, LGALS3 (galectin 3) [NCBI Gene 3958] {aka CBP35, GAL3, GALBP, GALIG, L31, LGALS2}, PRDM9 (PR/SET domain 9) [NCBI Gene 56979] {aka KMT8B, MEISETZ, MSBP3, PFM6, ZNF899}, Mir183 (microRNA 183) [NCBI Gene 387178] {aka Mirn183, mir-183, mmu-mir-183}, SOX2 (SRY-box transcription factor 2) [NCBI Gene 6657] {aka ANOP3, MCOPS3}, ENO2 (enolase 2) [NCBI Gene 2026] {aka HEL-S-279, NSE}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, POU1F1 (POU class 1 homeobox 1) [NCBI Gene 5449] {aka CPHD1, GHF-1, PIT1, POU1F1a, Pit-1}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, SUFU (SUFU negative regulator of hedgehog signaling) [NCBI Gene 51684] {aka BCNS2, JBTS32, PRO1280, SUFUH, SUFUXL}, Prl (prolactin) [NCBI Gene 19109] {aka Gha1, Prl1a1}, INSM1 (INSM transcriptional repressor 1) [NCBI Gene 3642] {aka IA-1, IA1}, ESR1 (estrogen receptor 1) [NCBI Gene 2099] {aka ER, ESR, ESRA, ESTRR, Era, NR3A1}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, MEN1 (menin 1) [NCBI Gene 4221] {aka MEAI, SCG2}, DLG1 (discs large MAGUK scaffold protein 1) [NCBI Gene 1739] {aka DLGH1, SAP-97, SAP97, hdlg}, SHH (sonic hedgehog signaling molecule) [NCBI Gene 6469] {aka HHG1, HLP3, HPE3, MCOPCB5, SMMCI, ShhNC}, Mir137 (microRNA 137) [NCBI Gene 387155] {aka Mirn137, mir-137, mmu-mir-137}, ATRX (ATRX chromatin remodeler) [NCBI Gene 546] {aka JMS, MRX52, RAD54, RAD54L, XH2, XNP}, NTRK1 (neurotrophic receptor tyrosine kinase 1) [NCBI Gene 4914] {aka MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, HMGA1 (high mobility group AT-hook 1) [NCBI Gene 3159] {aka HMG-R, HMGA1A, HMGIY}, PAX8 (paired box 8) [NCBI Gene 7849] {aka PAX-8}, TEAD4 (TEA domain transcription factor 4) [NCBI Gene 7004] {aka EFTR-2, RTEF1, TCF13L1, TEF-3, TEF3, TEFR-1}, LATS2 (large tumor suppressor kinase 2) [NCBI Gene 26524] {aka KPM}, CDH23 (cadherin related 23) [NCBI Gene 64072] {aka CDHR23, PITA5, USH1D}, Cdk4 (cyclin dependent kinase 4) [NCBI Gene 12567] {aka Crk3}, SSR2 (signal sequence receptor subunit 2) [NCBI Gene 6746] {aka HSD25, TLAP, TRAP-BETA, TRAPB}, LHX4 (LIM homeobox 4) [NCBI Gene 89884] {aka CPHD4}, POMC (proopiomelanocortin) [NCBI Gene 5443] {aka ACTH, CLIP, LPH, MSH, NPP, OBAIRH}, PCSK1 (proprotein convertase subtilisin/kexin type 1) [NCBI Gene 5122] {aka BMIQ12, NEC1, PC1, PC1/3, PC3, SPC3}, PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) [NCBI Gene 5573] {aka ACRDYS1, ADOHR, CAR, CNC, CNC1, PKR1}, SYP (synaptophysin) [NCBI Gene 6855] {aka MRX96, MRXSYP, XLID96}, DPPA4 (developmental pluripotency associated 4) [NCBI Gene 55211] {aka 2410091M23Rik}, USP48 (ubiquitin specific peptidase 48) [NCBI Gene 84196] {aka DFNA85, RAP1GA1, USP31}, MSH2 (mutS homolog 2) [NCBI Gene 4436] {aka COCA1, FCC1, HNPCC, HNPCC1, LCFS2, LYNCH1}, SMO (smoothened, frizzled class receptor) [NCBI Gene 6608] {aka CRJS, FZD11, Gx, PHLS, SMOH}, MSH6 (mutS homolog 6) [NCBI Gene 2956] {aka GTBP, GTMBP, HNPCC5, HSAP, LYNCH5, MMRCS3}, Gata2 (GATA binding protein 2) [NCBI Gene 14461] {aka Gata-2}, LHX3 (LIM homeobox 3) [NCBI Gene 8022] {aka CPHD3, LIM3, M2-LHX3}, TAFAZZIN (tafazzin, phospholipid-lysophospholipid transacylase) [NCBI Gene 6901] {aka BTHS, CMD3A, EFE, EFE2, G4.5, LVNCX}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, ASXL1 (ASXL transcriptional regulator 1) [NCBI Gene 171023] {aka BOPS, MDS}, GHRH (growth hormone releasing hormone) [NCBI Gene 2691] {aka GHRF, GRF, INN}, BMP4 (bone morphogenetic protein 4) [NCBI Gene 652] {aka BMP2B, BMP2B1, MCOPS6, OFC11, ZYME}, NGF (nerve growth factor) [NCBI Gene 4803] {aka Beta-NGF, HSAN5, NGFB}, SSR1 (signal sequence receptor subunit 1) [NCBI Gene 6745] {aka TRAPA}, GLI3 (GLI family zinc finger 3) [NCBI Gene 2737] {aka ACLS, GCPS, GLI3-190, GLI3FL, PAP-A, PAPA}, PITX1 (paired like homeodomain 1) [NCBI Gene 5307] {aka BFT, CCF, POTX, PTX1}, Cdkn1a (cyclin dependent kinase inhibitor 1A) [NCBI Gene 12575] {aka CAP20, CDKI, CIP1, Cdkn1, P21, SDI1}, SF1 (splicing factor 1) [NCBI Gene 7536] {aka BBP, D11S636, MBBP, ZCCHC25, ZFM1, ZNF162}, Tas2r103 (taste receptor, type 2, member 103) [NCBI Gene 667992] {aka EG667992, T2R3, TRB2, Tas2r10, Tas2r3, mGR03}, Cdkn1b (cyclin dependent kinase inhibitor 1B) [NCBI Gene 12576] {aka Kip1, p27, p27Kip1}
- **Diseases:** tumorigenesis (MESH:D063646), McCune Albright syndrome (MESH:D005359), FIPA (MESH:C566321), ACTH secreting tumors (MESH:D049913), gland (MESH:D000307), adrenal tumors (MESH:D000310), Multiple Endocrine Neoplasia type 1 (MESH:D018761), cafe-au-lait spots (MESH:D019080), endocrine tumors (MESH:D004701), pituitary lesions (MESH:D010900), non-syndromic pituitary gigantism (MESH:D005877), genetic disorder (MESH:D030342), fibrous dysplasia (MESH:D005357), CNC (MESH:D056733), adenomas (MESH:D000236), NETs (MESH:D018358), MEN4 (MESH:C567059), tumorigenic (MESH:D002471), Somatotroph (MESH:D049912), TSH-secreting tumors (MESH:D006964), Tumors (MESH:D009369), X-linked acrogigantism (MESH:C536424), non-small cell lung cancer (MESH:D002289), Brain Tumor (MESH:D001932), null (MESH:C564833), Lactotroph tumors (MESH:D015175), pituitary and extra-pituitary neuroendocrine tumors (MESH:D010911), acromegaly (MESH:D000172), Cushing's Disease (MESH:D047748), Null cell tumors (MESH:D005935), thyroid tumors (MESH:D013964), secretory tumors (MESH:D008579)
- **Chemicals:** 68Ga-DOTATATE (MESH:C513399), Osimertinib (MESH:C000596361), Gefitinib (MESH:D000077156), ipilimumab (MESH:D000074324), oligonucleotide (MESH:D009841), steroid hormones (MESH:D013256), Lapatinib (MESH:D000077341), temozolomide (MESH:D000077204), amines (MESH:D000588), R-roscovitine (MESH:D000077546), T3 (MESH:D014284), T4 (MESH:D013974), dopaminergic (MESH:D004298), GHR-LRx (-), cortisol (MESH:D006854), octreotide (MESH:D015282), nivolumab (MESH:D000077594)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090]
- **Mutations:** P453T, serine/threonine, R625H, R24C

## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12872688/full.md

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Source: https://tomesphere.com/paper/PMC12872688