PIK3R1

Overview

PIK3R1 encodes the p85-alpha regulatory subunit of PI3K; loss-of-function alterations activate PI3K signaling.

Alterations observed in the corpus

  • Frequent mutations (10%) discovered in GBM, mostly in the iSH2 domain (e.g., N564, D560), which disrupt interaction with p110α and lead to RTK/RAS/PI3K pathway activation PMID:18772890.
  • PIK3R1 mutations (with PIK3CA and TP53, plus broad CNV load) were used to define “molecular grade-intermediate” in 1p19q codeleted IDH-mutant oligodendrogliomas in a 128-patient MSKCC active-surveillance cohort PMID:37910594.
  • PIK3R1 mutations less common in Black endometrial carcinoma patients compared to White patients (13% vs. 28%), consistent with the lower frequency of PI3K pathway endometrioid-type alterations in the Black EC population; lower PIK3R1 frequency may reduce eligibility for PI3K/AKT/mTOR pathway-targeted trials PMID:37651310.
  • Recurrently mutated in prostate cancer identified in integrative genomic profiling of 218 tumors PMID:20579941
  • PIK3R1 somatic mutations identified in prostate cancer by WES of 112 primary tumors (Broad Institute cohort), implicating PI3K pathway dysregulation PMID:22610119
  • Mutations in 2% of non-hypermutated colorectal tumors; mutually exclusive with PIK3CA and PTEN loss in 276-tumor TCGA CRC cohort PMID:22810696
  • Identified as a novel significantly mutated gene (SMG) in TCGA breast cancer (510 tumors, brca_tcga_pub); statistically significant mutual exclusivity with PIK3CA, PTEN, and AKT1 mutations (P=0.025) across all breast cancer subtypes PMID:23000897
  • Mutated in 5/145 EAC tumors as part of PI3K-pathway alterations alongside PIK3CA and PTEN PMID:23525077
  • Co-deleted with PTEN in one chromoplexy chain in prostate cancer; represents PI3K-pathway disruption via structural rearrangement rather than point mutation PMID:23622249
  • Mutated in 65% of POLE-ultramutated endometrial tumors; mutually exclusive with PIK3CA across all endometrial subgroups PMID:23636398
  • PI3K p85α regulatory subunit altered as part of the PI3K-family mutation cluster in 18.3% of GBM (PIK3CA/PIK3R1 combined) PMID:24120142
  • Variants of uncertain significance identified in BRAF-inhibitor-resistant melanoma tumors; larger cohort validation and functional experiments needed to clarify contribution to resistance PMID:24265153
  • PIK3R1 PI3K pathway loss observed in gastric cancer (EGC); PTEN focally deleted in CIN subtype PMID:25079317
  • Private PI3K-pathway event of unknown significance in paired primary/metastasis CRC cohort; detected in spatially separate tumor regions indicating subclonality PMID:25164765
  • Expressed mutation seen in CRPC; MSK-PCa2 PIK3R1 mutation co-occurs with PTEN loss and is associated with PI3K-inhibitor sensitivity in patient-derived prostate cancer organoids PMID:25201530
  • In-frame indels and frameshift mutations in 3/22 (14%) uterine/ovarian carcinosarcoma cases; mutually exclusive with PIK3CA; first implication of PIK3R1 in carcinosarcoma PMID:25233892
  • Mutated in 1% of HNSCC; one of multiple genes with at least one identical COSMIC-reported mutation; component of PI(3)K pathway altered in 61–62% of tumours PMID:25631445
  • PIK3R1 mutated as part of the PI3K/AKT/mTOR pathway, disrupted in 39% ATC vs 11% PDTC (P=1×10⁻³) in a targeted-sequencing study of advanced thyroid cancers. PMID:26878173
  • Identified as a Mut-driver in the METABRIC 2,433-tumor breast cancer cohort (Akt-signaling pathway TSG); mutually exclusive with PIK3CA mutations (OR=0.092), reflecting Akt-pathway redundancy. Part of the Akt-pathway driver cluster in which 45.2% of all tumors carried ≥1 functional mutation. PMID:27161491
  • PIK3R1 mutation identified in 1 ACYC patient enrolled on a PI3K-inhibitor trial based on MSK-IMPACT sequencing PMID:27442865.
  • PI3K-pathway alteration enriched in ESCC2 subtype; part of a 24% PI3K-activating-alteration frequency in ESCCs (alongside PIK3CA and PTEN) in a multi-platform GEA genomic study PMID:28052061
  • Recurrent low-VAF oncogenic mutations in endometrial polyps (WGS, 23 polyps); co-occurs with PIK3CA, PTEN, ERBB2, PPP2R1A, and FBXW7 mutations, phenocopying the canonical endometrial cancer driver landscape PMID:28445112
  • G376R hotspot mutation in 1/19 (5%) of 1p/19q-codeleted anaplastic oligodendroglioma; unknown therapeutic implication PMID:28472509
  • Mutated in 15.9% of clear-cell endometrial carcinoma (CCEC; n=63); part of the 34.9% of CCECs with PI3K-pathway alterations (PIK3CA/PIK3R1/PTEN) PMID:28485815
  • PIK3CA and PIK3R1 alterations are predominantly known activating hotspots in advanced prostate cancer; one patient acquired a PIK3CA E545K hotspot ~3 years post-prostatectomy, illustrating late-emergent actionable events PMID:28825054
  • PIK3R1 identified as a driver-gene cluster member across signaling and cell growth functional groups in a 1001-patient DLBCL genomic cohort PMID:28985567
  • Referenced as the paralog of novel prostate-cancer SMG PIK3R2; the PIK3R2 p.Asp557Tyr variant is directly paralogous to the known oncogenic PIK3R1 p.Asp560Tyr mutation, supporting PI3K-pathway oncogenicity in prostate cancer PMID:29610475.

Cancer types (linked)

  • GBM — mutated in 10% of cases, primarily in the iSH2 domain, leading to PI3K pathway activation PMID:18772890.
  • ODG / DIFG — PI3K pathway alteration in intermediate-grade IDH-mutant oligodendroglioma PMID:37910594.
  • Endometrial carcinoma (UCEC) — PIK3R1 mutations less frequent in Black patients (13% vs. 28%); associated with endometrioid/PTEN-co-altered PI3K pathway subtype PMID:37651310.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • Not directly therapeutically targeted in the corpus.

Open questions

  • Whether PI3K-pathway mutations should upgrade IDH-mutant LGG molecular grade is unresolved PMID:37910594.

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:28985567

This page was processed by wiki-cli on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15.