CoChat
Sign Up
Cited by 48PI3K/AKT/mTOR signaling in cancerCancer Genomics and DiagnosticsGenomics and Rare Diseases

Integrating thousands of PTEN variant activity and abundance measurements reveals variant subgroups and new dominant negatives in cancers

Open access
Matreyek, Kenneth A., Stephany, Jason J., Ahler, Ethan, Fowler, Douglas M.·2021·Genome Medicine
DOI 10.1186/s13073-021-00984-xPMC PMC8518224
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: PTEN is a multi-functional tumor suppressor protein regulating cell growth, immune signaling, neuronal function, and genome stability. Experimental characterization can help guide the clinical interpretation of the thousands of germline or somatic PTEN variants observed in patients. Two large-scale mutational datasets, one for PTEN variant intracellular abundance encompassing 4112 missense variants and one for lipid phosphatase activity encompassing 7244 variants, were recently published. The combined information from these datasets can reveal variant-specific phenotypes that may underlie various clinical presentations, but this has not been comprehensively examined, particularly for somatic PTEN variants observed in cancers. Methods: Here, we add to these efforts by measuring the intracellular abundance of 764 new PTEN variants and refining abundance measurements for 3351 previously studied variants. We use this expanded and refined PTEN abundance dataset to explore the mutational patterns governing PTEN intracellular abundance, and then incorporate the phosphatase activity data to subdivide PTEN variants into four functionally distinct groups. Results: This analysis revealed a set of highly abundant but lipid phosphatase defective variants that could act in a dominant-negative fashion to suppress PTEN activity. Two of these variants were, indeed, capable of dysregulating Akt signaling in cells harboring a WT PTEN allele. Both variants were observed in multiple breast or uterine tumors, demonstrating the disease relevance of these high abundance, inactive variants. Conclusions: We show that multidimensional, large-scale variant functional data, when paired with public cancer genomics datasets and follow-up assays, can improve understanding of uncharacterized cancer-associated variants, and provide better insights into how they contribute to oncogenesis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s13073-021-00984-x

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • By amplifying and sequencing barcodes from each bin and using a predetermined barcode-variant index, a functional score can be computed for each variant.

    “By amplifying barcodes and sequencing them from each bin, then using the predetermined barcode-variant index to determine the distribution of each variant across bins, a functional score can be computed for each variant (e.g. (59, 92, 93)).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [92]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 54

  1. [1]Karczewski KJ Francioli LC Tiao G Cummings BB Alföldi J Wang Q The mutational constraint spectrum quantified from variation in 141,456 humans Nature. 2020 581 434 443 10.1038/s41586-020-2308-7 32461654 PMC7334197 · DOI · Paper page
  2. [2]Weinstein JN Collisson EA Mills GB Shaw KRM Ozenberger BA Ellrott K The cancer genome atlas pan-cancer analysis project Nat Genet. 2013 45 1113 10.1038/ng.2764 24071849 PMC3919969 · DOI · Paper page
  3. [3]Landrum MJ Lee JM Riley GR Jang W Rubinstein WS Church DM ClinVar: public archive of relationships among sequence variation and human phenotype Nucleic Acids Res. 2014 42 D980 D985 10.1093/nar/gkt1113 24234437 PMC3965032 · DOI · Paper page
  4. [4]Starita LM Ahituv N Dunham MJ Kitzman JO Roth FP Seelig G Variant interpretation: functional assays to the rescue Am J Hum Genet. 2017 101 315 325 10.1016/j.ajhg.2017.07.014 28886340 PMC5590843 · DOI · Paper page
  5. [6]Lee Y-R Chen M Pandolfi PP The functions and regulation of the PTEN tumour suppressor: new modes and prospects Nat Rev Mol Cell Biol. 2018 19 547 562 10.1038/s41580-018-0015-0 29858604 · DOI
  6. [7]Milella M Falcone I Conciatori F Cesta Incani U Del Curatolo A Inzerilli N PTEN: multiple functions in human malignant tumors Front Oncol. 2015 5 24 10.3389/fonc.2015.00024 25763354 PMC4329810 · DOI
  7. [8]Hasle N Matreyek KA Fowler DM The impact of genetic variants on PTEN molecular functions and cellular phenotypes Cold Spring Harb Perspect Med. 2019 9 11 a036228 10.1101/cshperspect.a036228 31451538 PMC6824405 · DOI
  8. [9]Matreyek KA Starita LM Stephany JJ Martin B Chiasson MA Gray VE Multiplex assessment of protein variant abundance by massively parallel sequencing Nat Genet. 2018 50 874 882 10.1038/s41588-018-0122-z 29785012 PMC5980760 · DOI · Paper page
  9. [10]Mighell TL Evans-Dutson S O’Roak BJ A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotype relationships Am J Hum Genet. 2018 102 943 955 10.1016/j.ajhg.2018.03.018 29706350 PMC5986715 · DOI · Paper page
  10. [11]Jepsen MM, Fowler DM, Hartmann-Petersen R, Stein A, Lindorff-Larsen K. Classifying disease-associated variants using measures of protein activity and stability. bioRxiv. 2019. 10.1101/688234. · DOI
  11. [12]Mighell TL Thacker S Fombonne E Eng C O’Roak BJ An integrated deep-mutational-scanning approach provides clinical insights on PTEN genotype-phenotype relationships Am J Hum Genet. 2020 106 818 829 10.1016/j.ajhg.2020.04.014 32442409 PMC7273526 · DOI
  12. [13]Gibson DG Young L Chuang R-Y Venter JC Hutchison CA 3rd Smith HO Enzymatic assembly of DNA molecules up to several hundred kilobases Nat Methods. 2009 6 343 345 10.1038/nmeth.1318 19363495 · DOI
  13. [15]Rubin AF Gelman H Lucas N Bajjalieh SM Papenfuss AT Speed TP A statistical framework for analyzing deep mutational scanning data Genome Biol. 2017 18 150 10.1186/s13059-017-1272-5 28784151 PMC5547491 · DOI · Paper page
  14. [16]Matreyek KA Stephany JJ Chiasson MA Hasle N Fowler DM An improved platform for functional assessment of large protein libraries in mammalian cells Nucleic Acids Res. 2020 48 1 e1 10.1093/nar/gkz1097 31612958 PMC7145622 · DOI
  15. [19]Taliun D Harris DN Kessler MD Carlson J Szpiech ZA Torres R Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program Nature. 2021 590 290 299 10.1038/s41586-021-03205-y 33568819 PMC7875770 · DOI · Paper page
  16. [20]Cerami E Gao J Dogrusoz U Gross BE Sumer SO Aksoy BA The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data Cancer Discov. 2012 2 401 404 10.1158/2159-8290.CD-12-0095 22588877 PMC3956037 · DOI · Paper page
  17. [21]Gao J Aksoy BA Dogrusoz U Dresdner G Gross B Sumer SO Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal Sci Signal. 2013 6 l1 10.1126/scisignal.2004088 PMC4160307 23550210 · DOI · Paper page
  18. [22]AACR Project GENIE Consortium AACR project GENIE: powering precision medicine through an international consortium Cancer Discov. 2017 7 818 831 10.1158/2159-8290.CD-17-0151 28572459 PMC5611790 · DOI · Paper page
  19. [23]Matreyek KA Stephany JJ Fowler DM A platform for functional assessment of large variant libraries in mammalian cells Nucleic Acids Res. 2017 45 e102 10.1093/nar/gkx183 28335006 PMC5499817 · DOI
  20. [24]Suiter CC Moriyama T Matreyek KA Yang W Scaletti ER Nishii R Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity Proc Natl Acad Sci U S A. 2020 117 10 5394 5401 10.1073/pnas.1915680117 32094176 PMC7071893 · DOI · Paper page
  21. [25]Chiasson MA Rollins NJ Stephany JJ Sitko KA Matreyek KA Verby M Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact Elife 2020 9 e58026 10.7554/eLife.58026 32870157 PMC7462613 · DOI
  22. [26]Amorosi CJ Chiasson MA McDonald MG Wong LH Sitko KA Boyle G Massively parallel characterization of CYP2C9 variant enzyme activity and abundance Am J Hum Genet. 2021 108 9 1735 1751 10.1016/j.ajhg.2021.07.001 34314704 PMC8456167 · DOI
  23. [27]Gray VE Hause RJ Luebeck J Shendure J Fowler DM Quantitative missense variant effect prediction using large-scale mutagenesis data Cell Syst. 2018 6 116 24.e3 10.1016/j.cels.2017.11.003 29226803 PMC5799033 · DOI
  24. [28]Weile J Sun S Cote AG Knapp J Verby M Mellor JC A framework for exhaustively mapping functional missense variants Mol Syst Biol. 2017 13 957 10.15252/msb.20177908 29269382 PMC5740498 · DOI · Paper page
  25. [29]Georgescu MM Kirsch KH Kaloudis P Yang H Pavletich NP Hanafusa H Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor Cancer Res. 2000 60 7033 7038 11156408
  26. [30]Han SY Kato H Kato S Suzuki T Shibata H Ishii S Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay Cancer Res. 2000 60 3147 3151 10866302
  27. [31]Fricano-Kugler CJ Getz SA Williams MR Zurawel AA DeSpenza T Jr Frazel PW Nuclear excluded autism-associated phosphatase and tensin homolog mutations dysregulate neuronal growth Biol Psychiatry. 2018 84 265 277 10.1016/j.biopsych.2017.11.025 29373119 PMC5984669 · DOI
  28. [32]He X Thacker S Romigh T Yu Q Frazier TW Jr Eng C Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits Mol Autism. 2015 6 63 10.1186/s13229-015-0056-6 26579216 PMC4647625 · DOI
  29. [33]Spinelli L Black FM Berg JN Eickholt BJ Leslie NR Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes J Med Genet. 2015 52 128 134 10.1136/jmedgenet-2014-102803 25527629 PMC4316932 · DOI
  30. [34]Choi SW Lee Y Shin K Koo H Kim D Sa JK Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma Cell Death Dis. 2021 12 374 10.1038/s41419-021-03657-0 33828082 PMC8027895 · DOI
  31. [35]Ngeow J He X Mester JL Lei J Romigh T Orloff MS Utility of PTEN protein dosage in predicting for underlying germline PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes J Clin Endocrinol Metab. 2012 97 E2320 E2327 10.1210/jc.2012-2944 23066114 PMC3513537 · DOI
  32. [36]Furnari FB Lin H Huang HS Cavenee WK Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain Proc Natl Acad Sci U S A. 1997 94 12479 12484 10.1073/pnas.94.23.12479 9356475 PMC25009 · DOI
  33. [37]Zhou X-P Marsh DJ Morrison CD Chaudhury AR Maxwell M Reifenberger G Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults Am J Hum Genet. 2003 73 1191 1198 10.1086/379382 14566704 PMC1180498 · DOI
  34. [38]Wong CW Wang Y Liu T Li L Cheung SKK Or PM-Y Autism-associated PTEN missense mutation leads to enhanced nuclear localization and neurite outgrowth in an induced pluripotent stem cell line FEBS J. 2020 287 4848 4861 10.1111/febs.15287 32150788 PMC7754348 · DOI
  35. [39]Mester JL Ghosh R Pesaran T Huether R Karam R Hruska KS Gene-specific criteria for PTEN variant curation: recommendations from the ClinGen PTEN Expert Panel Hum Mutat. 2018 39 11 1581 1592 10.1002/humu.23636 30311380 PMC6329583 · DOI
  36. [40]Papa A Wan L Bonora M Salmena L Song MS Hobbs RM Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function Cell. 2014 157 595 610 10.1016/j.cell.2014.03.027 24766807 PMC4098792 · DOI
  37. [41]Wang H Karikomi M Naidu S Rajmohan R Caserta E Chen H-Z Allele-specific tumor spectrum in pten knockin mice Proc Natl Acad Sci U S A. 2010 107 5142 5147 10.1073/pnas.0912524107 20194734 PMC2841921 · DOI
  38. [42]Barretina J Caponigro G Stransky N Venkatesan K Margolin AA Kim S The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity Nature. 2012 483 603 607 10.1038/nature11003 22460905 PMC3320027 · DOI · Paper page
  39. [43]Smith IN Thacker S Seyfi M Cheng F Eng C Conformational dynamics and allosteric regulation landscapes of germline PTEN mutations associated with autism compared to those associated with cancer Am J Hum Genet. 2019 104 861 78 10.1016/j.ajhg.2019.03.009 31006514 PMC6506791 · DOI
  40. [44]Aguissa-Touré A-H Li G Genetic alterations of PTEN in human melanoma Cell Mol Life Sci. 2012 69 1475 1491 10.1007/s00018-011-0878-0 22076652 PMC11114653 · DOI
  41. [45]Lee JO Yang H Georgescu MM Di Cristofano A Maehama T Shi Y Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association Cell. 1999 99 323 334 10.1016/S0092-8674(00)81663-3 10555148 · DOI
  42. [46]Tate JG Bamford S Jubb HC Sondka Z Beare DM Bindal N COSMIC: the catalogue of somatic mutations in cancer Nucleic Acids Res. 2019 47 D941 D947 10.1093/nar/gky1015 30371878 PMC6323903 · DOI · Paper page
  43. [47]Xiao Y Chia JYC Gajewski JE Lio DSS Mulhern TD Zhu H-J PTEN catalysis of phospholipid dephosphorylation reaction follows a two-step mechanism in which the conserved aspartate-92 does not function as the general acid—mechanistic analysis of a familial Cowden disease-associated PTEN mutation Cell Signal. 2007 19 1434 1445 10.1016/j.cellsig.2007.01.021 17324556 · DOI
  44. [48]Chia JY-C Gajewski JE Xiao Y Zhu H-J Cheng H-C Unique biochemical properties of the protein tyrosine phosphatase activity of PTEN—demonstration of different active site structural requirements for phosphopeptide and phospholipid phosphatase activities of PTEN Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 2010 1804 9 1785 1795 10.1016/j.bbapap.2010.05.009 20685300 · DOI
  45. [49]Nguyen H-N Yang J-M Jr Rahdar M Keniry M Swaney KF Parsons R A new class of cancer-associated PTEN mutations defined by membrane translocation defects Oncogene. 2015 34 3737 3743 10.1038/onc.2014.293 25263454 PMC4377315 · DOI
  46. [50]Hill VK Kim J-S James CD Waldman T Correction of PTEN mutations in glioblastoma cell lines via AAV-mediated gene editing PLoS One. 2017 12 e0176683 10.1371/journal.pone.0176683 28464039 PMC5413031 · DOI
  47. [51]Portelli S Barr L de Sá AGC Pires DEV Ascher DB Distinguishing between PTEN clinical phenotypes through mutation analysis Comput Struct Biotechnol J. 2021 19 3097 3109 10.1016/j.csbj.2021.05.028 34141133 PMC8180946 · DOI
  48. [52]Johnston SB Raines RT Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders Biochemistry. 2015 54 1576 1582 10.1021/acs.biochem.5b00028 25647146 PMC4372197 · DOI
  49. [53]Leslie NR Longy M Inherited PTEN mutations and the prediction of phenotype Semin Cell Dev Biol. 2016 52 30 38 10.1016/j.semcdb.2016.01.030 26827793 · DOI
  50. [54]Redfern RE Daou M-C Li L Munson M Gericke A Ross AH A mutant form of PTEN linked to autism Protein Sci. 2010 19 1948 1956 10.1002/pro.483 20718038 PMC2998728 · DOI
  51. [55]Rodríguez-Escudero I Oliver MD Andrés-Pons A Molina M Cid VJ Pulido R A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes Hum Mol Genet. 2011 20 4132 4142 10.1093/hmg/ddr337 21828076 · DOI
  52. [56]Starita LM Young DL Islam M Kitzman JO Gullingsrud J Hause RJ Massively parallel functional analysis of BRCA1 RING domain variants Genetics. 2015 200 413 422 10.1534/genetics.115.175802 25823446 PMC4492368 · DOI
  53. [57]Park J Selvam B Sanematsu K Shigemura N Shukla D Procko E Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits J Biol Chem. 2019 294 4759 4774 10.1074/jbc.RA118.006173 30723160 PMC6442050 · DOI
  54. [58]Andrews B Fields S Distinct patterns of mutational sensitivity for λ resistance and maltodextrin transport in Escherichia coli LamB Microb Genom. 2020 6 4 e000364 PMC7276705 32238226

Cited by

Sorted by citations

Authors
Matreyek, K. A., Stephany, J. J., Ahler, E., & Fowler, D. M.
Affiliations
University of Washington (US)
Corresponding author
  • Matreyek, Kenneth A.
  • Fowler, Douglas M.
ORCID
Venue
Genome Medicine
Publisher
Springer Science and Business Media LLC
Published
2021-10-14
Volume
13
Issue
1
Pages
165-165
ISSN
1756-994X (ISSN-L)
DOI
10.1186/s13073-021-00984-x
PMC
PMC8518224
OpenAlex
W3205136345
Cited by
48
References
2
Citations by year
2026: 20 · 2025: 9 · 2024: 13 · 2023: 4 · 2022: 2
FWCI
1.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of General Medical Sciences (R35GM142886, R01GM109110, RM1HG010461)
  • American Cancer Society (PF-15-221-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
PTEN, somatic mutations, lipid phosphatase activity, dominant-negative mutant, tumor suppressor, Akt signaling, breast cancer, uterine cancer, cancer genomics
MeSH terms
Humans, Mutation, Neoplasms, Phenotype, Genetic Variation, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, Mutation, Missense, Genomics, PTEN Phosphohydrolase, HEK293 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review