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Travis, G.; Mcgowan, E.M.; Simpson, A.M.; Marsh, D.J.; Nassif, N.T. PTEN and Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/50425 (accessed on 03 May 2024).
Travis G, Mcgowan EM, Simpson AM, Marsh DJ, Nassif NT. PTEN and Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/50425. Accessed May 03, 2024.
Travis, Glena, Eileen M. Mcgowan, Ann M. Simpson, Deborah J. Marsh, Najah T. Nassif. "PTEN and Cancer" Encyclopedia, https://encyclopedia.pub/entry/50425 (accessed May 03, 2024).
Travis, G., Mcgowan, E.M., Simpson, A.M., Marsh, D.J., & Nassif, N.T. (2023, October 18). PTEN and Cancer. In Encyclopedia. https://encyclopedia.pub/entry/50425
Travis, Glena, et al. "PTEN and Cancer." Encyclopedia. Web. 18 October, 2023.
PTEN and Cancer
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers15204954

The PTEN gene is an important and well-characterised tumour suppressor, known to be altered in many cancer types. Interestingly, the effect of the loss or mutation of PTEN is not dichotomous, and small changes in PTEN cellular levels can promote cancer development.

PTEN PTENP1 ceRNA networks microRNAs

1. Introduction

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN), also known as mutated in multiple advanced cancers 1 (MMAC1) and TGFß-regulated and epithelial cell-enriched phosphatase 1 (TEP-1) [1][2][3], is a well-known tumour suppressor gene located on chromosome 10q23.31 [2]. The gene and its protein product play a vital role in cell proliferation, migration, and survival [2][4][5][6][7]. As an antagonist of phosphoinositide 3-kinase (PI3K), PTEN dephosphorylates its substrate PIP3 to PIP2, thereby negatively regulating the pro-proliferative and anti-apoptotic PI3K/Akt pathway to maintain cellular homeostasis [8][9]. The regulation of PTEN cellular levels is critical in the negative modulation of tumorigenesis with disruption of PTEN signalling leading to significant cellular changes. Interestingly, subtle decreases in cellular levels of PTEN can result in malignancy and tight regulation of the expression, function, and cellular half-life of PTEN, at the transcriptional, post-transcriptional, and post-translational levels is necessary in the prevention of carcinogenesis [10][11]. PTEN is frequently mutated and/or deleted in the inherited PTEN hamartoma tumour syndromes (PHTS) [12][13] and multiple sporadic human malignancies, including those from the brain, breast, prostate [1], endometrium [14], skin (melanoma) [15], and colon [6].
Less well-known regulatory mechanisms of PTEN with emerging importance include the PTEN–miRNA–PTENP1 axis, which has been shown to play a critical role in the fine tuning of PTEN regulation and cellular integrity. PTENP1 is a processed pseudogene of PTEN termed the phosphatase and tensin homolog pseudogene 1 (PTENp1, PTENpg1, PTENP1, PTH2, and ψPTEN), which is located on 9p13 (Gene ID: 101243555) [16][17][18]. This pseudogene is transcribed to produce sense and antisense transcripts with the sense transcript showing high sequence similarity with the PTEN transcript; however, unlike PTEN, this transcript is not translated to produce a protein [19]. Although PTENP1 protein is undetected in cells, when transcribed in vitro as a fusion protein, the product is viable and has comparable phosphatase activity to the wild-type PTEN [19]. The sense and antisense long non-coding RNAs (lncRNA) produced from PTENP1 are important in the modulation of PTEN expression at the transcriptional and post-transcriptional levels, respectively. The PTENP1 sense transcript (PTENP1-S), acting as a competitive endogenous RNA (ceRNA) of PTEN, leads to alterations in PTEN cellular abundance. The characteristics of this PTEN pseudogene lncRNA include similarities in their microRNA (miRNA) binding sites, and as such, PTENP1 can act as a decoy or ‘sponge’, competing for miRNAs that target PTEN. Disruption of the PTEN–miRNA–PTENP1 axis and ceRNA networks in carcinogenic progression is contemporary and is an exciting area in the discovery of regulatory mechanisms that are altered in cancer. In addition to its regulation of PTEN expression, PTENP1 is able to act as a tumour suppressor independent of its PTEN regulatory function as described in a recent review of the role of PTENP1 in human disorders with a focus on its tumour suppressor functionality [20].

2. PTEN and Cancer: From Mutations to a Continuum Model of Tumorigenesis

Germline and somatic mutation of PTEN is known to contribute to many cancers, highlighting the importance of this tumour suppressor in cancer initiation, progression, and metastasis. Germline mutations of PTEN are the cause of four autosomal dominant inherited syndromes: Cowden syndrome (CS) [21], Bannayan–Riley–Ruvalcaba syndrome (BRRS) [22][23], Proteus syndrome (PS), and PS-like syndrome [24], which share common features, including the development of multiple benign hamartomas, and are all classified under the umbrella term of the PTEN hamartoma tumour syndromes (PTHSs) [12][13]. PTHS patients have an increased lifetime risk of developing specific malignancies, mainly breast cancer (approximately 80%) [12][13], thyroid cancer (approximately 30%) [12][13], renal cell carcinoma (approximately 34%) [13], endometrial cancer (approximately 28%) [13], and colorectal cancers (approximately 9%) [13]. In individual PHTS patients exhibiting clinical phenotypes, PTEN germline mutations are reported in 25-85% of CS patients [21][25][26], 60% of BRRS [21][22][25][27], up to 20% of PS [28], and between 50 and 67% of PS-like syndrome patients [24]. Interestingly, germline PTEN mutations are also associated with a subset of patients with autistic behaviour and extreme macrocephaly [29].
Somatic mutations of PTEN are frequently associated with tumorigenesis with somatic alterations of PTEN being described in over 50% of cancers of various types [30]. PTEN somatic mutations are most prevalent in prostate cancer [31], endometrial cancer [32], melanoma [33][34], non-small-cell lung cancer [35][36], kidney [37], breast cancer [38], and glioblastoma [39]. PTEN somatic alterations include the complete loss or inactivation of one allele (functional haploinsufficiency) due to point mutations and/or deletions and/or epigenetic silencing through hypermethylation of the PTEN promoter, which is characteristic of some advanced and metastatic cancers [1][4]. Deletion of both alleles of PTEN occurs at a lower incidence but is seen mostly in metastatic breast cancer, melanomas, and glioblastomas [1][4][40]. In contrast, a recent study showed that patients with high PTEN expression levels in endometrial cancer had low tumour malignancy, decreased cancer cell proliferation and a better prognosis [41]. There are different mechanisms of PTEN loss or inactivation, with some being more prevalent in specific tumour types (Table 1) [30][42][43].
Table 1. Mechanism and frequency (%) of PTEN loss in various cancer types.
Cancer Type Mutation Deletion Loss of Protein Promoter Methylation
Glioblastoma 30% [2][3][42][44][45][46] 78% [44][45][46][47] 65% [48] 6% [49]
Breast 3% [42][50][51] 27% [38][52] 40% [42] 35% [53][54]
Prostate 13% [55][56][57][58] 51% [56][57][58] 54% [55][56][57][58] <5% [42][59][60][61]
Colorectal 7% [6][42][62][63][64][65][66] 8.7% [42][62][63] 40% [67] 17% [68]
Lung 8% [42] 34% [42] 56% [42] 38% [69]
Endometrial 41% [14][42][70] 48% [14][42][70] 45% [14][41] 19% [42][71]
Ovarian 16% [42][43][72][73][74][75][76] 48% [42][43][72][73][74][75][76] 44% [42][43][72][73][74][75][76] 10% [42][77]
Note: Where multiple references are provided, the frequencies of mutation, deletion, and promoter methylation are an approximate average across the relevant publications.
The effect of the loss or mutation of PTEN is not dichotomous, and subtle changes in PTEN cellular levels have been shown to lead to deleterious consequences relating to tumour incidence, penetrance, and aggressiveness in several epithelial cancers [11][78]. In the hypomorphic transgenic Pten mouse, it has been shown that in susceptible organs such as the prostate, PTEN protein expression levels need to reach dramatically low levels (reduced by 70% compared to normal levels) to initiate tumorigenesis, however, in the mammary glands, a more subtle reduction (reduced by 20% compared to normal levels) can initiate tumorigenesis [78]. Thus, PTEN does not follow the ‘two-hit’ paradigm or stepwise model of tumour suppressor gene function but rather presents a new continuum model of tumorigenesis whereby tumorigenesis occurs in an incremental dose-dependent manner [11][78]. This has been evidenced in gastric cancer, where PTEN expression was shown to gradually decrease with increasing gastric cancer progression [79].

PTEN Loss, Tumour Immune Evasion, and Therapy Resistance

There are several recent studies that have explored the relationship between PTEN loss and tumour immunity, showing PTEN loss contributes to alterations in the tumour microenvironment (TME) to produce an immunosuppressive niche. The evidence suggests that PI3K signalling may influence the composition and functionality of the TME, thereby modulating the immune response in cancer. Vidotto et al. (2023) analysed PTEN copy number in 9793 cases from 30 tumour types, derived from the Cancer Genome Atlas, and showed that reduced tumour PTEN expression occurs with hemizygous loss leading to tumour anti-cancer immune responses [80]. In another integrative analysis of TCGA samples, Lin et al. (2021) found that both PTEN loss and activation of the PI3K pathway were associated with reduced T-cell infiltration and an enhanced immunosuppressive status in multiple tumour types [81]. Overall, the effect of PTEN loss of function in the different cellular compartments swings the balance towards an immunosuppressive TME [82]. There was also a correlation between PTEN loss and poor response to immunotherapy [81]. Interestingly, PTEN loss has also been shown to promote resistance to therapy in breast cancer. Reducing PTEN levels in breast cancer cells conferred resistance to trastuzamab, and patients with PTEN-deficient breast cancers showed poorer therapeutic responses with this drug. Thus, PTEN deficiency has become a good predictor for trastuzumab resistance [83][84]. Reduced PTEN expression has been shown in vivo, in mouse models, to be due to specific miRNAs. An example being PTEN as a target of mi-R22 in breast and prostate cancers, which have been shown to have a strong influence in a cancer immune TME, playing a role in cancer initiation, progression, and metastasis [85]. Importantly, in vivo, knockdown of miR-22 appears to invoke tumour resistance in an immunocompetent environment [85]. These findings open new avenues for immuno-targeting, such as modulating miRNAs targeting PTEN, hence improving the efficacy of immunotherapy and overcoming therapy resistance.

References

  1. Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S.I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275, 1943–1947.
  2. Steck, P.A.; Pershouse, M.A.; Jasser, S.A.; Yung, W.K.; Lin, H.; Ligon, A.H.; Langford, L.A.; Baumgard, M.L.; Hattier, T.; Davis, T.; et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 1997, 15, 356–362.
  3. Li, D.M.; Sun, H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997, 57, 2124–2129.
  4. Hollander, M.C.; Blumenthal, G.M.; Dennis, P.A. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat. Rev. Cancer 2011, 11, 289–301.
  5. Cantley, L.C.; Neel, B.G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. USA 1999, 96, 4240–4245.
  6. Nassif, N.T.; Lobo, G.P.; Wu, X.; Henderson, C.J.; Morrison, C.D.; Eng, C.; Jalaludin, B.; Segelov, E. PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene 2004, 23, 617–628.
  7. Maehama, T.; Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 1998, 273, 13375–13378.
  8. Stambolic, V.; Suzuki, A.; de la Pompa, J.L.; Brothers, G.M.; Mirtsos, C.; Sasaki, T.; Ruland, J.; Penninger, J.M.; Siderovski, D.P.; Mak, T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998, 95, 29–39.
  9. Hoxhaj, G.; Manning, B.D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 2020, 20, 74–88.
  10. Alimonti, A.; Carracedo, A.; Clohessy, J.G.; Trotman, L.C.; Nardella, C.; Egia, A.; Salmena, L.; Sampieri, K.; Haveman, W.J.; Brogi, E.; et al. Subtle variations in Pten dose determine cancer susceptibility. Nat. Genet. 2010, 42, 454–458.
  11. Berger, A.H.; Knudson, A.G.; Pandolfi, P.P. A continuum model for tumour suppression. Nature 2011, 476, 163–169.
  12. Tan, M.H.; Mester, J.L.; Ngeow, J.; Rybicki, L.A.; Orloff, M.S.; Eng, C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 2012, 18, 400–407.
  13. Bubien, V.; Bonnet, F.; Brouste, V.; Hoppe, S.; Barouk-Simonet, E.; David, A.; Edery, P.; Bottani, A.; Layet, V.; Caron, O.; et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J. Med. Genet. 2013, 50, 255–263.
  14. Risinger, J.I.; Hayes, K.; Maxwell, G.L.; Carney, M.E.; Dodge, R.K.; Barrett, J.C.; Berchuck, A. PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics. Clin. Cancer Res. 1998, 4, 3005–3010.
  15. Celebi, J.T.; Shendrik, I.; Silvers, D.N.; Peacocke, M. Identification of PTEN mutations in metastatic melanoma specimens. J. Med. Genet. 2000, 37, 653–657.
  16. Dahia, P.L.; FitzGerald, M.G.; Zhang, X.; Marsh, D.J.; Zheng, Z.; Pietsch, T.; von Deimling, A.; Haluska, F.G.; Haber, D.A.; Eng, C. A highly conserved processed PTEN pseudogene is located on chromosome band 9p21. Oncogene 1998, 16, 2403–2406.
  17. Poliseno, L.; Salmena, L.; Zhang, J.; Carver, B.; Haveman, W.J.; Pandolfi, P.P. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010, 465, 1033–1038.
  18. Whang, Y.E.; Wu, X.; Sawyers, C.L. Identification of a pseudogene that can masquerade as a mutant allele of the PTEN/MMAC1 tumor suppressor gene. J. Natl. Cancer Inst. 1998, 90, 859–861.
  19. Fujii, G.H.; Morimoto, A.M.; Berson, A.E.; Bolen, J.B. Transcriptional analysis of the PTEN/MMAC1 pseudogene, psiPTEN. Oncogene 1999, 18, 1765–1769.
  20. Ghafouri-Fard, S.; Khoshbakht, T.; Hussen, B.M.; Taheri, M.; Akbari Dilmaghani, N. A review on the role of PTENP1 in human disorders with an especial focus on tumor suppressor role of this lncRNA. Cancer Cell Int. 2022, 22, 207.
  21. Marsh, D.J.; Coulon, V.; Lunetta, K.L.; Rocca-Serra, P.; Dahia, P.L.; Zheng, Z.; Liaw, D.; Caron, S.; Duboue, B.; Lin, A.Y.; et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum. Mol. Genet. 1998, 7, 507–515.
  22. Marsh, D.J.; Dahia, P.L.; Zheng, Z.; Liaw, D.; Parsons, R.; Gorlin, R.J.; Eng, C. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat. Genet. 1997, 16, 333–334.
  23. Zigman, A.F.; Lavine, J.E.; Jones, M.C.; Boland, C.R.; Carethers, J.M. Localization of the Bannayan-Riley-Ruvalcaba syndrome gene to chromosome 10q23. Gastroenterology 1997, 113, 1433–1437.
  24. Yehia, L.; Eng, C. 65 YEARS OF THE DOUBLE HELIX: One gene, many endocrine and metabolic syndromes: PTEN-opathies and precision medicine. Endocr. Relat. Cancer 2018, 25, T121–T140.
  25. Zhou, X.P.; Waite, K.A.; Pilarski, R.; Hampel, H.; Fernandez, M.J.; Bos, C.; Dasouki, M.; Feldman, G.L.; Greenberg, L.A.; Ivanovich, J.; et al. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am. J. Hum. Genet. 2003, 73, 404–411.
  26. Tan, M.H.; Mester, J.; Peterson, C.; Yang, Y.; Chen, J.L.; Rybicki, L.A.; Milas, K.; Pederson, H.; Remzi, B.; Orloff, M.S.; et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am. J. Hum. Genet. 2011, 88, 42–56.
  27. Marsh, D.J.; Kum, J.B.; Lunetta, K.L.; Bennett, M.J.; Gorlin, R.J.; Ahmed, S.F.; Bodurtha, J.; Crowe, C.; Curtis, M.A.; Dasouki, M.; et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum. Mol. Genet. 1999, 8, 1461–1472.
  28. Zhou, X.; Hampel, H.; Thiele, H.; Gorlin, R.J.; Hennekam, R.C.; Parisi, M.; Winter, R.M.; Eng, C. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 2001, 358, 210–211.
  29. Butler, M.G.; Dasouki, M.J.; Zhou, X.P.; Talebizadeh, Z.; Brown, M.; Takahashi, T.N.; Miles, J.H.; Wang, C.H.; Stratton, R.; Pilarski, R.; et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 2005, 42, 318–321.
  30. Fusco, N.; Sajjadi, E.; Venetis, K.; Gaudioso, G.; Lopez, G.; Corti, C.; Rocco, E.G.; Criscitiello, C.; Malapelle, U.; Invernizzi, M. PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine? Genes 2020, 11, 719.
  31. Cairns, P.; Okami, K.; Halachmi, S.; Halachmi, N.; Esteller, M.; Herman, J.G.; Jen, J.; Isaacs, W.B.; Bova, G.S.; Sidransky, D. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 1997, 57, 4997–5000.
  32. Mutter, G.L.; Lin, M.C.; Fitzgerald, J.T.; Kum, J.B.; Baak, J.P.; Lees, J.A.; Weng, L.P.; Eng, C. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl. Cancer Inst. 2000, 92, 924–930.
  33. Whiteman, D.C.; Zhou, X.P.; Cummings, M.C.; Pavey, S.; Hayward, N.K.; Eng, C. Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma. Int. J. Cancer 2002, 99, 63–67.
  34. Guldberg, P.; thor Straten, P.; Birck, A.; Ahrenkiel, V.; Kirkin, A.F.; Zeuthen, J. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 1997, 57, 3660–3663.
  35. Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014, 511, 543–550.
  36. Ku, B.M.; Heo, M.H.; Kim, J.H.; Cho, B.C.; Cho, E.K.; Min, Y.J.; Lee, K.H.; Sun, J.M.; Lee, S.H.; Ahn, J.S.; et al. Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01). J. Pathol. Transl. Med. 2018, 52, 148–156.
  37. Shuch, B.; Ricketts, C.J.; Vocke, C.D.; Komiya, T.; Middelton, L.A.; Kauffman, E.C.; Merino, M.J.; Metwalli, A.R.; Dennis, P.; Linehan, W.M. Germline PTEN mutation Cowden syndrome: An underappreciated form of hereditary kidney cancer. J. Urol. 2013, 190, 1990–1998.
  38. Carbognin, L.; Miglietta, F.; Paris, I.; Dieci, M.V. Prognostic and Predictive Implications of PTEN in Breast Cancer: Unfulfilled Promises but Intriguing Perspectives. Cancers 2019, 11, 1401.
  39. Wang, S.I.; Puc, J.; Li, J.; Bruce, J.N.; Cairns, P.; Sidransky, D.; Parsons, R. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 1997, 57, 4183–4186.
  40. Verhaak, R.G.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golub, T.; Mesirov, J.P.; et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010, 17, 98–110.
  41. Liang, Y.; Lin, B.; Ye, Z.; Chen, S.; Yu, H.; Chen, C.; Zhang, X.; Zhou, K.; Zeng, J. Triple-high expression of phosphatase and tensin homolog (PTEN), estrogen receptor (ER) and progesterone receptor (PR) may predict favorable prognosis for patients with Type I endometrial carcinoma. J. Cancer 2020, 11, 1436–1445.
  42. Alvarez-Garcia, V.; Tawil, Y.; Wise, H.M.; Leslie, N.R. Mechanisms of PTEN loss in cancer: It’s all about diversity. Semin. Cancer Biol. 2019, 59, 66–79.
  43. Wang, Q.; Wang, J.; Xiang, H.; Ding, P.; Wu, T.; Ji, G. The biochemical and clinical implications of phosphatase and tensin homolog deleted on chromosome ten in different cancers. Am. J. Cancer Res. 2021, 11, 5833–5855.
  44. Denning, G.; Jean-Joseph, B.; Prince, C.; Durden, D.L.; Vogt, P.K. A short N-terminal sequence of PTEN controls cytoplasmic localization and is required for suppression of cell growth. Oncogene 2007, 26, 3930–3940.
  45. Walker, S.M.; Leslie, N.R.; Perera, N.M.; Batty, I.H.; Downes, C.P. The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. Biochem. J. 2004, 379, 301–307.
  46. Yang, J.M.; Schiapparelli, P.; Nguyen, H.N.; Igarashi, A.; Zhang, Q.; Abbadi, S.; Amzel, L.M.; Sesaki, H.; Quinones-Hinojosa, A.; Iijima, M. Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene 2017, 36, 3673–3685.
  47. Brennan, C.W.; Verhaak, R.G.; McKenna, A.; Campos, B.; Noushmehr, H.; Salama, S.R.; Zheng, S.; Chakravarty, D.; Sanborn, J.Z.; Berman, S.H.; et al. The somatic genomic landscape of glioblastoma. Cell 2013, 155, 462–477.
  48. Ruano, Y.; Ribalta, T.; de Lope, A.R.; Campos-Martin, Y.; Fiano, C.; Perez-Magan, E.; Hernandez-Moneo, J.L.; Mollejo, M.; Melendez, B. Worse outcome in primary glioblastoma multiforme with concurrent epidermal growth factor receptor and p53 alteration. Am. J. Clin. Pathol. 2009, 131, 257–263.
  49. Wiencke, J.K.; Zheng, S.; Jelluma, N.; Tihan, T.; Vandenberg, S.; Tamguney, T.; Baumber, R.; Parsons, R.; Lamborn, K.R.; Berger, M.S.; et al. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro Oncol. 2007, 9, 271–279.
  50. Lu, Y.; Lin, Y.Z.; LaPushin, R.; Cuevas, B.; Fang, X.; Yu, S.X.; Davies, M.A.; Khan, H.; Furui, T.; Mao, M.; et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 1999, 18, 7034–7045.
  51. Zhang, H.Y.; Liang, F.; Jia, Z.L.; Song, S.T.; Jiang, Z.F. PTEN mutation, methylation and expression in breast cancer patients. Oncol. Lett. 2013, 6, 161–168.
  52. Coughlin, C.M.; Johnston, D.S.; Strahs, A.; Burczynski, M.E.; Bacus, S.; Hill, J.; Feingold, J.M.; Zacharchuk, C.; Berkenblit, A. Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy. Breast Cancer Res. Treat. 2010, 124, 1–11.
  53. Xu, F.; Zhang, C.; Cui, J.; Liu, J.; Li, J.; Jiang, H. The prognostic value and potential drug target of phosphatase and tensin homolog in breast cancer patients: A meta-analysis. Medicine 2017, 96, e8000.
  54. Luo, S.; Chen, J.; Mo, X. The association of PTEN hypermethylation and breast cancer: A meta-analysis. OncoTargets Ther. 2016, 9, 5643–5650.
  55. Gray, I.C.; Phillips, S.M.; Lee, S.J.; Neoptolemos, J.P.; Weissenbach, J.; Spurr, N.K. Loss of the chromosomal region 10q23-25 in prostate cancer. Cancer Res. 1995, 55, 4800–4803.
  56. Jamaspishvili, T.; Berman, D.M.; Ross, A.E.; Scher, H.I.; De Marzo, A.M.; Squire, J.A.; Lotan, T.L. Clinical implications of PTEN loss in prostate cancer. Nat. Rev. Urol. 2018, 15, 222–234.
  57. Leinonen, K.A.; Saramaki, O.R.; Furusato, B.; Kimura, T.; Takahashi, H.; Egawa, S.; Suzuki, H.; Keiger, K.; Ho Hahm, S.; Isaacs, W.B.; et al. Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer. Cancer Epidemiol. Biomark. Prev. 2013, 22, 2333–2344.
  58. Yoshimoto, M.; Ludkovski, O.; DeGrace, D.; Williams, J.L.; Evans, A.; Sircar, K.; Bismar, T.A.; Nuin, P.; Squire, J.A. PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications. Genes Chromosomes Cancer 2012, 51, 149–160.
  59. Leslie, N.R.; Foti, M. Non-genomic loss of PTEN function in cancer: Not in my genes. Trends Pharmacol. Sci. 2011, 32, 131–140.
  60. Whang, Y.E.; Wu, X.; Suzuki, H.; Reiter, R.E.; Tran, C.; Vessella, R.L.; Said, J.W.; Isaacs, W.B.; Sawyers, C.L. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc. Natl. Acad. Sci. USA 1998, 95, 5246–5250.
  61. Gravina, G.L.; Biordi, L.; Martella, F.; Flati, V.; Ricevuto, E.; Ficorella, C.; Tombolini, V.; Festuccia, C. Epigenetic modulation of PTEN expression during antiandrogenic therapies in human prostate cancer. Int. J. Oncol. 2009, 35, 1133–1139.
  62. Cancer Genome Atlas, N. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012, 487, 330–337.
  63. Serebriiskii, I.G.; Pavlov, V.; Tricarico, R.; Andrianov, G.; Nicolas, E.; Parker, M.I.; Newberg, J.; Frampton, G.; Meyer, J.E.; Golemis, E.A. Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers. Nat. Commun. 2022, 13, 1618.
  64. Berg, M.; Danielsen, S.A.; Ahlquist, T.; Merok, M.A.; Agesen, T.H.; Vatn, M.H.; Mala, T.; Sjo, O.H.; Bakka, A.; Moberg, I.; et al. DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. PLoS ONE 2010, 5, e13978.
  65. Bohn, B.A.; Mina, S.; Krohn, A.; Simon, R.; Kluth, M.; Harasimowicz, S.; Quaas, A.; Bockhorn, M.; Izbicki, J.R.; Sauter, G.; et al. Altered PTEN function caused by deletion or gene disruption is associated with poor prognosis in rectal but not in colon cancer. Hum. Pathol. 2013, 44, 1524–1533.
  66. Jauhri, M.; Bhatnagar, A.; Gupta, S.; Shokeen, Y.; Minhas, S.; Aggarwal, S. Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing. Med. Oncol. 2016, 33, 106.
  67. Lin, P.C.; Lin, J.K.; Lin, H.H.; Lan, Y.T.; Lin, C.C.; Yang, S.H.; Chen, W.S.; Liang, W.Y.; Jiang, J.K.; Chang, S.C. A comprehensive analysis of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss in colorectal cancer. World J. Surg. Oncol. 2015, 13, 186.
  68. Goel, A.; Arnold, C.N.; Niedzwiecki, D.; Carethers, J.M.; Dowell, J.M.; Wasserman, L.; Compton, C.; Mayer, R.J.; Bertagnolli, M.M.; Boland, C.R. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004, 64, 3014–3021.
  69. Marsit, C.J.; Zheng, S.; Aldape, K.; Hinds, P.W.; Nelson, H.H.; Wiencke, J.K.; Kelsey, K.T. PTEN expression in non-small-cell lung cancer: Evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum. Pathol. 2005, 36, 768–776.
  70. Di Cristofano, A.; Ellenson, L.H. Endometrial carcinoma. Annu. Rev. Pathol. 2007, 2, 57–85.
  71. Salvesen, H.B.; MacDonald, N.; Ryan, A.; Jacobs, I.J.; Lynch, E.D.; Akslen, L.A.; Das, S. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int. J. Cancer 2001, 91, 22–26.
  72. Testa, U.; Petrucci, E.; Pasquini, L.; Castelli, G.; Pelosi, E. Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells. Medicines 2018, 5, 16.
  73. Steelman, L.S.; Bertrand, F.E.; McCubrey, J.A. The complexity of PTEN: Mutation, marker and potential target for therapeutic intervention. Expert Opin. Ther. Targets 2004, 8, 537–550.
  74. McConechy, M.K.; Ding, J.; Senz, J.; Yang, W.; Melnyk, N.; Tone, A.A.; Prentice, L.M.; Wiegand, K.C.; McAlpine, J.N.; Shah, S.P.; et al. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod. Pathol. 2014, 27, 128–134.
  75. Kolasa, I.K.; Rembiszewska, A.; Janiec-Jankowska, A.; Dansonka-Mieszkowska, A.; Lewandowska, A.M.; Konopka, B.; Kupryjanczyk, J. PTEN mutation, expression and LOH at its locus in ovarian carcinomas. Relation to TP53, K-RAS and BRCA1 mutations. Gynecol. Oncol. 2006, 103, 692–697.
  76. Merritt, M.A.; Cramer, D.W. Molecular pathogenesis of endometrial and ovarian cancer. Cancer Biomark. 2010, 9, 287–305.
  77. Schondorf, T.; Ebert, M.P.; Hoffmann, J.; Becker, M.; Moser, N.; Pur, S.; Gohring, U.J.; Weisshaar, M.P. Hypermethylation of the PTEN gene in ovarian cancer cell lines. Cancer Lett. 2004, 207, 215–220.
  78. Alimonti, A. PTEN breast cancer susceptibility: A matter of dose. Ecancermedicalscience 2010, 4, 192.
  79. Xu, W.T.; Yang, Z.; Lu, N.H. Roles of PTEN (Phosphatase and Tensin Homolog) in gastric cancer development and progression. Asian Pac. J. Cancer Prev. 2014, 15, 17–24.
  80. Vidotto, T.; Melo, C.M.; Lautert-Dutra, W.; Chaves, L.P.; Reis, R.B.; Squire, J.A. Pan-cancer genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome. Sci. Rep. 2023, 13, 5049.
  81. Lin, Z.; Huang, L.; Li, S.L.; Gu, J.; Cui, X.; Zhou, Y. PTEN loss correlates with T cell exclusion across human cancers. BMC Cancer 2021, 21, 429.
  82. Conciatori, F.; Bazzichetto, C.; Falcone, I.; Ciuffreda, L.; Ferretti, G.; Vari, S.; Ferraresi, V.; Cognetti, F.; Milella, M. PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy. Int. J. Mol. Sci. 2020, 21, 5337.
  83. Nagata, Y.; Lan, K.H.; Zhou, X.; Tan, M.; Esteva, F.J.; Sahin, A.A.; Klos, K.S.; Li, P.; Monia, B.P.; Nguyen, N.T.; et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004, 6, 117–127.
  84. Vidotto, T.; Melo, C.M.; Castelli, E.; Koti, M.; Dos Reis, R.B.; Squire, J.A. Emerging role of PTEN loss in evasion of the immune response to tumours. Br. J. Cancer 2020, 122, 1732–1743.
  85. Centomo, M.L.; Vitiello, M.; Poliseno, L.; Pandolfi, P.P. An Immunocompetent Environment Unravels the Proto-Oncogenic Role of miR-22. Cancers 2022, 14, 6255.
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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Glena Travis
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Eileen M. McGowan
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Ann M. Simpson
,
Deborah J. Marsh
,
Najah T. Nassif
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Revisions: 2 times (View History)
Update Date: 18 Oct 2023
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