PTEN Expression As a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Feb 27

PMID 32098071

Citations 16

Authors

Gianluca Lopez

Marianna Noale

Chiara Corti

Gabriella Gaudioso

Elham Sajjadi

Konstantinos Venetis

Donatella Gambini

Letterio Runza

Jole Costanza

Chiara Pesenti

Francesco Grossi

Stefania Maggi

Stefano Ferrero

Silvano Bosari

Nicola Fusco

Affiliations

Soon will be listed here.

Abstract

Mismatch repair (MMR) analysis in breast cancer may help to inform immunotherapy decisions but it lacks breast-specific guidelines. Unlike in other neoplasms, MMR protein loss shows intra-tumor heterogeneity and it is not mirrored by microsatellite instability in the breast. Additional biomarkers can improve MMR clinical testing. Phosphatase and tensin homolog (PTEN) inactivation is an early oncogenic event that is associated with MMR deficiency (dMMR) in several tumors. Here, we sought to characterize the diagnostic utility of PTEN expression analysis for MMR status assessment in breast cancer. A total of 608 breast cancers were profiled for their MMR and PTEN status. Proteins expression and distribution were analyzed by immunohistochemistry (IHC) on tissue microarrays and confirmed on full sections; PTEN copy number alterations were detected using a real-time PCR assay. Overall, 78 (12.8%) cases were MMR-heterogeneous (hMMR), while all patterns of PTEN expression showed no intra-tumor heterogeneity. Wild-type PTEN expression was observed in 15 (18.5%) dMMR tumors ( < 0.0001). Survival analyses revealed significant correlations between MMR-proficient (pMMR), PTEN expression, and a better outcome. The positive predictive value of PTEN-retained status for pMMR ranged from 94.6% in estrogen receptor (ER)+/HER2- tumors to 100% in HER2-amplified and ER-/HER2- cases. We propose a novel diagnostic algorithm where PTEN expression analysis can be employed to identify pMMR breast cancers.

Citing Articles

A retrospective analysis suggests PTEN expression is associated with favorable clinicopathological features of breast cancer.

Derkyi-Kwarteng L, Ghartey F, Aidoo E, Addae E, Imbeah E, Brown A Sci Rep. 2024; 14(1):21645.

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Predicting breast cancer-specific survival in metaplastic breast cancer patients using machine learning algorithms.

Feng Y, McGuire N, Walton A, Fox S, Papa A, Lakhani S J Pathol Inform. 2023; 14:100329.

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The molecular landscape of breast mucoepidermoid carcinoma.

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DNA Mismatch Repair System Imbalances in Breast Adenocarcinoma.

Metaxas G, Tsiambas E, Marinopoulos S, Adamopoulou M, Spyropoulou D, Falidas E Cancer Diagn Progn. 2023; 3(2):169-174.

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References

Lopez G, Fusco N . RE: Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort. Breast Cancer Res Treat. 2020; 180(1):265-266. DOI: 10.1007/s10549-020-05530-8. View

Pagni F, Guerini-Rocco E, Schultheis A, Grazia G, Rijavec E, Ghidini M . Targeting Immune-Related Biological Processes in Solid Tumors: We do Need Biomarkers. Int J Mol Sci. 2019; 20(21). PMC: 6862285. DOI: 10.3390/ijms20215452. View

Marusyk A, Polyak K . Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2009; 1805(1):105-17. PMC: 2814927. DOI: 10.1016/j.bbcan.2009.11.002. View

Corti C, Sajjadi E, Fusco N . Determination of Mismatch Repair Status in Human Cancer and Its Clinical Significance: Does One Size Fit All?. Adv Anat Pathol. 2019; 26(4):270-279. DOI: 10.1097/PAP.0000000000000234. View

Djordjevic B, Barkoh B, Luthra R, Broaddus R . Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas. Mod Pathol. 2013; 26(10):1401-12. PMC: 3720775. DOI: 10.1038/modpathol.2013.67. View

Ercoli G, Lopez G, Ciapponi C, Corti C, Despini L, Gambini D . Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers. J Vis Exp. 2017; (130). PMC: 5755531. DOI: 10.3791/56686. View

Gbelcova H, Bakes P, Priscakova P, Sisovsky V, Hojsikova I, Straka L . PTEN sequence analysis in endometrial hyperplasia and endometrial carcinoma in Slovak women. Anal Cell Pathol (Amst). 2015; 2015:746856. PMC: 4465682. DOI: 10.1155/2015/746856. View

Blumenthal G, Pazdur R . Approvals in 2018: a histology-agnostic new molecular entity, novel end points and real-time review. Nat Rev Clin Oncol. 2019; 16(3):139-141. DOI: 10.1038/s41571-019-0170-z. View

Maehama T, Dixon J . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273(22):13375-8. DOI: 10.1074/jbc.273.22.13375. View

10.

Stern H, Gardner H, Burzykowski T, Elatre W, OBrien C, Lackner M . PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance. Clin Cancer Res. 2015; 21(9):2065-74. PMC: 4417419. DOI: 10.1158/1078-0432.CCR-14-2993. View

11.

Subbiah V, Kurzrock R . The Marriage Between Genomics and Immunotherapy: Mismatch Meets Its Match. Oncologist. 2018; 24(1):1-3. PMC: 6324623. DOI: 10.1634/theoncologist.2017-0519. View

12.

Diaz-Padilla I, Romero N, Amir E, Matias-Guiu X, Vilar E, Muggia F . Mismatch repair status and clinical outcome in endometrial cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2013; 88(1):154-67. DOI: 10.1016/j.critrevonc.2013.03.002. View

13.

Lopez G, Costanza J, Colleoni M, Fontana L, Ferrero S, Miozzo M . Molecular Insights into the Classification of Luminal Breast Cancers: The Genomic Heterogeneity of Progesterone-Negative Tumors. Int J Mol Sci. 2019; 20(3). PMC: 6386970. DOI: 10.3390/ijms20030510. View

14.

Nanda R, Chow L, Dees E, Berger R, Gupta S, Geva R . Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016; 34(21):2460-7. PMC: 6816000. DOI: 10.1200/JCO.2015.64.8931. View

15.

Wen Y, Brogi E, Zeng Z, Akram M, Catalano J, Paty P . DNA mismatch repair deficiency in breast carcinoma: a pilot study of triple-negative and non-triple-negative tumors. Am J Surg Pathol. 2012; 36(11):1700-8. DOI: 10.1097/PAS.0b013e3182627787. View

16.

Davies H, Morganella S, Purdie C, Jang S, Borgen E, Russnes H . Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency. Cancer Res. 2017; 77(18):4755-4762. DOI: 10.1158/0008-5472.CAN-17-1083. View

17.

Kanaya T, Kyo S, Sakaguchi J, Maida Y, Nakamura M, Takakura M . Association of mismatch repair deficiency with PTEN frameshift mutations in endometrial cancers and the precursors in a Japanese population. Am J Clin Pathol. 2005; 124(1):89-96. DOI: 10.1309/PAACLG8DXDK0X2B1. View

18.

An H, Kim K, Kim J, Shim J, Kang H, Kim T . Microsatellite instability in endometrioid type endometrial adenocarcinoma is associated with poor prognostic indicators. Am J Surg Pathol. 2007; 31(6):846-53. DOI: 10.1097/01.pas.0000213423.30880.ac. View

19.

Invernizzi M, Michelotti A, Noale M, Lopez G, Runza L, Giroda M . Breast Cancer Systemic Treatments and Upper Limb Lymphedema: A Risk-Assessment Platform Encompassing Tumor-Specific Pathological Features Reveals the Potential Role of Trastuzumab. J Clin Med. 2019; 8(2). PMC: 6406664. DOI: 10.3390/jcm8020138. View

20.

Grizzi G, Ghidini M, Botticelli A, Tomasello G, Ghidini A, Grossi F . Strategies for Increasing the Effectiveness of Aromatase Inhibitors in Locally Advanced Breast Cancer: An Evidence-Based Review on Current Options. Cancer Manag Res. 2020; 12:675-686. PMC: 6996551. DOI: 10.2147/CMAR.S202965. View