Integrating Somatic CNV and Gene Expression in Breast Cancers from Women with PTEN Hamartoma Tumor Syndrome

Copy number variation and transcript features from breast cancers arising in the setting of germline PTEN mutations revealed distinct biological characteristics compared to sporadic breast cancers.
Published in Cancer

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Takae Brewer, Lamis Yehia, Peter Bazeley, and Charis Eng

4 contributors

Approximately 5-10% of breast cancers are hereditary, caused by mutations in breast susceptibility genes which can be inherited. Phosphatase and tensin homolog (PTEN), is a tumor suppressor gene1, which when mutated, causes PTEN hamartoma tumor syndrome (PHTS). Women with PHTS have up to 85-91% lifetime risk of breast cancer (BC), which is notably higher than that in the general population (12.9% lifetime risk) and the age of onset of breast cancer is approximately 10 years younger2,3.  PHTS-derived BCs are distinct not only at the clinical but also at the molecular and genomic levels. Recently, we found that BCs arising in the setting of PHTS had a distinct somatic mutational landscape compared to that of their sporadic counterparts4.

In this paper, we examined somatic copy number variations (CNV) and transcriptome data to further characterize the somatic landscape of PHTS-derived BCs. We analyzed exome sequencing data from 44 BCs from women with PHTS for CNV. The control group comprised of 558 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We identified several distinct CNV peaks in PHTS-derived BCs compared to TCGA.  Our data revealed distinct CNV and transcript features in PHTS-derived BCs, which further facilitate understanding of BC biology arising in the setting of germline PTEN mutations.


We identified distinct somatic CNVs in PHTS-derived BCs compared to sporadic BCs. This includes a significant amplification peak at 6p22.2, which contains several histone-related genes, including HIST1H2BI. This gene was also correlationally expressed with the copy number change. The PTEN protein is known to interact with histone H1 to maintain chromatin organization and integrity5. Thus, the significant 6p22.2 amplification peak may represent a feedback loop to compensate for the compromised genome integrity and increased instability. We further divided PHTS-derived BCs based on the pathogenicity of the underlining germline PTEN variants. Pathway analysis using transcriptome data revealed ᾳ-tocopherol (Vitamin E) degradation to be a significantly enriched canonical pathway in PHTS-derived BCs with underlying pathogenic or likely pathogenic mutations. Vitamin E being an antioxidant which may potentially suppress tumorigenesis in certain cancer types. One hypothesis is that vitamin E plays an important role in suppressing the development of cancer in cells with dysfunctional PTEN-related pathways. Additionally, the PHTS-BC transcriptomic data showed PHTS-derived BCs have a distinct immunologic cell type signature, which points towards cancer immune evasion. We found the predicted PHTS-BC immune cell populations to be more inactive or suppressive compared to the sporadic counterpart. This may be associated with an immunosuppressive tumor microenvironment and resistance to immune checkpoint blockade6,7.

Future Prospects:

This paper identified characteristic genomic features of BCs arising in the setting of germline PTEN mutations.  Our study helps understand the biology of PHTS-derived BCs, which serves as a model for other cancer types arising in hereditary cancer syndromes. In this context, extensive studies at the clinical, translational, and basic science levels are warranted to develop gene-specific/targeted and personalized treatments, and perhaps preventatives, to effectively manage these hereditary cancers.


1          Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943-1947, doi:10.1126/science.275.5308.1943 (1997).

2          Tan, M. H. et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 18, 400-407, doi:10.1158/1078-0432.CCR-11-2283 (2012).

3          Yehia, L. et al. Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants. JAMA Netw Open 6, e239705, doi:10.1001/jamanetworkopen.2023.9705 (2023).

4          Brewer, T., Yehia, L., Bazeley, P. & Eng, C. Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants. Am J Hum Genet 109, 1520-1533, doi:10.1016/j.ajhg.2022.07.005 (2022).

5          Chen, Z. H. et al. PTEN interacts with histone H1 and controls chromatin condensation. Cell Rep 8, 2003-2014, doi:10.1016/j.celrep.2014.08.008 (2014).

6          Cheng, F. & Eng, C. PTEN Mutations Trigger Resistance to Immunotherapy. Trends Mol Med 25, 461-463, doi:10.1016/j.molmed.2019.03.003 (2019).

7          Vidotto, T. et al. Emerging role of PTEN loss in evasion of the immune response to tumours. Br J Cancer 122, 1732-1743, doi:10.1038/s41416-020-0834-6 (2020).



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