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Takae.PhD.Thesis.v5.12.21.23.pdf (1.98 MB)

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GENOMIC LANDSCAPE PROFILING OF BREAST CANCER IN PTEN HAMARTOMA TUMOR SYNDROME

Mizukami, Takae
http://orcid.org/0000-0001-7725-3127
http://rave.ohiolink.edu/etdc/view?acc_num=case1704657067658585

Abstract Details

2023, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS) confer up to 85-91% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlining genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing from 44 breast tissues from women with germline PTEN variants who developed BC. The control cohort comprised of 497 sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p<0.001), and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p=0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p=0.01), but not in TCGA. There appear to be two genomically distinct groups of PHTS BCs, depending on the pathogenicity of underlying germline PTEN variants. We then examined copy number variations (CNV) and expression data to further characterize the somatic landscape of PHTS-derived BC. To examine CNV, we used the same exome sequencing data from 44 PHTS-derived BC cases described above and an expanded TCGA cohort with 558 women with sporadic BCs. We demonstrated that PHTS-derived BCs have several distinct CNV peaks compared to TCGA. Furthermore, RNA sequencing data revealed that PHTS-derived BCs have distinct inferred immunologic cell types, which points toward cancer immune evasion. Gene expression data also revealed previously described Tier-1 PHTS-derived BC, with pathogenic germline PTEN variants, appears to have vitamin E degradation as a key pathway in tumorigenesis. In conclusion, our findings have important implications for the personalized management of PTEN-related BCs, which are currently treated similarly to the sporadic BCs. Germline PTEN alterations are expected to be identified more frequently as an important underlying cause of BCs, especially in the context of more accessible genetic testing. More effective and targeted treatment strategies are warranted for this unique group of women affected by BCs.
Charis Eng (Advisor)
Thonas LaFramboise (Committee Member)
Ruth Keri (Committee Member)
Jonathan Smith (Committee Chair)
158 p.
Biology; Genetics; Oncology
cancer genetics, breast cancer, PTEN hamartoma tumor syndrome, PTEN, somatic profile, next generation sequencing, mutational signatures, copy number alterations, DNA sequencing, RNA sequencing

Recommended Citations

Citations

  • Mizukami, T. (2023). GENOMIC LANDSCAPE PROFILING OF BREAST CANCER IN PTEN HAMARTOMA TUMOR SYNDROME [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1704657067658585

    APA Style (7th edition)

  • Mizukami, Takae. GENOMIC LANDSCAPE PROFILING OF BREAST CANCER IN PTEN HAMARTOMA TUMOR SYNDROME. 2023. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1704657067658585.

    MLA Style (8th edition)

  • Mizukami, Takae. "GENOMIC LANDSCAPE PROFILING OF BREAST CANCER IN PTEN HAMARTOMA TUMOR SYNDROME." Doctoral dissertation, Case Western Reserve University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=case1704657067658585

    Chicago Manual of Style (17th edition)

case1704657067658585
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© 2023, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
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