High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing
Abstract The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation, and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population, and recurrent disease. Hence, we...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-06-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-022-00443-9 |
| _version_ | 1827775516501868544 |
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| author | Anna Kostecka Tomasz Nowikiewicz Paweł Olszewski Magdalena Koczkowska Monika Horbacz Monika Heinzl Maria Andreou Renato Salazar Theresa Mair Piotr Madanecki Magdalena Gucwa Hanna Davies Jarosław Skokowski Patrick G. Buckley Rafał Pęksa Ewa Śrutek Łukasz Szylberg Johan Hartman Michał Jankowski Wojciech Zegarski Irene Tiemann-Boege Jan P. Dumanski Arkadiusz Piotrowski |
| author_facet | Anna Kostecka Tomasz Nowikiewicz Paweł Olszewski Magdalena Koczkowska Monika Horbacz Monika Heinzl Maria Andreou Renato Salazar Theresa Mair Piotr Madanecki Magdalena Gucwa Hanna Davies Jarosław Skokowski Patrick G. Buckley Rafał Pęksa Ewa Śrutek Łukasz Szylberg Johan Hartman Michał Jankowski Wojciech Zegarski Irene Tiemann-Boege Jan P. Dumanski Arkadiusz Piotrowski |
| author_sort | Anna Kostecka |
| collection | DOAJ |
| description | Abstract The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation, and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population, and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor, and peripheral blood from 52 reportedly sporadic breast cancer patients. Targeted resequencing of 542 cancer-associated genes revealed subclonal somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3, and TSHR in the normal mammary gland at considerable allelic frequencies (9 × 10−2– 5.2 × 10− 1), indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low-level subclonal (in 10−2–10−4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumorous mammary gland tissue of breast-conserving surgery patients. |
| first_indexed | 2024-03-11T13:51:36Z |
| format | Article |
| id | doaj.art-cc2598149fc04588ac0c210c85b15585 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-11T13:51:36Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-cc2598149fc04588ac0c210c85b155852023-11-02T08:49:48ZengNature Portfolionpj Breast Cancer2374-46772022-06-018111010.1038/s41523-022-00443-9High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencingAnna Kostecka0Tomasz Nowikiewicz1Paweł Olszewski2Magdalena Koczkowska3Monika Horbacz4Monika Heinzl5Maria Andreou6Renato Salazar7Theresa Mair8Piotr Madanecki9Magdalena Gucwa10Hanna Davies11Jarosław Skokowski12Patrick G. Buckley13Rafał Pęksa14Ewa Śrutek15Łukasz Szylberg16Johan Hartman17Michał Jankowski18Wojciech Zegarski19Irene Tiemann-Boege20Jan P. Dumanski21Arkadiusz Piotrowski22Faculty of Pharmacy, Medical University of GdanskDepartment of Surgical Oncology, Ludwik Rydygier’s Collegium Medicum UMK3P Medicine Lab, Medical University of GdanskFaculty of Pharmacy, Medical University of Gdansk3P Medicine Lab, Medical University of GdanskInstitute of Biophysics, Johannes Kepler University3P Medicine Lab, Medical University of GdanskInstitute of Biophysics, Johannes Kepler UniversityInstitute of Biophysics, Johannes Kepler UniversityFaculty of Pharmacy, Medical University of GdanskFaculty of Pharmacy, Medical University of GdanskDepartment of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala UniversityDepartment of Surgical Oncology, Medical University of GdanskGenuity Science Genomics CentreDepartment of Patomorphology, Medical University of GdanskDepartment of Surgical Oncology, Ludwik Rydygier’s Collegium Medicum UMKDepartment of Tumor Pathology, Prof. F. Lukaszczyk Oncology CenterDepartment of Oncology and Pathology, Karolinska InstitutetDepartment of Surgical Oncology, Ludwik Rydygier’s Collegium Medicum UMKDepartment of Surgical Oncology, Ludwik Rydygier’s Collegium Medicum UMKInstitute of Biophysics, Johannes Kepler University3P Medicine Lab, Medical University of GdanskFaculty of Pharmacy, Medical University of GdanskAbstract The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation, and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population, and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor, and peripheral blood from 52 reportedly sporadic breast cancer patients. Targeted resequencing of 542 cancer-associated genes revealed subclonal somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3, and TSHR in the normal mammary gland at considerable allelic frequencies (9 × 10−2– 5.2 × 10− 1), indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low-level subclonal (in 10−2–10−4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumorous mammary gland tissue of breast-conserving surgery patients.https://doi.org/10.1038/s41523-022-00443-9 |
| spellingShingle | Anna Kostecka Tomasz Nowikiewicz Paweł Olszewski Magdalena Koczkowska Monika Horbacz Monika Heinzl Maria Andreou Renato Salazar Theresa Mair Piotr Madanecki Magdalena Gucwa Hanna Davies Jarosław Skokowski Patrick G. Buckley Rafał Pęksa Ewa Śrutek Łukasz Szylberg Johan Hartman Michał Jankowski Wojciech Zegarski Irene Tiemann-Boege Jan P. Dumanski Arkadiusz Piotrowski High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing npj Breast Cancer |
| title | High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing |
| title_full | High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing |
| title_fullStr | High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing |
| title_full_unstemmed | High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing |
| title_short | High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing |
| title_sort | high prevalence of somatic pik3ca and tp53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing |
| url | https://doi.org/10.1038/s41523-022-00443-9 |
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