Germline breast cancer susceptibility genes, tumor characteristics, and survival
Abstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-12-01
|
| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-021-00978-9 |
| _version_ | 1818735634664128512 |
|---|---|
| author | Peh Joo Ho Alexis J. Khng Hui Wen Loh Weang-Kee Ho Cheng Har Yip Nur Aishah Mohd-Taib Veronique Kiak Mien Tan Benita Kiat-Tee Tan Su-Ming Tan Ern Yu Tan Swee Ho Lim Suniza Jamaris Yirong Sim Fuh Yong Wong Joanne Ngeow Elaine Hsuen Lim Mei Chee Tai Eldarina Azfar Wijaya Soo Chin Lee Ching Wan Chan Shaik Ahmad Buhari Patrick M. Y. Chan Juliana J. C. Chen Jaime Chin Mui Seah Wai Peng Lee Chi Wei Mok Geok Hoon Lim Evan Woo Sung-Won Kim Jong Won Lee Min Hyuk Lee Sue K. Park Alison M. Dunning Douglas F. Easton Marjanka K. Schmidt Soo-Hwang Teo Jingmei Li Mikael Hartman |
| author_facet | Peh Joo Ho Alexis J. Khng Hui Wen Loh Weang-Kee Ho Cheng Har Yip Nur Aishah Mohd-Taib Veronique Kiak Mien Tan Benita Kiat-Tee Tan Su-Ming Tan Ern Yu Tan Swee Ho Lim Suniza Jamaris Yirong Sim Fuh Yong Wong Joanne Ngeow Elaine Hsuen Lim Mei Chee Tai Eldarina Azfar Wijaya Soo Chin Lee Ching Wan Chan Shaik Ahmad Buhari Patrick M. Y. Chan Juliana J. C. Chen Jaime Chin Mui Seah Wai Peng Lee Chi Wei Mok Geok Hoon Lim Evan Woo Sung-Won Kim Jong Won Lee Min Hyuk Lee Sue K. Park Alison M. Dunning Douglas F. Easton Marjanka K. Schmidt Soo-Hwang Teo Jingmei Li Mikael Hartman |
| author_sort | Peh Joo Ho |
| collection | DOAJ |
| description | Abstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions. |
| first_indexed | 2024-12-18T00:24:23Z |
| format | Article |
| id | doaj.art-324c3e5f19e348da8ee1b7ac569530b9 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-18T00:24:23Z |
| publishDate | 2021-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-324c3e5f19e348da8ee1b7ac569530b92022-12-21T21:27:17ZengBMCGenome Medicine1756-994X2021-12-0113111410.1186/s13073-021-00978-9Germline breast cancer susceptibility genes, tumor characteristics, and survivalPeh Joo Ho0Alexis J. Khng1Hui Wen Loh2Weang-Kee Ho3Cheng Har Yip4Nur Aishah Mohd-Taib5Veronique Kiak Mien Tan6Benita Kiat-Tee Tan7Su-Ming Tan8Ern Yu Tan9Swee Ho Lim10Suniza Jamaris11Yirong Sim12Fuh Yong Wong13Joanne Ngeow14Elaine Hsuen Lim15Mei Chee Tai16Eldarina Azfar Wijaya17Soo Chin Lee18Ching Wan Chan19Shaik Ahmad Buhari20Patrick M. Y. Chan21Juliana J. C. Chen22Jaime Chin Mui Seah23Wai Peng Lee24Chi Wei Mok25Geok Hoon Lim26Evan Woo27Sung-Won Kim28Jong Won Lee29Min Hyuk Lee30Sue K. Park31Alison M. Dunning32Douglas F. Easton33Marjanka K. Schmidt34Soo-Hwang Teo35Jingmei Li36Mikael Hartman37Genome Institute of Singapore, Human GeneticsGenome Institute of Singapore, Human GeneticsGenome Institute of Singapore, Human GeneticsSchool of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham MalaysiaSubang Jaya Medical CentreDepartment of Surgery, Faculty of Medicine, University of MalayaDepartment of Breast Surgery, Singapore General HospitalDepartment of Breast Surgery, Singapore General HospitalDivision of Breast Surgery, Changi General HospitalDepartment of General Surgery, Tan Tock Seng HospitalKK Breast Department, KK Women’s and Children’s HospitalDepartment of Surgery, Faculty of Medicine, University of MalayaDepartment of Breast Surgery, Singapore General HospitalDivision of Radiation Oncology, National Cancer Centre SingaporeLee Kong Chian School of Medicine, Nanyang Technology UniversityDivision of Medical Oncology, National Cancer Centre SingaporeCancer Research MalaysiaCancer Research MalaysiaDepartment of Hematology-oncology, National University Cancer Institute, National University Health SystemDepartment of Surgery, University Surgical Cluster, National University HospitalDepartment of Surgery, University Surgical Cluster, National University HospitalDepartment of General Surgery, Tan Tock Seng HospitalDepartment of General Surgery, Tan Tock Seng HospitalDivision of Breast Surgery, Changi General HospitalDivision of Breast Surgery, Changi General HospitalDivision of Breast Surgery, Changi General HospitalKK Breast Department, KK Women’s and Children’s HospitalKK Breast Department, KK Women’s and Children’s HospitalDepartment of Surgery, Breast Care Center, Daerim St. Mary’s HospitalDepartment of Surgery, University of Ulsan College of Medicine and Asan Medical CenterDepartment of Surgery, Soonchunhyang University and HospitalDepartment of Preventive Medicine, Seoul National University College of MedicineCentre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeCentre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeDivision of Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek HospitalCancer Research MalaysiaGenome Institute of Singapore, Human GeneticsSaw Swee Hock School of Public Health, National University of Singapore and National University Health SystemAbstract Background Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent. Methods Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease. Results PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]). Conclusions PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.https://doi.org/10.1186/s13073-021-00978-9Breast cancerProtein-truncating variantsOverall survival |
| spellingShingle | Peh Joo Ho Alexis J. Khng Hui Wen Loh Weang-Kee Ho Cheng Har Yip Nur Aishah Mohd-Taib Veronique Kiak Mien Tan Benita Kiat-Tee Tan Su-Ming Tan Ern Yu Tan Swee Ho Lim Suniza Jamaris Yirong Sim Fuh Yong Wong Joanne Ngeow Elaine Hsuen Lim Mei Chee Tai Eldarina Azfar Wijaya Soo Chin Lee Ching Wan Chan Shaik Ahmad Buhari Patrick M. Y. Chan Juliana J. C. Chen Jaime Chin Mui Seah Wai Peng Lee Chi Wei Mok Geok Hoon Lim Evan Woo Sung-Won Kim Jong Won Lee Min Hyuk Lee Sue K. Park Alison M. Dunning Douglas F. Easton Marjanka K. Schmidt Soo-Hwang Teo Jingmei Li Mikael Hartman Germline breast cancer susceptibility genes, tumor characteristics, and survival Genome Medicine Breast cancer Protein-truncating variants Overall survival |
| title | Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_full | Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_fullStr | Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_full_unstemmed | Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_short | Germline breast cancer susceptibility genes, tumor characteristics, and survival |
| title_sort | germline breast cancer susceptibility genes tumor characteristics and survival |
| topic | Breast cancer Protein-truncating variants Overall survival |
| url | https://doi.org/10.1186/s13073-021-00978-9 |
| work_keys_str_mv | AT pehjooho germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT alexisjkhng germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT huiwenloh germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT weangkeeho germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT chengharyip germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT nuraishahmohdtaib germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT veroniquekiakmientan germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT benitakiatteetan germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT sumingtan germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT ernyutan germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT sweeholim germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT sunizajamaris germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT yirongsim germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT fuhyongwong germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT joannengeow germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT elainehsuenlim germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT meicheetai germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT eldarinaazfarwijaya germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT soochinlee germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT chingwanchan germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT shaikahmadbuhari germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT patrickmychan germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT julianajcchen germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT jaimechinmuiseah germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT waipenglee germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT chiweimok germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT geokhoonlim germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT evanwoo germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT sungwonkim germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT jongwonlee germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT minhyuklee germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT suekpark germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT alisonmdunning germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT douglasfeaston germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT marjankakschmidt germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT soohwangteo germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT jingmeili germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival AT mikaelhartman germlinebreastcancersusceptibilitygenestumorcharacteristicsandsurvival |