Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort

Hosneara Akter, Nasima Sultana, Nazrana Martuza, Aaysha Siddiqua, Nushrat Jahan Dity, Md Atikur Rahaman, Bisan Samara, Ahmed Sayeed, Mohammed Basiruzzaman, Mohammad Mizanur Rahman, Md Rashidul Hoq, Md Robed Amin, Md Abdul Baqui, Marc Woodbury-Smith, K. M.Furkan Uddin, Syed S. Islam, Rayhana Awwal, Bakhrom Berdiev, Mohammed Uddin

Research output: Contribution to journal › Article

Abstract

Background: Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway, and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes. Methods: We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes (BRCA1, BRCA2, ERBB2 and TP53) in a homogeneous patient cohort from Bangladesh (n = 52) by using tumor and blood samples. Results: Blood derived targeted sequencing revealed 25.58% (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95% (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions in BRCA2, and missense mutations in BRCA1, BRCA2 and ERBB2 gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting both TP53 (c.322dupG; a novel frameshift insertion) and BRCA1 genes (c.116G > A). 22% of tissue samples had a clinically relevant TP53 mutation. Although the cohort is small, we have found pathogenic mutations to be enriched in BRCA2 (9.30%, 4/43) compare to BRCA1 (4.65%, 2/43). The frequency of germline VUS mutations found to be similar in both BRCA1 (4.65%; 2/43) and BRCA2 (4.65%; 2/43) compared to ERBB2 (2.32%; 1/43). Conclusions: This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.

Original languageEnglish
Article number150
JournalBMC Medical Genetics
Volume20
Issue number1
DOIs
Publication statusPublished - Sep 2 2019

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Neoplasm Genes
Breast Neoplasms
Mutation
Genetic Testing
BRCA2 Gene
BRCA1 Gene
Bangladesh
Germ-Line Mutation
Population Genetics
Missense Mutation
Early Detection of Cancer
Neoplasms
Costs and Cost Analysis

Keywords

  • BRCA1
  • BRCA2
  • Breast Cancer
  • Pathogenic
  • VUS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Akter, H., Sultana, N., Martuza, N., Siddiqua, A., Dity, N. J., Rahaman, M. A., ... Uddin, M. (2019). Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort. BMC Medical Genetics, 20(1), [150]. https://doi.org/10.1186/s12881-019-0881-0

Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort. / Akter, Hosneara; Sultana, Nasima; Martuza, Nazrana; Siddiqua, Aaysha; Dity, Nushrat Jahan; Rahaman, Md Atikur; Samara, Bisan; Sayeed, Ahmed; Basiruzzaman, Mohammed; Rahman, Mohammad Mizanur; Rashidul Hoq, Md; Amin, Md Robed; Baqui, Md Abdul; Woodbury-Smith, Marc; Uddin, K. M.Furkan; Islam, Syed S.; Awwal, Rayhana; Berdiev, Bakhrom; Uddin, Mohammed.

In: BMC Medical Genetics, Vol. 20, No. 1, 150, 02.09.2019.

Research output: Contribution to journal › Article

Akter, H, Sultana, N, Martuza, N, Siddiqua, A, Dity, NJ, Rahaman, MA, Samara, B, Sayeed, A, Basiruzzaman, M, Rahman, MM, Rashidul Hoq, M, Amin, MR, Baqui, MA, Woodbury-Smith, M, Uddin, KMF, Islam, SS, Awwal, R, Berdiev, B & Uddin, M 2019, 'Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort', BMC Medical Genetics, vol. 20, no. 1, 150. https://doi.org/10.1186/s12881-019-0881-0
Akter H, Sultana N, Martuza N, Siddiqua A, Dity NJ, Rahaman MA et al. Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort. BMC Medical Genetics. 2019 Sep 2;20(1). 150. https://doi.org/10.1186/s12881-019-0881-0
Akter, Hosneara ; Sultana, Nasima ; Martuza, Nazrana ; Siddiqua, Aaysha ; Dity, Nushrat Jahan ; Rahaman, Md Atikur ; Samara, Bisan ; Sayeed, Ahmed ; Basiruzzaman, Mohammed ; Rahman, Mohammad Mizanur ; Rashidul Hoq, Md ; Amin, Md Robed ; Baqui, Md Abdul ; Woodbury-Smith, Marc ; Uddin, K. M.Furkan ; Islam, Syed S. ; Awwal, Rayhana ; Berdiev, Bakhrom ; Uddin, Mohammed. / Novel mutations in actionable breast cancer genes by targeted sequencing in an ethnically homogenous cohort. In: BMC Medical Genetics. 2019 ; Vol. 20, No. 1.
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abstract = "Background: Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway, and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes. Methods: We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes (BRCA1, BRCA2, ERBB2 and TP53) in a homogeneous patient cohort from Bangladesh (n = 52) by using tumor and blood samples. Results: Blood derived targeted sequencing revealed 25.58{\%} (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95{\%} (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions in BRCA2, and missense mutations in BRCA1, BRCA2 and ERBB2 gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting both TP53 (c.322dupG; a novel frameshift insertion) and BRCA1 genes (c.116G > A). 22{\%} of tissue samples had a clinically relevant TP53 mutation. Although the cohort is small, we have found pathogenic mutations to be enriched in BRCA2 (9.30{\%}, 4/43) compare to BRCA1 (4.65{\%}, 2/43). The frequency of germline VUS mutations found to be similar in both BRCA1 (4.65{\%}; 2/43) and BRCA2 (4.65{\%}; 2/43) compared to ERBB2 (2.32{\%}; 1/43). Conclusions: This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.",
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AU - Akter, Hosneara

AU - Sultana, Nasima

AU - Martuza, Nazrana

AU - Siddiqua, Aaysha

AU - Dity, Nushrat Jahan

AU - Rahaman, Md Atikur

AU - Samara, Bisan

AU - Sayeed, Ahmed

AU - Basiruzzaman, Mohammed

AU - Rahman, Mohammad Mizanur

AU - Rashidul Hoq, Md

AU - Amin, Md Robed

AU - Baqui, Md Abdul

AU - Woodbury-Smith, Marc

AU - Uddin, K. M.Furkan

AU - Islam, Syed S.

AU - Awwal, Rayhana

AU - Berdiev, Bakhrom

AU - Uddin, Mohammed

PY - 2019/9/2

Y1 - 2019/9/2

N2 - Background: Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway, and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes. Methods: We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes (BRCA1, BRCA2, ERBB2 and TP53) in a homogeneous patient cohort from Bangladesh (n = 52) by using tumor and blood samples. Results: Blood derived targeted sequencing revealed 25.58% (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95% (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions in BRCA2, and missense mutations in BRCA1, BRCA2 and ERBB2 gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting both TP53 (c.322dupG; a novel frameshift insertion) and BRCA1 genes (c.116G > A). 22% of tissue samples had a clinically relevant TP53 mutation. Although the cohort is small, we have found pathogenic mutations to be enriched in BRCA2 (9.30%, 4/43) compare to BRCA1 (4.65%, 2/43). The frequency of germline VUS mutations found to be similar in both BRCA1 (4.65%; 2/43) and BRCA2 (4.65%; 2/43) compared to ERBB2 (2.32%; 1/43). Conclusions: This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.

AB - Background: Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway, and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes. Methods: We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes (BRCA1, BRCA2, ERBB2 and TP53) in a homogeneous patient cohort from Bangladesh (n = 52) by using tumor and blood samples. Results: Blood derived targeted sequencing revealed 25.58% (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95% (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions in BRCA2, and missense mutations in BRCA1, BRCA2 and ERBB2 gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting both TP53 (c.322dupG; a novel frameshift insertion) and BRCA1 genes (c.116G > A). 22% of tissue samples had a clinically relevant TP53 mutation. Although the cohort is small, we have found pathogenic mutations to be enriched in BRCA2 (9.30%, 4/43) compare to BRCA1 (4.65%, 2/43). The frequency of germline VUS mutations found to be similar in both BRCA1 (4.65%; 2/43) and BRCA2 (4.65%; 2/43) compared to ERBB2 (2.32%; 1/43). Conclusions: This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.

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