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Hereditary Breast Cancer and Pathogenic Germline Variants

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Screening and Risk Reduction Strategies for Breast Cancer

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Abstract

Response to standard breast cancer therapies is variable and unpredictable prompting a shift in focus with design of multigene panels for more accurate monitoring and detection of malignant disease and prediction of response to treatment. More than 200 gene panels have been developed by academic and diagnostic laboratories relating to a variety of malignancies including breast cancer. After more than 25 years since identification of BRCA1 [1, 2] and BRCA2 [3–5] genes and their association with hereditary breast cancer (HBC) other driver genes predisposing to HBC risk such as TP53, CHEK2, PTEN, ATM, PALB2 amongst others have been widely linked in different ethnic groups. In the past decade, improved sequencing technologies and advanced algorithms to detect and stratify genomic variants have helped identify specific germline variants that are confirmed or likely pathogenic and positively contribute to diagnosis and treatment of HBC. A hallmark of breast cancers is their heterogeneous nature, and it is paramount to understand the biological and clinical significance of pathogenic germline variants (PGVs) in terms of risk level and the features of PGV-associated tumours. Genetic screening can potentially be employed for prevention of breast and other cancers together with management of disease among PGV carriers. This chapter reviews varying patterns of HBC among different ethnic populations and how genomic technology is continuing to reveal additional HBC predisposition genes. The potential role of pathogenic germline variants (PGVs) in HBC screening and prevention will be considered and how early detection might lead to improved treatment outcomes.

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Abbreviations

ASI:

Allele-specific imbalance

DCIS:

Ductal carcinoma in situ

FDA:

Food and Drug Administration

HBC:

Hereditary breast cancer

HCR:

Hereditary Cancer Registry

HRD:

Homologous recombination deficiency

IFN:

Interferon

LOH:

Loss of heterozygosity

MHC:

Major Histocompatibility Complex

OMIM:

Online Mendelian Inheritance in Man

OR:

Odds ratio

pCR:

Pathological complete response

PGVs:

Pathogenic germline variants

PheWAS:

Phenome-wide association studies

RR:

Relative risk

SNPs:

Single nucleotide polymorphisms

SNV:

Single nucleotide variant

TILs:

Tumour infiltrating lymphocytes

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Authors and Affiliations

  1. Breast Surgery, Graduate School of Medicine, Kyoto University Hospital, Kyoto University, Kyoto, Japan

    Ravi Velaga, Masakazu Toi, Nobuko Kawaguchi-Sakita & Noriko Senda

  2. Cambridge Breast Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    John R. Benson

  3. School of Medicine, Anglia Ruskin University, Cambridge, UK

    John R. Benson

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  1. Ravi Velaga
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  2. Masakazu Toi
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Correspondence to Masakazu Toi .

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  1. Grad. School Medicine, Surgery, Kyoto University, Kyoto, Japan

    Masakazu Toi

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Velaga, R., Toi, M., Kawaguchi-Sakita, N., Benson, J.R., Senda, N. (2023). Hereditary Breast Cancer and Pathogenic Germline Variants. In: Toi, M. (eds) Screening and Risk Reduction Strategies for Breast Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-19-7630-8_3

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  • DOI: https://doi.org/10.1007/978-981-19-7630-8_3

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