Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients

Diana Carolina Sierra-Díaz; Adrien Morel; Dora Janeth Fonseca-Mendoza; Nora Contreras Bravo; Nicolas Molano-Gonzalez; Mariana Borras; Isabel Munevar; Mauricio Lema; Henry Idrobo; Daniela Trujillo; Norma Serrano; Ana Isabel Orduz; Diego Lopera; Jaime González; Gustavo Rojas; Paula Londono-De Los Ríos; Ray Manneh; Rodrigo Cabrera; Wilson Rubiano; Jairo de la Peña; María Catalina Quintero; William Mantilla; Carlos M. Restrepo

doi:10.1186/s40246-024-00623-7

Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients

Diana Carolina Sierra-Díaz
, Adrien Morel
, Dora Janeth Fonseca-Mendoza
, Nora Contreras Bravo
, Nicolas Molano-Gonzalez
, Mariana Borras
, Isabel Munevar
, Mauricio Lema
, Henry Idrobo
, Daniela Trujillo
, Norma Serrano
, Ana Isabel Orduz
, Diego Lopera
, Jaime González
, Gustavo Rojas
, Paula Londono-De Los Ríos
, Ray Manneh
, Rodrigo Cabrera
, Wilson Rubiano
, Jairo de la Peña

María Catalina Quintero, William Mantilla, Carlos M. Restrepo

Breast and Soft Tissue Surgery

Universidad del Rosario
Fundación Cardioinfantil - Instituto de Cardiología
Clínica de Oncología Astorga
Centro Médico Julián Coronel
Hospital Internacional de Colombia
Oncólogos del Occidente S.A.S
Oncologos del Occidente SAS
SOHEC
Integrative IPS

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Background: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted. Results: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure. Conclusion: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.

Original language	English
Article number	68
Pages (from-to)	68
Journal	Human Genomics
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s40246-024-00623-7
State	Published - 18 Jun 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Minigene assay
Pathogenic germline variants
Unselected breast cancer
Whole exome sequencing
Genetic Predisposition to Disease
Ataxia Telangiectasia Mutated Proteins/genetics
Exome Sequencing
Humans
Middle Aged
Colombia/epidemiology
BRCA2 Protein/genetics
Genetic Testing/methods
Female
Germ-Line Mutation/genetics
Adult
Breast Neoplasms/genetics
Aged
BRCA1 Protein/genetics

Centers and Institutes Mederi

Cancer Institute

Access to Document

10.1186/s40246-024-00623-7

Functional genomics for the description of mutations in the molecular diagnosis of sporadic breast cancer in Colombian population
Restrepo, C. M. (PI), Sierra, D. (CoI), Fonseca-Mendoza, D. J. (PI), Ortega-Recalde, O. (CoI), Bravo, N. C. C. (CoI), Morel, A. (CoI) & Cabrera, R. (CoI)
1/02/22 → 31/08/23
Project: Research › Translational Research

Cite this

Sierra-Díaz, D. C., Morel, A., Fonseca-Mendoza, D. J., Bravo, N. C., Molano-Gonzalez, N., Borras, M., Munevar, I., Lema, M., Idrobo, H., Trujillo, D., Serrano, N., Orduz, A. I., Lopera, D., González, J., Rojas, G., Londono-De Los Ríos, P., Manneh, R., Cabrera, R., Rubiano, W., ... Restrepo, C. M. (2024). Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients. Human Genomics, 18(1), 68. Article 68. https://doi.org/10.1186/s40246-024-00623-7

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title = "Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients",

abstract = "Background: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2\_5496 + 5delTAAG), a minigene assay was conducted. Results: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5\%), ATM (1.25\%), BRCA1 (0.75\%), PALB2 (0.50\%), CHEK2 (0.50\%), BARD1 (0.25\%), and RAD51D (0.25\%) genes in the population of study. P/LP variants account for 6\% of the total population analyzed. No LGRs were detected in our study. We identified 1.75\% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2\_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure. Conclusion: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.",

keywords = "Minigene assay, Pathogenic germline variants, Unselected breast cancer, Whole exome sequencing, Genetic Predisposition to Disease, Ataxia Telangiectasia Mutated Proteins/genetics, Exome Sequencing, Humans, Middle Aged, Colombia/epidemiology, BRCA2 Protein/genetics, Genetic Testing/methods, Female, Germ-Line Mutation/genetics, Adult, Breast Neoplasms/genetics, Aged, BRCA1 Protein/genetics",

author = "Sierra-D{\'i}az, \{Diana Carolina\} and Adrien Morel and Fonseca-Mendoza, \{Dora Janeth\} and Bravo, \{Nora Contreras\} and Nicolas Molano-Gonzalez and Mariana Borras and Isabel Munevar and Mauricio Lema and Henry Idrobo and Daniela Trujillo and Norma Serrano and Orduz, \{Ana Isabel\} and Diego Lopera and Jaime Gonz{\'a}lez and Gustavo Rojas and \{Londono-De Los R{\'i}os\}, Paula and Ray Manneh and Rodrigo Cabrera and Wilson Rubiano and \{de la Pe{\~n}a\}, Jairo and Quintero, \{Mar{\'i}a Catalina\} and William Mantilla and Restrepo, \{Carlos M.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = jun,

day = "18",

doi = "10.1186/s40246-024-00623-7",

language = "Ingl{\'e}s",

volume = "18",

pages = "68",

journal = "Human Genomics",

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publisher = "BioMed Central Ltd.",

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Sierra-Díaz, DC, Morel, A, Fonseca-Mendoza, DJ, Bravo, NC, Molano-Gonzalez, N, Borras, M, Munevar, I, Lema, M, Idrobo, H, Trujillo, D, Serrano, N, Orduz, AI, Lopera, D, González, J, Rojas, G, Londono-De Los Ríos, P, Manneh, R, Cabrera, R, Rubiano, W , de la Peña, J, Quintero, MC, Mantilla, W & Restrepo, CM 2024, 'Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients', Human Genomics, vol. 18, no. 1, 68, pp. 68. https://doi.org/10.1186/s40246-024-00623-7

TY - JOUR

T1 - Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients

AU - Sierra-Díaz, Diana Carolina

AU - Morel, Adrien

AU - Fonseca-Mendoza, Dora Janeth

AU - Bravo, Nora Contreras

AU - Molano-Gonzalez, Nicolas

AU - Borras, Mariana

AU - Munevar, Isabel

AU - Lema, Mauricio

AU - Idrobo, Henry

AU - Trujillo, Daniela

AU - Serrano, Norma

AU - Orduz, Ana Isabel

AU - Lopera, Diego

AU - González, Jaime

AU - Rojas, Gustavo

AU - Londono-De Los Ríos, Paula

AU - Manneh, Ray

AU - Cabrera, Rodrigo

AU - Rubiano, Wilson

AU - de la Peña, Jairo

AU - Quintero, María Catalina

AU - Mantilla, William

AU - Restrepo, Carlos M.

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/6/18

Y1 - 2024/6/18

N2 - Background: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted. Results: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure. Conclusion: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.

AB - Background: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted. Results: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure. Conclusion: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.

KW - Minigene assay

KW - Pathogenic germline variants

KW - Unselected breast cancer

KW - Whole exome sequencing

KW - Genetic Predisposition to Disease

KW - Ataxia Telangiectasia Mutated Proteins/genetics

KW - Exome Sequencing

KW - Humans

KW - Middle Aged

KW - Colombia/epidemiology

KW - BRCA2 Protein/genetics

KW - Genetic Testing/methods

KW - Female

KW - Germ-Line Mutation/genetics

KW - Adult

KW - Breast Neoplasms/genetics

KW - Aged

KW - BRCA1 Protein/genetics

UR - https://www.scopus.com/pages/publications/85196143073

UR - https://www.mendeley.com/catalogue/1dfb4252-cf38-35c4-a5a1-177ee819b91b/

U2 - 10.1186/s40246-024-00623-7

DO - 10.1186/s40246-024-00623-7

M3 - Artículo

C2 - 38890714

AN - SCOPUS:85196143073

SN - 1473-9542

VL - 18

SP - 68

JO - Human Genomics

JF - Human Genomics

IS - 1

M1 - 68

ER -

Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients

Abstract

UN SDGs

Keywords

Centers and Institutes Mederi

Access to Document

Fingerprint

Projects

Functional genomics for the description of mutations in the molecular diagnosis of sporadic breast cancer in Colombian population

Cite this