Prevalence of specific and recurrent/founder pathogenic variants in <i>BRCA</i> genes in breast and ovarian cancer in North Africa

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Abstract

Background

Elucidation of specific and recurrent/founder pathogenic variants (PVs) in BRCA ( BRCA1 and BRCA2) genes can make the genetic testing, for breast cancer (BC) and/or ovarian cancer (OC), affordable for developing nations.

Methods

To establish the knowledge about BRCA PVs and to determine the prevalence of the specific and recurrent/founder variants in BRCA genes in BC and/or OC women in North Africa, a systematic review was conducted in Morocco, Algeria, and Tunisia.

Results

Search of the databases yielded 25 relevant references, including eleven studies in Morocco, five in Algeria, and nine in Tunisia. Overall, 15 studies investigated both BRCA1 and BRCA2 genes, four studies examined the entire coding region of the BRCA1 gene, and six studies in which the analysis was limited to a few BRCA1 and/or BRCA2 exons. Overall, 76 PVs (44 in BRCA1 and32 in BRCA2) were identified in 196 BC and/or OC patients (129 BRCA1 and 67 BRCA2 carriers). Eighteen of the 76 (23.7%) PVs [10/44 (22.7%) in BRCA1 and 8/32 (25%) in BRCA2] were reported for the first time and considered to be novel PVs. Among those identified as unlikely to be of North African origin, the BRCA1 c.68_69del and BRCA1 c.5266dupC Jewish founder alleles and PVs that have been reported as recurrent/founder variants in European populations (ex: BRCA1 c.181T>G, BRCA1 c1016dupA). The most well characterized PVs are four in BRCA1 gene [c.211dupA (14.7%), c.798_799detTT (14%), c.5266dup (8.5%), c.5309G>T (7.8%), c.3279delC (4.7%)] and one in BRCA2 [c.1310_1313detAAGA (38.9%)]. The c.211dupA and c.5309G>T PVs were identified as specific founder variants in Tunisia and Morocco, accounting for 35.2% (19/54) and 20.4% (10/49) of total established BRCA1 PVs, respectively. c.798_799delTT variant was identified in 14% (18/129) of all BRCA1 North African carriers, suggesting a founder allele. A broad spectrum of recurrent variants including BRCA1 3279delC, BRCA1 c.5266dup and BRCA2 c.1310_1313detAAGA was detected in 42 patients. BRCA1 founder variants explain around 36.4% (47/129) of BC and outnumber BRCA2 founder variants by a ratio of ≈3:1.

Conclusions

Testing BC and/or OC patients for the panel of specific and recurrent/founder PVs might be the most cost-effective molecular diagnosis strategy.

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Most cited references 157

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

Jeffery P Struewing, Patricia Hartge, Sholom Wacholder … (1997)

Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area. We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers. One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.

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Author and article information

Contributors

Oubaida ElBiad: obdo90@gmail.com

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 25 February 2022

Publication date PMC-release: 25 February 2022

Publication date Collection: 2022

Volume: 22

Electronic Location Identifier: 208

Affiliations

[1 ]Laboratoire de Recherche et de Biosécurité P3, Hôpital Militaire d’Instruction Mohammed V, Rabat, Maroc

[2 ]GRID grid.31143.34, ISNI 0000 0001 2168 4024, Unité de séquençage, Laboratoire de Virologie, Centre de Virologie, des Maladies Infectieuses et Tropicales, Hôpital Militaire d’Instruction Mohammed V, Faculté de Médecine et de Pharmacie, , Université Mohammed V, ; Rabat, Maroc

[3 ]GRID grid.31143.34, ISNI 0000 0001 2168 4024, Laboratoire de Biodiversité, Ecologie et Génome, Faculté des Sciences, , Université Mohammed V, ; Rabat, Maroc

[4 ]GRID grid.31143.34, ISNI 0000 0001 2168 4024, Centre de virologie, des maladies infectieuses et tropicales, Hôpital militaire d’Instruction Mohammed V, Faculté de Médecine et de Pharmacie, , Université Mohammed V, ; Rabat, Maroc

[5 ]GRID grid.20715.31, ISNI 0000 0001 2337 1523, Laboratoire de Biochimie-Toxicologie, Hôpital Militaire Moulay Ismail Meknès, Faculté de Médecine et de Pharmacie, , Université Sidi Mohamed Ben Abdellah, ; Fès, Maroc

[6 ]Laboratoire de Virologie, Microbiologie, Qualité, Biotechnologies/Ecotoxicologie et Biodiversité, Faculté des sciences et techniques, Mohammadia, Université Hassan II, Casa, Maroc

[7 ]GRID grid.31143.34, ISNI 0000 0001 2168 4024, Service de Gynécologie Obstétrique, Hôpital militaire d’Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Université Mohammed V, ; Rabat, Maroc

[8 ]GRID grid.31143.34, ISNI 0000 0001 2168 4024, Laboratoire d’Anatomopathologie, Hôpital militaire d’Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Université Mohammed V, ; Rabat, Maroc

[9 ]GRID grid.31143.34, ISNI 0000 0001 2168 4024, Service d’Oncologie Médicale, Hôpital militaire d’Instruction Mohammed V, Faculté de Médecine et de Pharmacie, Université Mohammed V, ; Rabat, Maroc

Article

Publisher ID: 9181

DOI: 10.1186/s12885-022-09181-4

PMC ID: 8876448

PubMed ID: 35216584

SO-VID: 9199f291-eb67-4232-8675-d9218ff9922a

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 22 July 2021

Date accepted : 24 November 2021

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: brca genes,specific variant,recurrent/founder variant,north africa

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: brca genes, specific variant, recurrent/founder variant, north africa

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Prevalence of specific and recurrent/founder pathogenic variants in BRCA genes in breast and ovarian cancer in North Africa

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Abstract

Background

Methods

Results

Conclusions

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Karger: Oncology

Most cited references 157

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

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