Moukadem HA, Fakhreddine MA, Assaf N, Safi N, Al Masry A, Al Darazi M, Mahfouz R, El Saghir NS. Germline pathogenic variants among high hereditary risk patients with breast and ovarian cancer and unaffected subjects in Lebanese Arab women. World J Clin Oncol 2024; 15(12): 1481-1490 [DOI: 10.5306/wjco.v15.i12.1481]
Corresponding Author of This Article
Nagi S El Saghir, MD, Professor, Division of Hematology Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Cairo Street, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon. ns23@aub.edu.lb
Research Domain of This Article
Oncology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Hiba A Moukadem, Mohammad A Fakhreddine, Nadine Safi, Ahmad Al Masry, Monita Al Darazi, Nagi S El Saghir, Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon
Nada Assaf, Rami Mahfouz, Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut 1001, Lebanon
Author contributions: El Saghir NS was responsible for conception and design and administrative support; Mahfouz R and El Saghir NS were responsible for provision of study materials or patients; Moukadem HA, Fakhreddine MA, Assaf N, Safi N, Al Masry A, Al-Darazi MH and El Saghir NS were responsible for collection and assembly of data; Moukadem HA, Fakhreddine MA, Assaf N and El Saghir NS were responsible for data analysis and interpretation; Moukadem HA, Fakhreddine MA, Assaf N, Safi N, Al Masry A, Al Darazi M, Mahfouz R and El Saghir NS were responsible for manuscript writing and final approval of manuscript; all of the authors read and approved the final version of the manuscript to be published.
Institutional review board statement: The study was reviewed and approved by the Institutional Review board at the American University of Beirut Medical Center.
Informed consent statement: No consent form was required since patients were not approached.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Data sharing statement: Study data are available upon request from the corresponding author.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Nagi S El Saghir, MD, Professor, Division of Hematology Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Cairo Street, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon. ns23@aub.edu.lb
Received: July 10, 2024 Revised: August 23, 2024 Accepted: October 11, 2024 Published online: December 24, 2024 Processing time: 103 Days and 11.8 Hours
Abstract
BACKGROUND
The prevalence of germline pathogenic variants in high hereditary risk breast and/or ovarian cancer patients and unaffected subjects referred for testing is an unmet need in low and middle-income countries.
AIM
To determine the prevalence of germline pathogenic variants in high hereditary risk patients with breast and/or ovarian cancer and unaffected individuals.
METHODS
We retrospectively reviewed records of patients and unaffected subjects referred for germline pathogenic variant testing due to high hereditary risk between 2010-2020. Data was collected and analyzed on Excel sheet.
RESULTS
In total, 358 individuals were included, including 257 patients and 101 unaffected individuals with relatives with breast or ovarian cancer. The prevalence of breast cancer susceptibility gene (BRCA) 1/2 pathogenic variants was 8.63% (19/220) in patients with breast cancer, and 15.1% (5/33) in those with ovarian cancer. Among the 25 of 220 patients with breast cancer tested by next-generation sequencing, 3 patients had pathogenic variants other than BRCA1/2. The highest risk was observed in those aged 40 years with breast cancer and a positive family history, where the BRCA1/2 prevalence was 20.1% (9/43). Among the unaffected subjects, 31.1% (14/45) had the same BRCA1/2 pathogenic variants in their corresponding relatives. Among the subjects referred because of a positive family history of cancer without known hereditary factors, 5.35% (3/56) had pathogenic variants of BRCA1 and BRCA2. The c.131G>T nucleotide change was noted in one patient and two unrelated unaffected subjects with a BRCA1 pathogenic variant.
CONCLUSION
This study showed a 8.63% prevalence of pathogenic variants in patients with breast cancer and a 15.1% prevalence in patients with ovarian cancer. Among the relatives of patients with BRCA1/2 pathogenic variants, 31% tested positive for the same variant, while 5.3% of subjects who tested positive due to a family history of breast cancer had a BRCA pathogenic variant.
Core Tip: This is the first study on referred patients with breast and/or ovarian cancer and subjects at high hereditary risk for germline pathogenic variant testing among ethnic Lebanese Arab women. The prevalence of pathogenic variants was 8.63% in patients with breast cancer and 15.1% in patients with ovarian cancer. Among the relatives of patients with breast cancer susceptibility gene (BRCA) 1/2 pathogenic variants, 31% tested positive for the same variant, while 5.3% of subjects who tested positive due to a family history of breast cancer had a BRCA pathogenic variant. The results of this study support the hypothesis that the c.131G>T nucleotide change is a founder pathogenic variant in this population.
Citation: Moukadem HA, Fakhreddine MA, Assaf N, Safi N, Al Masry A, Al Darazi M, Mahfouz R, El Saghir NS. Germline pathogenic variants among high hereditary risk patients with breast and ovarian cancer and unaffected subjects in Lebanese Arab women. World J Clin Oncol 2024; 15(12): 1481-1490
According to the Global Cancer Observatory 2022, breast cancer is the most common cancer in females, accounting for 23.8% of new cancer cases worldwide, while ovarian cancer accounts for 3.4% of all cases[1]. In Lebanon, breast cancer constitutes 35%-40% of cancers in women, with 50% of cases diagnosed below the age of 50 years, and ovarian cancer constitutes 1.7% of cases[2-3]. The age-standardized incidence-rate of breast cancer was estimated at 91.7 per 100000 between 2005 and 2015, and 7.10 per 100000 for ovarian cancer between 2005 and 2016[3].
Most breast cancer cases are sporadic, with up to 15% familial and up to 10% hereditary[4]. High-penetrance genes, including BRCA1 and BRCA2, are responsible for 50% of the hereditary breast cancer cases[5]. BRCA1 and BRCA2 are tumor suppressor genes located on chromosomes 17q and 13q, with 22 and 26 coding exons, respectively[6]. Most pathogenic variants in the coding sequences of these genes are point mutations, insertions, or deletions that cause shortening of the BRCA1 protein, ultimately leading to alterations in the DNA repair systems. The prevalence of pathogenic BRCA variants ranges from 0.6%-36.9% across different countries[5].
The criteria for testing for germline pathogenic variants in breast cancer cases include women with triple-negative breast cancer (TNBC) below the age of 60 years, young age at diagnosis, or a family history of breast or ovarian cancer[7-10]. Studies have shown that 15%-25% of ovarian cancer cases are associated with breast cancer susceptibility gene (BRCA) 1/2 germline pathogenic variants[11,12]. The estimated lifetime risk of developing breast cancer in women with BRCA1/2 pathogenic variants ranges between 59%-69% for BRCA1 and 48%-72% for BRCA2; for ovarian cancer, the risk is between 39%-58% and 13%-29% for carriers of BRCA1 and BRCA2, respectively[13]. Breast cancer predisposition is also significantly elevated in partner and localizer of BRCA2 (PALB2) pathogenic variants, whose carriers have a 41%-60% lifetime risk of developing breast cancer[14,15].
In 2015, a prospective study of 250 Arab Lebanese women with breast cancer who met the criteria for genetic testing showed an overall prevalence of BRCA1 and BRCA2 pathogenic variants of 5.6%[16], while it was estimated to be 10%-15% in similar cohorts from the United States and Europe[17]. Studies from neighboring Arab countries showed a prevalence up to 20%[18]. Higher estimates have been reported in studies from Jordan (19.6% of BRCA pathogenic variants)[19] and Saudi Arabia (12.9%)[20]. For ovarian cancer, scarce data exist from Arab countries, and none from Lebanon.
The discovery of a pathogenic variant in either patient group (breast or ovarian cancer)[21-24] has implications not only for screening and early detection but also for patient management diagnosed with early or metastatic disease[25-27]. The detection of pathogenic variants could also benefit family members of patients with germline alterations, who are typically counseled about the risks of developing cancers and appropriate preventive and early detection options[28].
Identifying pathogenic variants in other moderate-risk genes [such as PALB2, ataxia telengectasia mutated (ATM), checkpoint kinase 2 (CHEK2), BRCA1 interacting protein C-terminal helicase 1 (BRIP1)] is also gaining clinical importance[29-32]. Antoniou et al[14] analyzed the risk of breast cancer in 362 patients with the PALB2 pathogenic variant and found that carriers were associated with an 8-9 times higher probability of developing breast cancer in those younger than 40 years, 6-8 times higher in those aged between 40 years and 60 years, and 5 times higher in those older than 60 years. Data on these variants in Arab populations are either missing or scarce[20].
The aim of this study was to assess the prevalence of BRCA1/2 and other germline pathogenic variants in patients and nonaffected subjects at high-risk for hereditary breast and/or ovarian cancer in ethnic Lebanese Arab referred for testing at the American University of Beirut Medical Center (AUBMC) Genetics Laboratory between 2010 and 2020. In our initial Institutional Review Board (IRB)-approved project, we planned to include the prevalence of pathogenic variants in patients with prostate cancer; however, the number of patients was only three. Therefore, we present and analyze data on patients with breast and/or ovarian cancer in this article.
MATERIALS AND METHODS
A retrospective chart review was conducted to retrieve the clinical, radiologic, pathologic, and genetic data of 358 individuals with a high hereditary risk for breast and ovarian cancer who were referred to the AUBMC laboratory for genetic testing between January 1, 2010, and August 25, 2020. Between January 1, 2010 and January 1, 2019, testing for BRCA1 and BRCA2 was performed by Sanger sequencing of all coding exons and immediately flanking introns. In 2019, Sanger sequencing was replaced by next-generation sequencing (NGS) panels of 70 cancer-related genes at Centogene Laboratories in Germany. The study was reviewed and approved by the IRB of AUBMC.
Data collection and analysis
Patient data were accessed through electronic medical records from papers and electronic (EPIC) medical records. The EPIC Program started at the AUBMC in November 2018. The data collection sheet included the following variables: (1) Demographics; (2) Age; (3) Tumor pathology; (4) Tumor staging; (5) Tumor characteristics; (6) Family history of cancer; (7) Treatment received; (8) Laboratory and imaging results; and (9) Outcomes. All male and female subjects with a family history of breast or ovarian cancer and patients with breast or ovarian cancer who underwent germline pathogenic variant testing performed between January 01, 2010, and August 25, 2020, at the AUBMC were included in this study. The National Comprehensive Cancer Network (NCCN) criteria were used for germline genetic testing. All the included participants were eligible for testing. The NCCN criteria for testing of unaffected individuals with a positive family history: (1) > 1 first-degree or second-degree relative with breast cancer at age ≤ 50 years, male breast, ovarian, pancreatic, metastatic prostate cancers; Or (2) > 3 first-degree or second-degree relatives with breast and/or prostate cancer. Because this was a retrospective study, the sample size was not calculated. All patients who fulfilled the eligibility criteria were enrolled. The patients and unaffected participants were referred from various hospitals and communities for testing. The principal investigator and research team had exclusive access to the patients’ medical records for data collection and analysis. Data were de-identified after collection, and each patient was given a unique code, which was used for data analysis to ensure confidentiality. The list of code numbers with corresponding patient names was recorded on a separate datasheet accessible only to the research team. The linking documents were shredded after the data collection was completed. Consent forms were not required because the patients were not approached. All medical and genetic variants were verified against germline variants in the ClinVar international database. The collected data were entered on a Microsoft Excel sheet and analyzed, and the results were calculated using the same program.
Sanger sequencing
DNA was extracted from blood and saliva samples received (blood/saliva). It was then PCR amplified for sequence-based analysis to screen for mutations in all 24 coding exons of BRCA1 and 27 coding exons of BRCA2. Sanger sequencing was performed using the Applied Biosystems strategy for automated fluorescent sequencing with a Big Dye Terminator. The analysis consisted of sequencing all coding exons immediately flanking the intronic regions of BRCA1 and BRCA2. The sequence was obtained and analyzed by comparison with published BRCA1 and BRCA2 gene sequences. Software analysis was performed using Mutation Taster (http://mutationtaster.org), Polyphen-2 (http://genetics.bwh.harvard.edu), SIFT software (http://sift.jcvi.org), and the International Agency for Research on Cancer database (http://brca.iarc.fr) to predict the nature of the detected variants.
NGS testing
Starting with DNA isolated from the blood or saliva, sequencing-ready libraries are generated using highly multiplexed oligonucleotide probes. The sample-specific indices were added to each library. The pooled libraries were loaded onto a MiSeq system (Illumina) for automated sequencing and data analysis. The oligo pool targeted 65 full-length genes and 125 single nucleotide polymorphisms. This panel uses hybrid-capture chemistry to provide uniform coverage of the target regions (exons plus 10 bp flanking regions), enabling > 20 × coverage for > 99% of the amplicons. Known pathogenic and likely pathogenic variants described in Human Gene Mutation Database® and the CENTOGENE’s Biodatabank, including relevant deep intronic and regulatory variants known at the time of the assay design. Genes tested in this panel include: (1) Anaphase-promoting-complex; (2) ATM; (3) Axis inhibition protein 2; (4) BRCA associated protein 1; (5) Breast cancer susceptibility 1-associated RING domain; (6) Bleomycin; (7) Bone morphogenetic protein receptor, type IA; (8) BRCA1; (9) BRCA2; (10) BRIP1; (11) E-cadherin; (12) Cyclin-dependent kinases 4; (13) CDKN2A; (14) CHEK2; (15) Dicer 1, ribonuclease III; (16) DIS3 like 3'-5' exoribonuclease 2; (17) Epithelial cell adhesion molecule; (18) FANCC; (19) Fused hirudin; (20) Folliculin; (21) Polypeptide N-acetylgalactosaminyltransferase 12; (22) Homeobox protein B13; (23) KIT; (24) Melano-cortin 1 receptor; (25) Multiple endocrine neoplasia type 1; (26) Methylation; (27) Microphthalmia-associated transcription factor; (28) MutL homolog (MLH) 1; (29) MLH3; (30) Meiotic recombination 11; (31) MutS homolog (MSH)2; (32) MSH3; (33) MSH6; (34) MutY human homologue; (35) Nitrogen balance; (36) Neurofibromatosis type 1; (37) N tabacum hybrid lethality 1; (38) PALB2; (39) PMS1 homolog 2; (40) Polymerase delta 1; (41) Polymerase (DNA) epsilon, catalytic subunit; (42) Peroxisomal 3-oxoacyl-CoA thiolase gene; (43) Cationic trypsinogen gene; (44) Patched 1; (45) Chromosome 10; (46) RAD50; (47) RAD51C; (48) RAD51D; (49) RecQ like helicase; (50) Glial cell derived neurotrophic factor receptor-beta; (51) Ring finger protein 43; (52) Ribosomal protein S20; (53) Succinate dehydrogenase complex flavoprotein subunit A; (54) Succinate dehydrogenase assembly factor 2; (55) Succinate dehydrogenase B; (56) Shunt-dependent hydrocephalus; (57) Succinate dehydrogenase complex subunit D; (58) Mothers against decapentaplegic homolog 4; (59) Matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4; (60) Serine/threonine kinase 11; (61) Tumor protein p53 (TP53); (62) Tuberous sclerosis complex (TSC)1; (63) TSC2; (64) Von hippel-lindau; (65) Wilms' tumor 1; (66) X-ray repair of cross-complementary (XRCC) 2; and (67) XRCC3. Unaffected family members with known familial pathogenic or likely pathogenic variants of a cancer predisposition gene were subjected to targeted sequencing for known familial variants. PCR analysis was performed by means of PCR followed by Sanger sequencing of the exons harboring a known mutation in the gene of interest.
RESULTS
Patients with breast cancer
Of the 358 individuals included in the study, 220 had breast cancer. Two hundred and nineteen were females and one was a male. Forty-three were diagnosed at age ≤ 40 years, 75 were aged between 41-50 years, and 102 were aged > 50 years at diagnosis. One hundred and seventy-five subjects underwent BRCA1/2 Sanger sequencing, and 25 underwent NGS panel testing. One male patient with both breast and prostate cancers also underwent BRCA1/2 Sanger sequencing (Figure 1, Tables 1 and 2).
Table 2Breast cancer susceptibility gene 2 pathogenic variants identified in patients with breast/ovarian cancer.
Nucleotide change
Molecular consequence
Location
Number of patients
Breast cancer
C.9257-1G>A
Splice acceptor
Intron 24
3
C.3189_3192del
P.Ser1064fs
Exon 11
1
C.2808_2811del
P.Ala938fs
Exon 11
1
Ovarian cancer
C.9257-1G>A
Splice acceptor
Intron 24
1
C.7806-2A>T
Splice acceptor
Intron 16
1
Patients with ovarian cancer
Of the 358 individuals referred for genetic testing, 33 had ovarian cancer. Thirty patients underwent Sanger sequencing and three underwent NGS panel testing. Three patients had both ovarian and breast cancers (Figure 1, Tables 1 and 2).
In this study, the incidence of BRCA1 and BRCA2 pathogenic variants in women with breast and ovarian cancers was 8.63% (19/220) and 15.1% (5/33), respectively (Table 3). Of the three patients with both breast and ovarian cancers, two had a BRCA1 pathogenic variant.
Table 3 Genetic testing results for patients diagnosed with breast and/or ovarian cancer.
Type of cancer
Affected gene
Pathogenic variant
Breast
BRCA1
6.36 (14/220)
BRCA2
2.27 (5/220)
BRCA1/2
8.63 (19/220)
Ovarian
BRCA1
9.09 (3/33)
BRCA2
6.06 (2/33)
BRCA1/2
15.15 (5/33)
Breast and ovarian
BRCA1
2/3
Pathogenic variants and age
Forty-three of the 220 patients with breast cancer were aged 40 years or younger, nine of whom had a BRCA1/2 pathogenic variant (20.1%). Of the 19 patients with breast cancer and BRCA1/2 pathogenic variants, 9 were ≤ 40 years old. Among the 28 patients who underwent NGS panel sequencing (25 with breast cancer and 13 with ovarian cancer), two had a PALB2 pathogenic variant, and one had a TP53 pathogenic variant. All three patients had breast cancer (Table 4).
Table 4 Sequence mutations identified in patients with germline pathogenic variants other than breast cancer susceptibility gene 1/2 (all 3 patients were diagnosed with breast cancer).
Genes
Nucleotide change
Molecular consequence
Location
Number of patients
PALB2
C.2257C>T
P.Arg753Ter
Exon 5
1
PALB2
C.93dupA
P.Leu32fs
Exon 2
1
Tumor protein p53
C.375G>A
P.(Thr125)
Exon 4
1
Pathogenic variants and pathology data: Pathological data were available for all the 207 patients. Of these, 166 patients (80.19%) had Infiltrating Ductal Carcinoma, 10 patients (4.83%) had Infiltrating Lobular Carcinoma, 30 patients (14.49%) had ductal Carcinoma in situ, one had invasive tubulolobular carcinoma and one had a high-grade neuroendocrine tumor. Data were available for 205 patients; 22 patients (10.7%) had grade 1 disease, 70 patients (34.1%) had grade 2 disease, and 113 patients (55.1%) had grade 3 disease. Estrogen receptors were positive in 143/208 patients (68.75%), progesterone receptor was positive in 129/208 patients (62%), human epidermal growth factor receptor 2 (HER2) was overexpressed in 74/207 patients (35.74%), and HER2 was not available in one patient. TNBC was present in 43/208 patients (20.67%).
BRCA1 pathogenic variants were found in 23.25% (10/43) of patients with TNBC, and 62.5% of BRCA1 pathogenic variant (10/16) had TNBC. Of the five BRCA2 patients with breast cancer, one had TNBC, two had HER2 overexpression with hormone-receptor (HR)-positive sensitivity, and two had HR+. Complete pathological information was available for all patients with pathogenic variants.
Nonaffected subjects
A total of 101 individuals without a cancer diagnosis were referred for testing because of a positive family history of cancer or a known deleterious pathogenic variant in first-degree or second-degree family members. Of these, 31% were pathogenic BRCA variants. Eleven subjects (out of 30) who underwent targeted sequencing for BRCA1 carried the familial variant, and three subjects (out of 15) with known familial BRCA2 pathogenic variants were found to be carriers. Of the remaining 56 (out of 101) patients tested due to a positive family history of cancer, three (5.3%) had a BRCA pathogenic variant, two had a pathogenic BRCA1 variant, and one had a pathogenic BRCA2 variant (Figure 2, Table 5).
Figure 2 Non-affected subjects results. BRCA: Breast cancer susceptibility gene.
Table 5 Sequence pathogenic variants identified in non-affected subjects with deleterious breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2 variants.
To our knowledge, this is the first study of germline pathogenic variants in ethnic Lebanese Arab patients with cancer and in unaffected subjects at high risk for hereditary breast and ovarian cancer referred for testing. The types of pathogenic variants observed were comparable to those described in the literature and genetic banks, including stop codons, frameshifts, and splice-site mutations. The total incidence of BRCA1/2 pathogenic variants in our cohort of patients with breast cancer was 8.63% (19/220). Other small studies have shown a BRCA1/2 prevalence of 7.4%[19] and 12.5%[33] among individuals with a high risk for hereditary breast or ovarian cancer genes. In Lebanon, approximately 50% of the patients with breast cancer are younger than 50 years[4]. The first BRCA testing study was published in 2012, in which 72 unrelated patients with a reported family history of breast and/or ovarian cancers were tested, and 9 subjects were identified to carry a deleterious mutation (12.5%)[33]. In a study of ethnic Arab patients with hereditary breast cancer in Saudi Arabia, 40 patients (12.9%) had BRCA1/2 pathogenic variants (BRCA1 in 10.7% and BRCA2 in 2.2%)[20]. A recent study of 81 patients with breast cancer in Egypt showed a 14.8% risk of BRCA1/2 pathogenic variants among this population[18].
In our study, almost all patients with hereditary breast cancer had a positive family history (11/14 for BRCA1 and 5/5 for BRCA2) and most were younger than 40 years (8/14 for BRCA1 and 2/5 for BRCA2). BRCA1 pathogenic variants were found in 23.25% (10/43) of patients with TNBC and in 62.5% of BRCA1 (10/16) of patients with TNBC. Of the five BRCA2 patients with breast cancer, one had TNBC, two had HER2 overexpression with HR-positive sensitivity, and two had HR+. Data from Saudi Arabia showed that TNBC was present in 93.9% of patients with BRCA1 and 57.1% of patients with BRCA2[20]. According to the present and previously reported data[16], the TNBC subtype, age at diagnosis < 40 years, and positive family history are the most useful criteria for selecting patients with breast cancer for pathogenic variant testing, especially when resources are limited.
Additionally, the c.131G > T nucleotide change was present in one patient and two unaffected subjects harboring BRCA1 pathogenic variants, which was reported in our previous study in a different Lebanese Arab patient cohort, whose DNA sequencing was performed at the Institut Jean Perrin in France[16], supporting the suggestion that this gene sequence found in several unrelated subjects is a founder pathogenic variant in this population.
For ovarian cancer, the overall incidence of BRCA1/2 pathogenic variants was 15.1% (5/33), with all five patients having a positive family history of ovarian cancer. This is the first study to report almost a 15% rate of BRCA1/2 pathogenic variants in patients with ovarian cancer in ethnic Lebanese Arab women. Other studies conducted in the Arab world reported 21.8% (14/64) of BRCA1/2 pathogenic variants in ovarian cancer in Kuwait, with 10 having BRCA1 and four having BRCA2[34]. Another study conducted in Saudi Arabia reported a prevalence of BRCA1/2 pathogenic variants of 20.5% (24/117) in a high-risk Middle Eastern population[35]. Despite variable incidences reported due to small size studies, the average of BRCA1/2 pathogenic variants in patients with ovarian cancer was approximately 20% in the Gulf Arab countries[36]. A prospective study from five Gulf countries tested BRCA1/2 in 105 patients with ovarian cancer, of whom 17% harbored a pathogenic variant[37]. In an Arabian Peninsula study, 173 patients were tested for BRCA1/2 pathogenic variants, with 10.2% pathogenic in 108 patients with breast cancer and 30.7% in 65 patients with ovarian cancer[38]. The largest epidemiological study of ovarian cancer in Arab countries was conducted by Younes and Zayed[39], which included 802 subjects, of whom 53 (approximately 15%) tested positive for a pathogenic variant in the BRCA1/2 genes.
Testing relatives of patients with pathogenic variants yielded significant information about these subjects. Of the subjects, 36.7% (11/30) carried the same BRCA1 pathogenic variant and 20% (3/15) carried the same BRCA2 pathogenic variant. A smaller number of subjects with familial non-hereditary breast cancer had a pathogenic variant (two with BRCA1 and one with a BRCA2 variant). In this retrospective real-world study of unaffected individuals referred for genetic testing by virtue of a family history of malignancy, we recognize that the limitation of our study is that more than one unaffected individual per family may have been tested, which may have caused an increase in the variant frequency in this group.
The presence of a pathogenic variant in patients with diagnosed cancer or in unaffected subjects could have clinical implications at multiple levels, including the management of patients with cancer, screening for early detection with imaging of the breasts, such as mammography alternating with breast magnetic resonance imaging every 6 months, risk-reducing surgeries (bilateral prophylactic mastectomies and bilateral salpingo-oophorectomy), and chemoprevention with tamoxifen. The use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors such as olaparib is one example of a positive BRCA pathogenic variant affecting the medical management of patients with breast and/or ovarian cancer. In patients harboring a pathogenic variant of the BRCA gene, olaparib is indicated in an adjuvant setting for high-risk early breast cancer and for the treatment of patients with metastatic breast cancer[21,24]. PARP inhibitors are also used in advanced ovarian cancer after debulking surgery for maintenance or treatment of recurrent ovarian disease[25].
Variations among patients in the Middle East emphasize the need for periodic studies of germline variants in various ethnic populations, as penetrance and occurrence of cancer may be modified by other genetic alterations, reproductive factors, environmental factors, exercise, or diet. Recognizing population divergence underscores the need to deeply study population-specific genomes and environmental modifiers to better understand the fundamental genotype-phenotype correlations in such wide populations[40]. Pathogenic variants of PALB2 and TP53 were identified in patients who underwent NGS, emphasizing the importance of NGS in screening eligible patients.
CONCLUSION
In this cohort of patients and subjects with or at high hereditary risk for breast and/or ovarian cancer referred for germline testing, the prevalence of BRCA1/2 pathogenic variants was approximately 8.63% in patients with breast cancer. Patients with breast cancer who had TNBC or were young and had a positive family history had a 23.25% or 20.1% chance to have a BRCA1/2 pathogenic variant, respectively. Our study showed an almost 15% rate of BRCA1/2 pathogenic variants. This high percentage highlights the need to refer all patients with ovarian cancer for counseling and genetic testing in accordance with the current international society guidelines. We report 31% positivity (14/45 subjects) in relatives of patients with hereditary breast cancer and emphasize the importance of testing healthy relatives of patients identified as carrying familial germline pathogenic variants. The introduction of NGS techniques for germline pathogenic variant testing has also allowed the detection of pathogenic variants in other inherited cancer genes and subsequent better counseling and management. One limitation of this study was its retrospective nature. Patients were referred for testing by different primary physicians and centers in the country; therefore, there was a potential selection bias. In addition, complete medical records were not available from our genetic laboratory for all patients.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: Lebanon
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Zou YZ S-Editor: Luo ML L-Editor: A P-Editor: Zhao S
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