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BRCA1 and BRCA2 mutation rates by family history. (A) Two or more close relatives with breast cancer. (B) One or more close relatives with breast cancer diagnosed at age 50 years or younger. (C) One or more close relatives with breast cancer at any age.
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BRCA1 and BRCA2 mutations are not uncommon in breast cancer patients. Western studies show that such mutations are more prevalent among younger patients. This study evaluates the prevalence of germline mutations in BRCA1 and BRCA2 among breast cancer patients diagnosed at age 40 or younger in Jordan. Blood samples of patients with breast cancer dia...
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Citations
... 32 Moreover, the BRCA2 c.2254_2257del p.(Asp752Phefs*19) variant was found in conjunction with the BRCA2 c.5351dup (p.Asn1784Lysfs*3) variant in six patients in our study. This co-occurrence in Jordanian patients has been previously described 33,34 and may represent a shared Jordanian founder allele. 35 In addition, the TP53 c.541C>T (p. ...
PURPOSE
Germline genetic testing (GGT) significantly affects cancer care. While universal testing has been studied in Western societies, less is known about adoption elsewhere.
MATERIALS AND METHODS
In this study, 3,319 unselected, pan-cancer Jordanian patients diagnosed between April 2021 and September 2022 received GGT. Pathogenic germline variant (PGV) frequency among patients who were in-criteria (IC) or out-of-criteria (OOC; 2020 National Comprehensive Cancer Network criteria) and changes in clinical management in response to GGT results were evaluated. Statistical analysis was performed using two-tailed Fisher's exact test with significance level P < .05.
RESULTS
The cohort was predominantly female (69.9%), with a mean age of 53.7 years at testing, and 53.1% were IC. While patients who were IC were more likely than patients who were OOC to have a PGV (15.8% v 9.6%; P < .0001), 149 (34.8%) patients with PGVs were OOC. Clinical management recommendations in response to GGT, including changes to treatment and/or follow-up, were made for 57.3% (161 of 281) of patients with high- or moderate-risk PGVs, including 26.1% (42 of 161) of patients who were OOC.
CONCLUSION
Universal GGT of patients with newly diagnosed cancer was successfully implemented in Jordan and led to identification of actionable PGVs that would have been missed with guidelines-based testing.
... We have recently completely one of the biggest germline genetic testing studies in the region, in which 3319 unselected Jordanian patients with any cancer (>50% were breast cancer) received germline genetic testing (GGT). In this study, and in many previous studies from our group [38], over 13% of Jordanian breast cancer patients tested as per the international guidelines had pathogenic or likely pathogenic variants [39]. ...
Simple Summary
As the most common cancer diagnosed worldwide, breast cancer treatment represents a great opportunity to set up processes to improve the integration of all elements of cancer control programs. The journey starts with prevention, screening, and early detection, and includes survivorship programs that manage late after-treatment effects and, when needed, hospice and palliative care. Active treatment, using cost-effective up-to-date anti-cancer therapy delivered through a multidisciplinary approach, is the main pillar of this process. In this review, we address issues related to breast cancer in Jordan, some of which may also exist in neighboring and other low-resourced countries, such as presentation at a younger age and with advanced-stage disease. The rising number of newly diagnosed patients and the financial impact of the many recently introduced immunotherapies and targeted and endocrine therapies pose a great burden on most health care systems.
Abstract
Jordan is a relatively small country with a rapidly growing population and a challenged economy. Breast cancer is the most diagnosed cancer among women worldwide and also in Jordan. Though the age-standardized rate (ASR) of breast cancer incidence is still lower than that in Western societies, the number of newly diagnosed cases continues to increase, involving younger women, and new cases are usually detected at more advanced stages. Improvements in breast cancer care across the health care continuum, including early detection, prevention, treatment, and survivorship and palliative care, have become very visible, but may not match the magnitude of the problem. More organized, goal-oriented work is urgently needed to downstage the disease and improve awareness of, access to, and participation in early detection programs. The cost of recently introduced anti-cancer therapies poses a great challenge, but the impact of these therapies on treatment outcomes, including overall survival, is becoming very noticeable. Though the concept of a multidisciplinary approach to breast cancer treatment is often used at most health care facilities, its implementation in real practice varies significantly. The availability of breast reconstruction procedures, survivorship programs, germline genetic testing, counselling, and palliative care is improving, but these are not widely practiced. In this manuscript, we review the status of breast cancer in Jordan and highlight some of the existing challenges and opportunities.
... According to limited published data, almost 10-15% of breast cancer occurrences are inherited with the most commonly identified genetic alterations in BRCA1/2. The results of BRCA1/2 genetic testing from Jordan have been published between the years 2018 and 2021 [23,[25][26][27][28], in addition to an old report of a smaller cohort dating back to 2004 [29]. Reports are only available from the two major mentioned centers. ...
... Since P/LP mutations of BRCA1/2 genes are associated with early onset breast cancer and/or highrisk features (HR), this review analyzes the results of the two largest published cohorts from KHCC including 616 young female patients (i.e. younger than 40 years) [26] and 500 patients with high-risk (HR) features (median age = 39 years) [28], together with the largest published cohort of 192 female patients with HR features from Al-Bashir hospital (mean age = 43.6 years) [23]. ...
... Eighty (12.2%) patients of the first cohort, seventy-two (13%) of the second and twenty-nine (14.5%) of the third had a P/LP variant of BRCA1/2 [23,26,28]. The prevalence of P/LP BRCA1/2 gene mutations among the specific subgroup of triple negative (TN) disease was 33.9%, and it was 60% among patients with both TN disease and a family history of breast cancer as published by KHCC group [30]. ...
A founder variant is a genetic alteration, that is inherited from a common ancestor together with a surrounding chromosomal segment, and is observed at a high frequency in a defined population. This founder effect occurs as a consequence of long-standing inbreeding of isolated populations. For high-risk cancer predisposition genes, such as BRCA1/2, the identification of founder variants in a certain population could help designing customized cost-effective cancer screening panels. This advantage has been best utilized in designing a customized breast cancer BRCA screening panel for the Ashkenazi Jews (AJ) population, composed of the three BRCA founder variants which account for approximately 90% of identified BRCA alterations. Indeed, the high prevalence of pathogenic BRCA1/2 variants among AJ (~ 2%) has additionally contributed to make population-based screening cost-effective in comparison to family-history-based screening. In Jordan there are multiple demographic characteristics supporting the proposal of a founder effect. A high consanguinity rate of ~ 57% in the nineties of the last century and ~ 30% more recently is a prominent factor, in addition to inbreeding which is often practiced by different sub-populations of the country.
This review explains the concept of founder effect, then applies it to analyze published Jordanian BRCA variants, and concludes that nine pathogenic (P) and likely pathogenic (LP) BRCA2 variants together with one pathogenic BRCA1 variant are potential founder variants. Together they make up 43% and 55% of all identified BRCA1/2 alterations in the two largest studied cohorts of young patients and high-risk patients respectively. These variants were identified based on being recurrent and either specific to ethnic groups or being novel. In addition, the report highlights the required testing methodologies to validate these findings, and proposes a health economic evaluation model to test cost-effectiveness of a population-based customized BRCA screening panel for the Jordanian population. The aim of this report is to highlight the potential utilization of founder variants in establishing customized cancer predisposition services, in order to encourage more population-based genomic studies in Jordan and similar populations.
... Thus, negative BRCA1/2 results alone may not necessarily lead to the decision to conduct TP53 genetic testing. In contrast, HER2 positivity is present in 19% of breast cancer patients below the age of 49 years in the U.S., which may create a dilemma regarding whether to conduct genetic testing for all HER2-positive patients [8]. Although we were able to conduct genetic testing for TP53 due to the history of multiple cancers, our case highlights the importance of considering genetic testing for TP53 even if the revised Chompret and classic LFS diagnostic criteria are not satisfied. ...
Li-Fraumeni syndrome (LFS) is a rare familial disorder caused by germline TP53 mutations. Despite the establishment of the revised Chompret criteria to guide genetic testing for TP53, identifying LFS in patients who do not satisfy these criteria remains a challenge. Herein, we present the case of a 50-year-old woman with a history of breast, lung, colorectal, and tongue cancers who did not satisfy the revised Chompret criteria. However, genetic testing ultimately revealed a TP53 mutation, leading to the diagnosis of LFS. Although her family history did not satisfy the classic LFS criteria, she had a TP53 core tumor before the age of 46 years. This case highlights the importance of considering LFS in patients with a history of multiple cancers and suggests that genetic testing should be considered even in patients who do not satisfy the revised Chompret criteria.
... The median age at presentation is 52 years, ten years younger than the median age in developed countries. Additionally, about a third of patients present with locally advanced or metastatic disease, highlighting the critical nature of early detection programmes (3). ...
Introduction:
Breast cancer diagnosis and treatment have been shown in studies to have a negative impact on patients' physical, psychological, and social well-being, as well as overall quality of life. Psychologically, it's linked to sadness, anxiety, and demoralisation. Stigma contributes to the hidden burden of breast cancer as a chronic illness. Research on the elements that breast cancer survivors encounter as influences on stigma associated to the disease is lacking. Based on the lived experiences of breast cancer survivors, this study sought to investigate the factors that lead to the manifestations of both self- and public breast cancer stigma.
Methods:
Individual semi-structured interviews with 24 patients diagnosed with breast cancer were performed, followed by five focus groups with 25 patients diagnosed with breast cancer. Interviews were verbatim transcribed and analysed using thematic framework analysis.
Results:
Two major themes have emerged from the data: a) Breast cancer stigma among breast cancer survivors, highlighting the various manifestations of stigma and the variables that influence them; including disease-related factors, patients' views of cancer, public perceptions of breast cancer, family and interpersonal dynamics, and b) Stigma resilience and empowerment, emphasising the necessity of sociocultural transformation and coping strategies to preserve resilience.
Conclusions:
To improve the well-being of breast cancer survivors, practitioners and health policymakers should be aware of the breast cancer stigma that underpins patients' emotional and behavioural outlooks and its potential consequences on patients' quality of life. They need to develop interventions to address the different stages of cancer stigma taking into consideration sociocultural influences, norms, and beliefs.
... The diagnosis of breast cancer in young women and its possible genetic associations have potentially serious effects on patients and their family members, too. Physicians and genetic counselors can help cross such complex medical and psychosocial problems (24). ...
Background. Breast cancer is among the most common female cancers worldwide according to WHO 2020 data. Breast cancer tumor suppressor genes (BRCA1 and BRCA2) are the most susceptibility genes for breast cancer. Thus, authors aimed to detect germline mutations of BRCA1 and BRCA2 genes among Egyptian female breast cancer patients.
Methods. Blood samples were collected from primary breast cancer patients (n=22), benign breast lesions (n=5) and healthy control (n=7). Then DNA was extracted and germline mutational profiling of BRCA1 and BRCA2 were studied using next generation sequencer (Ion Torrent personal Genome Machine [PGM]).
Results. A total of 135 genetic variations were detected, 59 in BRCA1 and 76 BRCA2, 2indels and 133 SNV, nearly 55% of those variants were missense variants, 38% were synonyms and 7% were nonsense. Ten exonic and 49 intronic variations were detected in BRCA1. The exonic variants in BRCA1were grouped as 6 synonymous variants, one 3-prime UTR variant, 12 missense variants, 11 non coding transcript exon variants, 2 splice_region_variant,synonymous_variant, and 2 stop gain variants were previously reported to be pathogenic in Clinvar database. For BRCA2, 55 intronic variations and 21 exonic variants were detected, from the exonic variations there were 13 new mutations and 8 previously reported (7 were benign and only one were reported to be with conflicting pathogenicity on the clinvar database).
Conclusion. This study reports gremline profiling of BRCA1 and BRCA2genetic mutations among Egyptian females with breast cancer using next generation sequencing as high throughput technology for a better coverage for mutational analysis that may benefit in clinical routine practice.
... In BRCA2 gene, we identified three pathogenic variants, two frameshift mutations and one missense mutation, in three unrelated patients. The frameshift variant c.6445_6446del, (p.Ile2149*) [18] was identified in a patient with breast ductal carcinoma, diagnosed at age of 37 and no family history of breast cancer; the frameshift variant c.6757_6758del, (p.Leu2253Phefs*7) [15] was identified in a patient with breast ductal carcinoma, diagnosed at age of 37 and with a family history of breast cancer. The missense mutation, c.8009C>T, (p. ...
Background
Breast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among women in Africa after cervical cancer. Even if the epidemiological data are now aligned with those relating to industrialized countries, the knowledge concerning breast cancer in Africa, particularly in Western Africa, still lack clinical data, medical treatments, and the evaluation of genetic and non-genetic factors implicated in the etiology of the disease. The early onset and the aggressiveness of diagnosed breast cancers in patients of African ancestry strongly suggest that the genetic risk factor may be a key component, but so far, very few studies on the impact of germ line mutations in breast cancer in Africa have been conducted, with negative consequences on prevention, awareness and patient management. Through Next Generation sequencing (NGS), we analyzed all of the coding regions and the exon–intron junctions of BRCA1 and BRCA2 genes—the two most important genes in hereditary breast cancer—in fifty-one women from Burkina Faso with early onset of breast cancer with or without a family history.
Results
We identified six different pathogenic mutations (three in BRCA1 , three in BRCA2 ), two of which were recurrent in eight unrelated women. Furthermore, we identified, in four other patients, two variants of uncertain clinical significance (VUS) and two variants never previously described in literature, although one of them is present in the dbSNP database.
Conclusions
This is the first study in which the entire coding sequence of BRCA genes has been analyzed through Next Generation Sequencing in Burkinabe young women with breast cancer. Our data support the importance of genetic risk factors in the etiology of breast cancer in this population and suggest the necessity to improve the genetic cancer risk assessment. Furthermore, the identification of the most frequent mutations of BRCA1 and BRCA2 in the population of Burkina Faso will allow the development of an inexpensive genetic test for the identification of subjects at high genetic cancer risk, which could be used to design personalized therapeutic protocols.
Background:
This paper explores and discusses local challenges oncologists face for diagnosing and managing breast cancer patients with BRCA gene mutations in Jordan.
Methods:
A task force involving key opinion leaders, experts in the management of breast cancer, and stakeholders in healthcare systems where genetic testing is available in Jordan discussed current evidence and local real-life practice. The task force then formulated recommendations to achieve better patient outcomes and satisfaction based on evidence-based medicine and their clinical experience in BRCA-mutated breast cancer management.
Results and conclusion:
Eligibility of patients for genetic testing, physician acceptance and willingness to integrate genetic testing into routine practice is encouraging but remains restricted by testing availability and financial coverage. Until more data is available, genetic testing should be targeted for breast cancer patients based on tumor subtypes, as well as family and personal history of cancer, as per international guidelines. Whenever possible, genetic testing should aim to detect all actionable genes through a multigene panel including BRCA1/2. Major challenges faced in clinical practice in Jordan include fear of genetic discrimination and social stigmatization, as well as hesitancy toward risk-reducing surgery. Pre-testing counseling is therefore critical to promote acceptance of genetic testing. Since geneticists are in short supply in Jordan, genetic counseling can be offered through a specially trained genetic counselor or through a hybrid system that includes oncologist-based counselling. In addition to cancer prevention, germline genetic testing may assist in the selection of specific anti-cancer therapy, such as PARP inhibitors, in patients with BRCA1/2 mutation. Nationwide initiatives are also needed to ensure access to PARP inhibition therapy and provide financial coverage for genetic screening, mastectomies and reconstructive surgery across Jordan.
