BRCA mutation screening and patterns among high-risk Lebanese subjects

Germline mutations in BRCA1 and BRCA2 genes have important implications for treatment of patients diagnosed with breast or ovarian cancers as well as unaffected carriers of these mutations. Various guidelines have been established to guide physicians as to which patients should be referred for germline genetic testing. The National Comprehensive Cancer Network (NCCN) guidelines which are developed in the United Sates are freely available to practitioners worldwide and include broad guidelines for mutation testing based on clinical criteria without a calculation of expected mutation frequency.

A number of on-line calculators for risk of mutation assessment, based on clinical data are also available and largely used by clinical genetics specialists. The Manchester Score is a simple scoring system using basic clinical data that has been validated in several European populations to estimate an individual’s mutation risk and determine eligibility for genetic screening.

Patients with breast cancer in the Middle East, particularly in Lebanon, tend to present at a younger age with a median of 50 years compared with the median age at diagnosis of 63 years in Europe and North America [1]. In Lebanon, the prevalence of BRCA mutation were reported to be 5.7% among a cohort of patients with breast cancer meeting high-risk criteria [2]. In another study, it was found that 12.5% of referred subjects had deleterious BRCA mutation in a cohort of high risk individuals referred for genetic testing [3].

In order to further explore the landscape of BRCA mutations in the Lebanese population, we have reviewed all cases referred for BRCA mutation testing at the American University of Beirut Medical Center (AUBMC), the largest tertiary referral center in the country. We also aimed at addressing the practice of referral for genetic testing and establishing whether clinician-friendly risk prediction models or guidelines could be helpful in identifying individuals meeting high-risk criteria in our population lacking access to genetic counselors [4], specifically the Manchester Score and NCCN guidelines.

After Institutional Review Board (IRB) approval, we retrospectively reviewed the cases of all individuals referred for BRCA mutation testing at the Medical Genetics Unit of AUBMC from April 2011 to May 2016. Data regarding family history and the frequency and characteristics of BRCA variants were collected from medical charts in order to calculate the Manchester score for this cohort (Table 1) [5]. Receiver Operating Characteristics (ROC) analysis was used to determine the predictive performance of the scoring system to identify those at risk of harboring a pathogenic mutation. Criteria for genetic risk evaluation according to NCCN guidelines were taken from NCCN guidelines version 1.2017 (www.​nccn.​org).

In a population of high-risk individuals referred for genetic testing at our institution, the prevalence of BRCA1/2 mutation was 7.8%. A c.131G > T mutation was detected among 5/17 (28%) of individuals found to have a mutation in BRCA1 and among 7/28 (25%) families. The c.131G > T mutation has only recently been classified as pathogenic [7] and can be considered as a founder mutation in the Lebanese population. It is present in a relatively large number of families in our study and has previously identified in other studies conducted in Lebanon [2, 3, 15], and in a study conducted in Palestinians [14]. All individuals referred for genetic testing fit the broad NCCN guidelines however in a resource-limited health-care system where genetic testing is not usually covered by third-party payers, as is the situation in Lebanon and many other countries, identifying the individuals at highest risk for priority testing is desirable. The BRCA1 c.131G > T and c.3436_3439delTGTT along with the BRCA2 mutations account for 54% of the total BRCA mutations found in our cohort. In a resource limited environment, if the frequency of these mutations is validated in larger studies we could consider a cost-effective targeted screening test for these 3 common mutations as had been proposed in an Italian population harboring a founder mutation [16].

The Lebanese population has limited access to clinical genetics specialists and information regarding genetic testing is usually delivered by other health-care professionals such as oncologists [4]. The Manchester Score is a simple and accessible scoring system that has been used in Europe to identify individuals at high risk of harboring a BRCA mutation but has not been validated in the Middle Eastern population were the median age of diagnosis of breast cancer is significantly lower. In this cohort the Manchester score failed to discriminate between positive and negative tests. One of the limitations of this study is the size of the cohort and low absolute number of individuals tested and mutations identified. Another limitation is the retrospective nature of the data collection, although patients were prospectively assessed by a clinical geneticist at the time of testing. The relatively low rate of mutations in the BRCA1 and 2 genes in this high-risk population with breast cancer diagnosed in the relatively young, suggests that mutations in other genes may be prevalent.

To give a broader perspective on our results, we reviewed the reported mutations in the MENA region (Tables 5 and 6, Fig. 2). The founder mutation identified in our cohort seems to be unique to the Lebanese/Palestinian populations. An interesting finding is the mutual exclusivity of reported founder mutations in each of the countries in the region, with the exception of the BRCA1 c.798_799delTT identified in several North African populations.

In a cohort of high-risk Lebanese individuals referred for genetic testing, pathogenic BRCA1/2 mutations were detected in 7.8%. While all subjects fit current NCCN guidelines for testing, the Manchester score failed to discriminate between those with positive and negative test results in this study. The BRCA1 mutation c.131G > T was detected among 5/17 (29%) of individuals found to have a pathogenic BRCA1 mutation in the cohort and can be considered a founder mutation in the Lebanese population. On review of recently published data regarding the landscape of BRCA mutations in the MENA, each region appears to have a unique spectrum of mutations. Further investigation of other genes involved in young-onset and familial breast cancer in Lebanon are ongoing.