In this descriptive study we have established the prevalence of BRCA1 germline mutations in a group of 20 pregnancy associated breast cancer patients, which were selected regardless of family history. All in all, we identified seven PABC patients carrying known pathogenic germline mutations (35%), six of them in the BRCA1 gene and one in the CHEK2 gene. Additionally, variants of unknown/uncertain significance (VUS) in breast cancer susceptibility genes CHEK2, BRCA2 and BRIP1 were determined to be present in three different PABC patients (15%). To our knowledge, this is the first recent study aiming to investigate the germline mutation frequency and spectra in a clinic-based series of PABC patients.
The notably high frequency of BRCA1 mutations found in the present PABC group (30%) places pregnant breast cancer patients in a high-risk setting. Previous studies, however heterogenous they are, report high BRCA1 mutation prevalence in PABC patients, ranging from 11.4 - 19.6% [22, 23]. In this setting, PABC patients with germline mutations in BC susceptibility genes should be placed under close clinical monitoring, in accordance to the evidence-based clinical practice guidelines that have been developed to ensure the appropriate management for carriers of a BRCA pathogenic variant [24, 25]. This suggestion is consistent with the findings of the only similar study to ours published more than two decades ago by Johansson et al. (1998), who investigated the influence of pregnancy on the risk of developing breast cancer in germline BRCA1/2 mutation carriers . According to their results, more women with BRCA1 mutations developed PABC and in the same context they proposed close monitoring of women with BRCA1 familial mutations during and after pregnancy, thus substantiating our observations.
Nowadays, reports state that BRCA1/2 mutations account for only approximately 50% of the identifiable germline cancer predisposition variants in BC patients . In parallel, overwhelming evidence suggest that germline pathogenic variants in genes of intermediate penetrance, such as ATM and CHEK2, confer an increased risk of BC, and their analysis is encompassed in gene panels alongside the BRCA1/2 genes [25, 28]. Notably, the checkpoint kinase 2 (CHEK2) gene is a tumor suppressor gene involved in cell cycle checkpoint regulation, DNA damage repair activation and apoptosis . Given its essential role, CHEK2 inherited pathogenic variants have been implicated in BC predisposition . Of these, the founder mutation CHEK2 c.1100delC is one of the most frequently identified among Northern Europeans , while it is considered to be less common in the Mediterranean region, including BC patients of Greek decent (0.16%) . This observation does not coincide with our results, since we identified one carrier of the pathogenic CHEK2 c.1100delC and another carrier of a CHEK2 VUS among our PABC patients, highlighting the importance of further investigations of other mutations in order to unravel their contribution to PABC susceptibility.
Notably, multigene panel testing (MGPT) allows the sequencing of multiple genes simultaneously and has offered a cost effective and efficient way to assess cancer genetics in a phenotypically directed clinical setting [27, 33]. Multigene panel tests in general depict more clearly the proportion of breast cancers attributable to genetic predisposition, since they allow detection of even moderate or low penetrance genetic variants . However, there are several issues to take into consideration regarding their use. Specifically, as gene panel testing options for breast cancer risk assessment continue to grow in variety, the specific multigene test that will be used should be chosen carefully . Additionally, multigene tests increase the likelihood of detecting a variant of unknown/uncertain significance (VUS). These VUSs add complexity that may cause difficulty for clinicians in making management recommendations and advising patients. In our study, a PABC patient carried a VUS in BRIP1 (BRCA1 interacting protein C-terminal helicase 1) which is a gene that contributes to the DNA repair function of BRCA1; the impact of this variant on molecular function and subsequent roles in cancer risk is uncertain. This is not a rare finding, since according to data available in ClinVar, 933 variants in BRIP1 clinically classified as a VUS have been reported to date . However, it is a noteworthy observation, since classification of VUSs identified in PABC patients can contribute to earlier detection and screening of breast cancer and, as data from multigene panel testing accumulates, eventually improve treatment options in PABC.
Limitations of the study include that large genomic rearrangements (LGRs), such as copy number variants (CNVs) are usually missed by multigene panel testing; hence they were not reported in our study. Furthermore, it is important to point out that our analysis focused on a small number of patients due to the rarity of the disease, deeming our results merely indicative and in need of further confirmation in a larger cohort of patients, in order to draw safe conclusions on whether a pathogenic variant of a gene can be associated with PABC. Lastly, the age of disease onset was not included in our selection criteria; however, our results support the recommendation of at least BRCA1 testing for all PABC patients, regardless of family history and age of diagnosis.