A New de novo BRCA1 Mutation in a Young Breast Cancer Patient: A Case Report

Background

Hereditary cancer results from mutations in specific genes, such as those involved in regulating cell growth and DNA repair. Some of these mutations are inherited from one parent.¹ De novo mutations are genetic alterations arising for the first time in a germ cell (ie, ovum or sperm) or in the fertilized egg itself during early embryogenesis. The majority of hereditary breast and ovarian cancer cases are due to pathogenic or likely pathogenic variants in the BRCA1/2 genes.² Pathogenic germline variants in the BRCA1 or BRCA2 gene lead to an increased lifetime risk of breast, ovarian and further less frequently present cancers in women and an increased lifetime risk of breast, prostate and other tumors in men.

BRCA1 and BRCA2 genes were discovered in 1994 and 1995, respectively,^3,4 and represent the most investigated breast and ovarian cancer predisposition genes. In recent years, numerous mutations have been described in these genes, of which very few cases involved de novo BRCA1/2 alterations. In fact, only ten cases of de novo BRCA1 mutations and six cases of de novo BRCA2 mutations have been reported at present.^5–15 The BRCA1/2 de novo mutation rate was previously estimated to be 0.3% (0.1–0.7%). In a French study population of 12805 patients diagnosed with breast and/or ovarian cancer, 1527 were found to be BRCA1/2 mutated (12%), of whom three BRCA1 mutations and one BRCA2 mutation were de novo.⁶ This is in contrast with other genes, ie, TP53, NF1 and RB1.

We report a new case of a de novo BRCA1 gene mutation in a woman with an early onset breast cancer without a relevant family history.

Case Presentation

A 30-year-old woman with no health issues so far was diagnosed with a hormone receptor positive/HER2 negative invasive breast cancer. Her family history was not suggestive of a hereditary cancer syndrome (Figure 1). Only a cousin of her father had been diagnosed with a breast cancer at the age of 55 years. She underwent a neoadjuvant chemotherapy, followed by bilateral mastectomy and salpingo-ovarectomy. Regarding the early onset of her cancer, genetic testing was offered to the patient. It revealed a pathogenic variant (c.4065_4068delTCAA) and a variant of unknown significance (VUS) in the BRCA1 gene. Her healthy sister and her father were tested thereafter and both were found to be carriers of the VUS – but not the pathogenic variant – in the BRCA1 gene. In her mother neither the pathogenic BRCA1 mutation (c.4065_4068delTCAA) nor the described BRCA1 VUS was detected. The findings were confirmed by an analysis of additional blood samples taken from each parent and the patient. In the absence of a germline mutation in both parents, we assume a de novo origin of the mutation during parenteral germ cell gametogenesis. A non-paternity event could be excluded by the detection of the VUS in the BRCA1 gene, which was first reported in the patient and later in her father and sister. We concluded that our patient must be a carrier of a de novo BRCA1 mutation.

Figure 1 Family pedigree chart for case.

Materials and Methods

DNA extraction from blood leucocytes was done followed by PCR amplification and DNA sequencing (Cancer Panel V2, Illumina, MiSeq-Tec (Illumina), Alignment: NextGene V2.4.1.1 (Softgenetics)). A pathogenic mutation (NM_007294.3:c.4065_4068delTCAA/p.(Asn1355Lysfs*10)) and a VUS (NM_007294.3:c.1868T>C)/p.Leu623Pro) were found in the BRCA1 gene. The detected pathogenic variant was already reported by Friedman et al.¹⁶ Recently, it has been also described by Rashid et al as founder mutation in breast cancer patients from Pakistan.¹⁷

This pathogenic variant NM_007294.3:c.4065_4068delTCAA/p.(Asn1355Lysfs*10) results in a frameshift of the reading frame and, presumably, a premature stop codon. Thus, this deletion leads to a shortened protein and/or degradation of the transcript by NMD (nonsense mediated mRNA decay).

PCR amplification and Sanger sequencing were performed in the healthy sister and parents.

Results and Discussion

Our patient with a pathogenic BRCA1 variant is a Swiss citizen without a migration background. Neither the mother nor the father or sister are carriers of the pathogenic BRCA mutation, providing additional evidence for the de novo occurrence of this variant.

A search in PubMed (Search Terms: BRCA/germline/mutation/de novo) yielded 13 publications reporting 16 de novo BRCA1/2 mutations.^{6–15,18–20,21} The largest published clinical trial – from Golmard et al – detected – on a series of 12805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines – a BRCA1 or BRCA2 variation in 1527 (12%) patients. A total of 801 (6.3%) BRCA1 and 726 (5.7%) BRCA2 mutation carriers were identified. In this study, de novo status was found for three BRCA1 mutations and one BRCA2 mutation, resulting in de novo mutation rates of 0.4% and 0.1% for BRCA1 and BRCA2 genes, respectively, and an overall BRCA1/2 de novo mutation rate of 0.3%.

de novo mutations are generally identified in sporadic cases in most genetic diseases. However, in the 2015 study by Golmard et al, cases with a family history of breast cancer significantly outnumbered, while in the other published cases, half were found to have a family history of breast cancer (Table 1). The authors attribute this observation to the high incidence of breast cancer in the normal population, bias for family cancer cases due to the strong impact of family history as a criterion for BRCA1/2 genetic testing, and genetic heterogeneity in breast cancer.

Table 1 BRCA1 and BRCA2 de Novo Mutations Reported in the Literature and in This Case Report Updated and Revised from L Golmard et al 2015

Conclusion

We report a new case of de novo BRCA1 mutation, confirmed by repeated germline testing of the index patient and her parents. The published BRCA1/2 de novo mutation rate is low. This is probably due – in part – to the strict testing criteria, which are not uniform internationally and the restrictions regarding the cost coverage by the insurance companies. Most described de novo BRCA1/2 variations were found in patients with early-stage breast cancer and without a family history of the disease. Genetic testing of breast cancer patients based on their young age or family history does not allow detection of all BRCA1/2 carriers who may benefit from preventive interventions. In our opinion, we should focus on identifying as many carriers of a pathogenic BRCA variant as possible. Genetic testing based on selection criteria mainly considering family history, age of onset and tumor characteristics may underestimate the prevalence of de novo mutations. By detecting a larger number of de novo mutations, more patients could benefit from preventive interventions and tailored treatments. Genetic testing for a pathogenic variant in offspring of a carrier of a de novo variant is useful in identifying individuals at high risk for malignancies.