Ir J Med Sci (2016) 185:955–957 DOI 10.1007/s11845-014-1238-5
CASE BASED REVIEW
Genetic testing and interpretive complexity: a BRCA1 gene mutation example D. S. Gogarty • M. P. Farrell • D. J. Gallagher
Received: 8 May 2014 / Accepted: 30 November 2014 / Published online: 13 December 2014 Ó Royal Academy of Medicine in Ireland 2014
Abstract Diagnosis and interpretation of hereditary breast cancer can be a complex and challenging dilemma. Advances in genetic testing have resulted in guidelines for clinical evaluation and recommendations. Here, we present a case of one family with multiple cases of early-onset breast cancer, some due to a familial BRCA1 mutation but others unrelated to this pathogenic E143X nonsense mutation. In this case report, we highlight the complexities associated with adhering strictly to guidelines and highlight the need for clinical experience in when to deviate from recommended protocols. Keywords
Breast Cancer BRCA E143X Hereditary
Background A family history of breast cancer (BC) is associated with a 2.1-fold relative risk of developing the disease [1]. Pathogenic mutations in BRCA1 and BRCA2 genes confer an increased lifetime risk of breast [2] and ovarian [3] cancer, and are responsible for constellations of these diagnoses in certain families [4, 5]. Both BRCA1 and BRCA2 are involved in the recognition and repair of DNA damage through transcriptional regulation of gene expression, transcription-coupled repair of oxidative damage, D. S. Gogarty (&) M. P. Farrell D. J. Gallagher Department of Medical Oncology, Mater Hospital, 73 Eccles St, Dublin 7, Ireland e-mail:
[email protected] M. P. Farrell e-mail:
[email protected] D. J. Gallagher e-mail:
[email protected]
chromatin remodelling and in control of cell cycle checkpoints [6]. The majority of the estimated 27 % of BC that is hereditary remains unexplained. It remains uncertain whether common, low penetrance germline variants or rare, as yet unidentified variants are responsible for familial clustering of BC cases, a dilemma that next-generation sequencing may answer.
Case presentation We report an Irish family with multiple cases of early-onset BC, some due to a familial BRCA1 mutation, a relatively common mutation in the Irish population, but others unrelated to this pathogenic E143X nonsense mutation. There are no cases of (OC) or other BRCA-associated cancers in this family. The index case (II-1; Fig. 1) was diagnosed with metachronous BC’s at 25 years and 36 years of age following comprehensive BRCA1-BRCA2 Gene Sequence testing of blood using the BRCAnalysis method 12 years ago. Diagnostic BRCA1 and BRCA2 testing was completed by Sanger sequencing. A c.427G [ T (p.Glu143X) nonsense mutation on exon 7 of BRCA1 was identified. This analysis will not detect all RNA transcript processing errors, regulatory mutations, or balanced rearrangements. Three of the proband’s sisters were also diagnosed with early-onset BC. One sister (II-3; Fig. 1) was diagnosed at 34 years and died at 42 years of age before predisposition work-up and genetic testing were undertaken in this family. A second affected sister (II-4; Fig. 1) was diagnosed with BC at 41 years and was confirmed to carry the familial BRCA1 mutation. Three unaffected sisters (II-5, II-6 and II7; Fig. 1) were found not to harbour the known familial nonsense BRCA1 mutation following predictive testing.
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Fig. 1 Pedigree
One sister (II-2; Fig. 1) was diagnosed with BC at 37 and tested negative for the known familial mutation on predictive testing using a positive control. Full sequencing of BRCA1/2 genes was subsequently undertaken in this woman revealing no abnormality. Her niece (I-1; Fig. 1), a daughter of a non-carrier (II-7; Fig. 1), was then diagnosed with BC at 37. Full sequencing of BRCA1/2 also confirmed that this individual was wild type for a BRCA1/2 mutation.
Discussion Two cases of early-onset BC in this family were not caused by the familial deleterious BRCA1 mutation. Cancer predisposition genetic testing is first offered to the youngest affected individual in a family. Negative testing in an appropriately tested individual generally leads to no further testing in a family. This pedigree illustrates how this approach may be flawed. If the earliest onset BC in this family occurred in one of the BRCA1/2 mutation-negative women, the pathogenic BRCA1 mutation in this family would have been missed. When the pathogenic BRCA1 mutation was identified, non-carriers were falsely reassured. The subsequent development of early-onset BC in two women with normal BRCA1/2 full sequencing highlights the importance of considering diagnoses in both paternal and maternal lineages, and identifying the source of the pathogenic mutation. It also raises the possibility of
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unidentified modifiers of expression of the BRCA1 mutation, whether genetic or epigenetic, that may affect risks in non-carriers of the familial mutation. The contributory role of less penetrant, moderate risk breast cancer genes in families like these remains to be fully elucidated. Future predictive testing for the familial BRCA1 mutation in this family is of debatable benefit for predicting BC risk. There are no confirmed cases of OC, or other BRCAassociated cancers, in this family. However, the familial BRCA1 mutation confers a lifetime risk of up to 54 % of developing OC by 70 years [3]. National Comprehensive Cancer Network guidelines for OC management in Hereditary Breast Ovarian Cancer, HBOC, syndrome recommend risk reducing salpingo-oophorectomy (ideally between 35 and 40 years, and upon family completion) [7]. For those who do not wish to choose risk reducing surgery, concurrent transvaginal ultrasound with CA125 monitoring is recommended. A recent randomised controlled trial has shown that this simultaneous screening OC does not reduce ovarian cancer mortality [8]. BRCA1/2 mutation-negative site-specific BC families are not thought to be at increased risk of ovarian cancer [9]. If the youngest affected individual in this pedigree, i.e. patient II-1 diagnosed with breast cancer at 25 years, had been a non-carrier all siblings would have been reassured regarding their risk of developing ovarian cancer. BRCA1 mutation carriers in this family have been advised to consider prophylactic salpingo-oophorectomy prior to 40 years of age.
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Conclusions This family illustrates the phenotypic variation of HBOC syndrome, and the complexity of assessing risk even when a deleterious mutation has been identified. Furthermore, it emphasises that it is occasionally reasonable to offer more than one family member diagnostic testing. Consideration must be given to both sides of a family history when counselling subsequent generations on cancer risk, and when offering cancer screening and prevention recommendations.
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