Multi gene panel testing for hereditary breast cancer – is it ready to be used?

Table of Contents


Breast cancer (BC) is one of the most common malignancies and the leading cause of death among women worldwide [1]. About 20% of breast cancers are hereditary [2]. Hereditary BC is defined by an onset at a young age, bilateral breast cancer, multiple primaries and a history of first or second- degree family members with similar diagnoses [3].

Mutations in the BRCA1 and BRCA2 genes are responsible for two thirds of hereditary BC, being the most well-known cause of inherited cancer predisposition. The cumulative risk of developing BC by the age of 70 for a BRCA mutation carrier is 65% for BRCA1 and 45% for BRCA2 [4,5].

Although genetic predisposition testing for BRCA1 and BRCA2 has been available since 1996, about 30% of the patients have remained negative in BRCA1 and BRCA2 mutations even in families with a history of a Mendelian inheritance pattern (autosomal dominant or recessive) for BC [6,7]. Additional non-BRCA genes have been identified as predisposing for breast cancer: ATM, CHEK2, PALB2, PTEN, TP53, and others [8].

ATM is a protein coding gene which activates cellular responses to DNA double-strand breaks and plays a crucial role in DNA damage-pathways. The ataxia-teleangiectasia mutated (ATM) gene has been supposed to predispose to breast cancer when the findings from the epidemiological studies of ataxia teleangiectasia (AT) families showed an increased risk of breast cancer in AT heterozygote women [9].

The Checkpoint kinase 2 (CHEK2) gene, located on chromosome 22, is involved in DNA repair and apoptosis, being a tumor suppressor gene. CHEK2 loss of function is implicated in different types of cancer, especially breast cancer [10].

Read more  Cancer risks among BRCA1 and BRCA2 mutation carriers

PALB2 (Partner and Localizer of BRCA2) was firstly identified as a protein that interacts with BRCA2 and later, with BRCA1. It might function as a tumor suppressor. PALB2 loss of activity is associated with Fanconi’s anemia as well as breast and pancreatic cancer [11].

PTEN (phosphatase and tensin homolog deleted from chromosome 10) acts as a tumor suppressor gene affecting cell survival, proliferation and apoptosis through the action of its phosphatase protein product. Loss of PTEN function has been correlated with many primary and metastatic malignancies, including breast cancer [12].

TP53 gene regulates cell proliferation, cell repair and apoptosis and it is located on the short arm of the chromosome 17. TP53 is found altered in 20–40% of BC and it seems to be an early event in breast carcinogenesis [13].

Next generation sequencing (NGS) and the recent discovery of the new genes now permit multi gene panel testing, which provides clinicians with more information in a single test. Multi gene testing becomes a routine diagnosis in hereditary cancer syndromes. However, there are several details to consider when recommending testing, such as the large number of variants of unknown significance (VUS), low or incomplete penetrant mutations, high costs, as well as the emotional impact on the person and the family [14]. Multi-gene panel testing should always be preceded and followed by appropriate genetic counseling. In this context, the objective of this review is to evaluate the latest and most important literature data on multi gene panel testing in hereditary breast cancer.


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About the Author: Tung Chi