Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges

Abstract

Despite the initial enthusiasm following the discovery of the association of BRCA germline mutations with hereditary breast and/or ovarian cancer, in many families affected by the syndrome no pathogenic mutations were detected in the two genes, although exhaustively searched. Many other genes have also been implicated due to their role in the same pathway of DNA repair where the BRCA1/2 genes are involved: homologous recombination (HR). Among them, PALB2 clearly emerges as the third breast cancer susceptibility gene. Its mutations have been detected in most populations investigated so far, albeit rarely: in 1%-4% of families negative for BRCA mutations, with either partial or complete penetrance. In some populations, PALB2 recurrent mutations have been identified and the estimated hazard risks are comparable to those of BRCA mutations. Since new effective targeted therapeutic options are becoming available ("synthetic lethality" with novel PARP inhibitors, etc.) that are applicable to all those patients with a defect in HR pathway, it is imperative to detect all these candidate patients. Data obtained from laboratory tests in the tumor (simple immunohistochemistry, gene expression analysis, etc.) can assist in the recognition of a specific pattern (BRCA1ness, HRless) so that even patients that look "sporadic" could benefit from these targeted therapies. Therefore, a genetic analysis algorithm is proposed, although with the advent of Next Generation Sequencing it is predicted that in the future most germline genetic alterations and also somatic or epigenetic events in the tumor of these genes will be detected.

Association of survivin splice variants with prognosis and treatment of breast cancer

“…There are numerous factors associated with the occurrence of breast cancer, such as: genetic susceptibility arising from mutations in high/moderate penetrance genes (such as BRCA1/2, PALB2, CHEK2, BRIP1, RAD50, NSB1 etc.) [2][3] , hormone-associated reproductive factors such as increased menstrual cycles arising from either earlier age at menarche or later age at menopause or decreased parity, older age at first birth and use of hormone therapy; consumption of alcohol and type of diet; obesity; exposure to radiation; atypical hyperplasia of the mammary gland [4] . Inhibition of apoptosis causes tumorigenesis through cell survival resulting in accumulation of genetic mutations that lead normal tissues to transformation.…”

“…Metastatic cancer -despite the progress in molecular-targeted therapies-is the first cause of breast cancer death and presents a true challenge for selecting optimal treatment. Triple negative breast cancer (TNBC) is a high-risk category with negative expression of both estrogen and progesterone hormone receptors and no Her2 protein overexpression (or c-erbb2 gene amplification) that has limited therapeutic options [2] . TNBC patients represent approximately 15% of total breast cancers.…”

Cancer diagnosis: from dogs to DNA or from DNA to dogs?

“…A biomarker may be defi ned as a parameter that can be detected in the laboratory and is associated with malignant transformation or tumor progression. The utilization of biomarkers encompasses predicting the subject ' s risk of cancer [e.g., determining BRCA1 mutation to identify individuals with high risk of breast and ovarian cancer (2) ], contributing to the diagnosis [e.g., utilization of tumor markers for pre-operative diagnosis of ovarian cancer (3,4) ], predicting the prognosis and response to therapy, or monitoring the therapeutic response or detecting the recurrence. Biomarkers are also used to assess the toxicity of anti-cancer therapy (5) .…”

“…This more conventional approach of utilization of laboratory medicine in the management of cancer patients is highlighted in the current issue of Clinical Chemistry and Laboratory Medicine by several papers (2,13,14) and in an article by Soh et al recently published in this Journal (15).…”

“…Considerable progress that has been achieved during the last two decades in the genetics of breast cancer is reviewed by Poumpouridou and Kroupis (2) . The identifi cation of subjects with a high risk of malignancy is of obvious importance for selection of a population for cancer screening.…”