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Application of Personalised Medicine Using an Integrated Service and Research Approach: Evaluation of Vitamin D in Breast Cancer Patients

Prof Maritha Kotze

Project ended 30 June 2021

Prof Maritha Kotze

Title of the project

Application of personalised medicine using an integrated service and research approach: Evaluation of vitamin D in breast cancer patients.

Project Description

The high global incidence of cancer drives the development of novel approaches for prevention and treatment in an affordable yet efficient manner. BRCA1 and BRCA2 are the most frequently mutated tumour suppressor genes in familial breast cancer and loss of expression is associated with an increased risk of many common cancers. Although carriers of BRCA1/2 germline mutations have a significantly increased lifetime risk (60-85%), incomplete mutation penetrance implicates the involvement of other genetic and environmental factors as modifiers of disease risk and metastatic potential. These include vitamin D deficiency suggested promoting malignancy by causing DNA repair defects and activation of mechanisms underlying drug resistance (Graziano et al. 2016).

In this study, the genetic contribution to vitamin D levels will be studied in relation to breast cancer development, recurrence, and treatment response. The aim is to determine the measurement range associated with high-risk clinical outcomes. Breast cancer patients with vitamin D deficiency (<20 ng/ml) at increased risk for the adverse outcomes will be selected for whole-exome sequencing (WES) and their genetic profile compared with vitamin D sufficient (>30 ng/ml) patients.

Non-scientific report

Advances in genomic technologies have the potential to improve breast cancer risk management across the continuum of care, ranging from early-stage to metastatic disease and survivorship. Lack of an effective data integration system led to the development of the PSGT platform (Kotze et al., 2015) applied in this study to facilitate research translation. This concept involves both the germline genome that determines familial risk and governs treatment toxicity and the somatic genome that determines prognosis and the tumour’s response to therapy.

The following results obtained in this study add value to the pathology-supported genetic testing (PSGT) platform in relation to postmenopausal hormone receptor-positive breast cancer (diagnosis) in patients at risk of osteoporosis (co-morbidity) that may be triggered by treatment with aromatase inhibitors:

  1. Lifestyle-triggered vitamin D deficiency: obesity and lack of outdoor physical activities
  2. Genetic predisposition for osteoporosis: variation in the VDR gene
  3. Tumour histopathology and familial risk: Clinical relevance of pathogenic BRCA1/2 mutations interpreted in relation to VUS identified in the CDH1 gene
  4. Nanopore sequencing using the MinION pocket-size device confirming the accuracy of long-range sequencing beyond gene coding regions covered by WES

To our knowledge, this is the first study using WES to investigate the significance of genetic variation in vitamin D-related genes in postmenopausal South African breast cancer patients at risk of aromatase inhibitor-induced bone loss. The ability of PSGT to address different aspects of the same disease in a patient is a major benefit as demonstrated by WES to simultaneously target familial, lifestyle risk and treatment implications of vitamin D deficiency that has a significant impact on VDR expression. In the absence of vitamin D, this receptor remains in the cytoplasm and prevents activation of target genes such as CDH1 and BRCA1. Variation in the VDR gene provides a genetic link between vitamin D dysfunction and shared disease mechanisms in chronic diseases of lifestyle, including hormone receptor-positive breast cancer and osteoporosis. These findings strengthen the importance of knowledge relating to both genetic and pathology test results in the attainment of effective therapies.

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