Breast cancer awareness in the genomic landscape

Researchers at the University of Pretoria (UP) are making today matter by battling aggressive breast cancer through identifying genes that make African women more susceptible to certain forms of breast cancer. However, this is no easy task as very little genomic information is known about African populations. This is just one of UP's research projects that aim to ensure that there is a clear benefit for society, and that in the future many more lives could be saved from the scourge of cancer. 

October is Breast Cancer Awareness Month in South Africa. It highlights an important drive by public healthcare organisations and the private sector to increase breast cancer awareness.

Breast cancer is the most prevalent cancer in women globally. According to the World Health Organization approximately 2.5 million women are diagnosed with breast cancer annually with a mortality rate of almost 700 000 women.

In South Africa it is estimated that approximately 1 in 27 women will develop breast cancer in their lifetime. Since the end of 2020, an estimated number of 7.8 million women have been living with breast cancer.

Cancer is caused by mutations in the genome. Many gene mutations may occur during a person’s life and are therefore not inherited. The latter may be triggered by risk factors including acute or chronic stress, carcinogens, alcohol consumption, tobacco products, diet, lack of physical activity, environmental pollutants, ultraviolet radiation, reproductive and hormonal factors, occupational exposures, infection-attributable cancers, number of pregnancies and age.

Developing breast cancer can also be an inherited genetic risk. About 5% to 10% of breast cancer cases are thought to be hereditary. Specific genetic variants (mutations) that women inherit from their parents may affect their probability of developing breast cancer. Having a first or second degree relative with breast cancer may increase the risk of being diagnosed with breast cancer by two to three-fold.

Breast cancer susceptibility genes typically contain specific variants that decrease the ability of the woman’s body to repair damaged DNA. There are two types of variants that play a role in breast cancer. The first type is referred to as a germ line variant that is inherited. When specific germ line variants occur the body is less likely to repair detrimental mutations that may cause cancer. The second type of variant is called a somatic variant and this takes place when DNA damage occurs during a woman’s lifetime and is found in the DNA of cancerous cells.  

Germ line variants may increase a woman’s susceptibility to get breast cancer. While variants in several germ line breast cancer susceptibility genes play a role, the most-researched genes are involved in the repair of damaged DNA and include BRCA1 and BRCA2, followed by PALB2. Examples of other important genes are ATM and TP53.

Having inherited specific mutations in BRCA1 or BRCA2 may increase a women’s risk of developing breast cancer up to 7 out of 10 times by the age of 80 years. PALB2 interacts with BRCA2 in DNA repair processes.  

Literature has shown that women with mutations in PALB2 may experience a 35% likelihood to develop breast cancer by the age of 70 years. Other important genes are ATM and TP53. Detrimental variants in BRCA1 and BRCA2 are responsible for 90% of inherited breast cancer, however, many breast cancer patients have been shown not to have a BRCA1 or BRCA2 mutation.

They way breast cancer is diagnosed has developed significantly during the past years. It is attempted to target the treatment to the type of breast cancer that is identified in the patient.

The classification of breast cancer is as follows:

Breast cancer is classified as Luminal A, Luminal B, HER2+, triple negative, Claudin-low and Normal-like. In terms of common markers, testing is done for the presence of the progesterone receptor (PR), estrogen receptor (ER) and for human epidermal growth factor receptor 2 (HER2) status. The presence of ER and PR implies that they can be treated with receptor-targeted treatment methods, where high HER2 levels typically indicate fast cancer growth, but may be targeted with drugs aimed at HER2.

Cancers without ER and PR and having low HER2 levels are termed triple-negative and are typically more challenging to treat and require chemotherapy.

The type of breast cancer as described above will assist in determining the path to follow in terms of ER, PR and HER2-targeted treatments and the need for precision targeted-therapy, surgery, chemotherapy, and radiation. Therefore, unlike many years ago, there is no blanket treatment for breast cancer, but it is individualized according to the type of cancer and the presence of specific gene variants.

An important factor is that the majority of studies to design breast cancer susceptibility tests have been conducted on European and Asian populations and breast cancer tests have been mainly designed from the latter data.

Only a small number of gene panel tests have been performed for African populations, with Nigerian patients and with patients from Uganda and Cameroon. Recent research conducted by Eygelaar, Janse van Rensburg and Joubert from the University of Pretoria in 2022 investigated 165 South African breast cancer patients from various ethnolinguistic groups and indicated 9% of women with a family history of breast cancer (higher than the other two studies mentioned above). The UP team identified pathogenic/likely pathogenic variants in 13 patients in 10 different genes including BRCA1, BRCA2, PALB2 and others.

Larger scale cancer susceptibility gene studies are crucial in South Africa and the rest of Africa and future research should include large whole exome (protein-coding part of the genome) or genome sequencing studies.

Recently human genome sequencing has become much more affordable and several studies are taking place in Africa and specifically South Africa. This will inform researchers about the frequency of not only breast-cancer susceptibility variants in Africans, but also about variants that influence a wealth of other inheritable conditions.

The complete strategy for the elimination of cancer requires a combination of awareness to address the burden of this disease, prevention strategies, contributing to early detection, promoting health and well-being education, together with the acceleration of science and discovery and progress in technology.

Professor Joubert believes that "We do what we do every day, because we want to make a difference in someone's life. Our life’s journey has been truly shaped by people suffering from cancer and by family, friends, colleagues, peers, our executive and students, as well as indirectly by every individual who has crossed their paths".

Some early warning symptoms of breast cancer

According to the American Cancer Society the most common symptom of breast cancer is a new lump or mass (although most breast lumps are not cancer). A painless, hard mass that has irregular edges is more likely to be cancer, but breast cancers can also be soft, round, tender, or even painful.

  • Swelling of all or part of a breast (even if no lump is felt)
  • Skin dimpling (sometimes looking like an orange peel)
  • Breast or nipple pain
  • Nipple retraction (turning inward)
  • Nipple or breast skin that is red, dry, flaking, or thickened
  • Nipple discharge (other than breast milk)
  • Swollen lymph nodes under the arm or near the collar bone 

Click on the infographic in the sidebar for more fast facts on breast cancer.

Prof Annie Joubert and Prof Fourie Joubert

October 10, 2022

  • Estimated Reading Time: 5 minutes

Researchers
  • Professor Annie Joubert
    Professor Joubert commenced research in molecular and cellular cancer physiology at the University of Pretoria (UP) in 1998 when she was appointed as a senior technical assistant in the Department of Physiology after obtaining a PhD in Biochemistry (UP).

    Through her work, she hopes to strengthen collaborations with industry, and national and international research collaborations with the University of Oxford (UK), University of Bath (UK), University of Florida (USA), Baylor College of Medicine (USA), CRI INSERM (France), Joseph Fourier University (France) and Sabanci University (Turkey).

    The focus of Prof Joubert’s research is mainly breast cancer, which is one of the most common forms of the disease in women – the lifetime risk of South African women getting breast cancer is one in 27. Her research focuses specifically on:
    a) the in silico design performed by computer simulation of potential anti-cancer agents;
    b) the chemical synthesis thereof in liaison with a pharmaceutical company; and
    c) the evaluation of these agents for improved anti-cancer treatment.

    The prevalence of cancer is increasing worldwide. Globally, 14 million people are diagnosed with the disease each year, and about nine million lose their lives to it annually. According to the Cancer Association of South Africa, breast cancer in women and prostate cancer in men are among the top five cancers prevalent in the country. However, according to the World Health Organisation, between 30 and 50% of all cancer cases are preventable.

    The research findings of Prof Joubert’s group contribute to the use of in silico virtual screening (VS) methods to identify lead compounds that are likely to succeed in further downstream assays and screens, including whole genome microarrays as well as protein arrays, in the search for potential anti-cancer agents. Making use of in silico VS methods helps scientists to identify novel compounds that significantly lower the cost of drug development by negating the need to synthesise unnecessary compounds that could not be removed prior to screening.

    Prof Joubert is also contributing to translational research that entails scientific discoveries that can be applied to improve health outcomes and health care in the Faculty of Health Sciences and the Faculty of Natural and Agricultural Sciences at UP, thus addressing the United Nations’ Sustainable Development Goal 3 (Good Health and Well-being).

    She recently commenced with a leukaemia research project that looks at the role of platelets in the progression of chronic myeloid leukaemia, a condition that affects mostly older adults and is a type of leukaemia of the haematopoietic stem cells. Her fundamental cancer research links with clinical research, further contributing to translational research with a specific benefit for South African and African populations with unique genotypic and phenotypic characteristics.

    Prof Joubert’s research efforts were prompted by the passing of her father, after he was diagnosed with chronic myeloid leukaemia in September 2020 and COVID-19. She says that he taught her to believe in herself and to do her part to improve the quality of life of the people that she interacts with every day. Her other role models are Prof Albert Neitz, who supervised her PhD degree, and Prof Dirk van Papendorp, Head of the Department of Physiology. Both academics inspired her and motivated her to go the extra mile in her career, Prof Joubert says.

    Keeping in mind the life skills her father taught her, Prof Joubert dreams of touching lives and hopes to be regarded as a good mentor to students and colleagues. “I would like to be remembered for having contributed to someone’s life in a positive way, whether it is teaching undergraduates and postgraduates, or contributing to the good health and well-being of all people.”

    For relaxation, she enjoys pilates and gardening.
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  • Professor Fourie Joubert

    Professor Fourie Joubert grew up in Pretoria and received all his degrees from the University of Pretoria (UP). He was offered an academic position towards the end of his PhD and has been doing research at UP for 30 years; this includes his postgraduate projects. “I have not moved out of Pretoria, for employment or for personal reasons,” he says. “I have always respected the University of Pretoria.”

    Prof Joubert says his research contributes to the betterment of the world because bioinformatics, and especially genomics, is relevant to every living organism. He is particularly interested in human health from a genomic perspective, and his own research programme focuses on breast cancer.

    Within his academic discipline, his research group has worked on novel genomic variants that influence breast cancer susceptibility among South African patients. He collaborates widely with various groups at UP – including other faculties and institutes – that work on viruses, bacteria, fungi, insects, nematodes, plants, animals and humans. Prof Joubert particularly enjoys his collaborations with Prof Michael Pepper, Director of UP’s Institute for Cellular and Molecular Medicine, on subjects such as cystic fibrosis, pharmacogenomics, COVID-19 and neonatal encephalopathy with suspected hypoxic-ischemic encephalopathy.

    His research group’s most recent highlight was having a paper published in Scientific Reports in February 2022 (Eygelaar, Jansen van Rensburg and Joubert). It describes novel breast cancer susceptibility variants among South African women.

    Looking back on his journey as a researcher, he says there has been many people who have inspired his research effort and specifically mentions Dr. Francis Collins, former Director of the National Human Genome Research Institute, (USA), at the time at the National Institutes of Health who led the public Human Genome sequencing project. He mentions that Dr. Collins remains a great advocate of Christianity, in the face of much adversity, which has inspired him in a personal regard.

    “As a side line, I have also been following the work on neanderthal genomes and other ancient genome projects and was happy to see Svante Pääbo win this year’s Nobel Prize in Physiology or Medicine for his neanderthal genome work”.

    As for academic role models, he mentions his wife, Prof Annie Joubert, who is the Head of UP’s Department of Physiology. “She has the best work ethic and the most caring nature for her colleagues that I have ever seen.”

    Prof Joubert hopes to make a real difference in people’s lives through his research, including his students and the public. His research matters, he says, because African genomes have been severely neglected in the genomics era, particularly in terms of health. Many of the projects he is involved in attempt to remedy this situation.

    The field of bioinformatics and genomics is crucial to much of the biological science research that is being done. Learners and undergraduates who are interested in the field should take note that it is highly multidisciplinary and never gets boring, he says. “There is a place for everyone in the field.”

    His hobbies and interests include riding his Harley Davidson motorcycles with his son Louis and wife Annie, and importantly Luke and Leia, his Golden Retrievers.

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