Sunday Article 05: Not All Breast Cancer Carriers Show Symptoms
Breast cancer is one of the most common cancers in women, affecting 2.1 million women each year. According to the World Health Organization (WHO), 627000 women died due to breast cancer in 2018. This figure increases every year and the trend increases with age.
Breast cancer is an autosomal dominant disease caused by a gene mutation. A variety of diagnosis and genetic screening can be done at an early age to detect the risk of getting breast cancer. If it is detected, chemotherapy, radiation therapy, and mastectomy are the general treatments needed.
However, statistics showed that only 80% of the mutant gene carriers will suffer from breast cancer by while the rest of the 20% showed no symptoms even if they have the mutant gene.
This is due to the incomplete penetrance of breast cancer genes. Incomplete penetrance happens when the mutant disease-causing genes are not fully transcribed and translated. Hence, the gene carrier will be safe from the disease.
The most crucial genes in breast cancer are BRCA1 and BRCA2. They are the most common variants of cancer susceptibility genes with the highest probability of mutations. The function of BRCA1 and BRCA2 is to regulate the stability and functionality of chromosomes. The BRCA1 protein interacts with other tumour suppressor proteins to form a complex called BRCT domains. When a faulty DNA is detected, the BRCT domains will bind to the DNA and fix the condition. It can be down by correcting the damaged DNA or stopping the cell cycle.
（Ashok R. Venkitaraman, 1999）
When the BRCA1 and BRCA2 gene are mutated, the BRCT domain is not formed. Unstoppable cell cycles cause rapid accumulation of genome rearrangements which are more error-prone. They will eventually lead to malignant cancers. The research found that a breast cancer patient must have ancestors with the same BRCA1 and BRCA2 gene mutation background, where they can either be a carrier or a cancer patient. Theoretically, when a patient is found to possess mutant BRCA1 and BRCA2 genes, they should develop breast cancer. However, the degree of breast cancer genes penetrance is not 100%, hence they can live without showing any symptom of breast cancer.
Factors affecting the degree of penetrance of the mutant genes
Many factors are influencing the degree of penetrance of the mutant genes. For instance, genetic variations and environmental factors.
In the context of genetic variations, evolution positively selects the general human disease-protective variants to restrain the oncogenesis when the mutant genes are passed down to the next generation. Consequently, the mutant gene carriers generate a disease-resistance mechanism to shield the expression of the mutant phenotype. Through whole-exome sequencing, a single nucleotide polymorphism (SNP) was found to perform this mechanism. This SNP is highly cancer-specific. As in breast cancer, one of the protective variants identified by whole-exome sequencing is rs3735400, where a single nucleotide C is replaced by a nucleotide G. This variant is only present in the mutant gene carriers without breast cancer.
On the other hand, the interactions between the environment and the gene will also affect the penetrance of breast cancer. The most common environmental factors that will increase the risk of getting breast cancer are alcohol intake, radiation, and diet. Fried food is the most powerful risk factor that contributes to the increase in breast cancer penetrance. However, an optimum 90 times increase in vegetables and fruits intake can reduce the probability of getting breast cancer.
Inheriting the mutant genes without developing the diseases is not disadvantageous to the carriers as they do not need to suffer from the diseases. However, one drawback of incomplete penetrance is that it is very challenging to look for the human disease protective variants to carry out further investigations as they look normal from their phenotype.
1. Deng N., Zhou H., Fan H., Yuan Y. 2017. Single Nucleotide Polymorphisms and Cancer Susceptibility. Oncotarget, 8, 110635-110649
2. Downs B., Sherman S., Cui J., Kim Y.C., Synder C., Christensen M., Luo J., Lynch H., Wang S.M. 2018. Common genetic variants contribute to incomplete penetrance: evidence from cancer-free BRCA1 mutation carriers. European Journal of Cancer, 107, pp 68-78
3. Marzbani B., Nazari J., Amini S., Najafi F., Moradinazar M., Marzbani B., Shahabadi S., Amini M., Pasdar Y., Shakiba E., 2019. Dietary patterns, nutrition and risk of breast cancer: case-control study in the west of Iran. Epidemiology and Health, e2019003
4. Scally A. 2016. The mutation rate in human evolution and demographic inference. Current Opinion in Genetics and Development,41, pp 36-43
5. Shawky R.M. 2014. Reduced penetrance in human inherited disease. Egyptian Journal of Medical Human Genetics, 15, pp 103-111
6. Shiovitz S., Korde L.A. 2015. Genetics of breast cancer: a topic in evolution. Annals of Oncology, 26, pp 1291-1299
7. Solodskikh S.A., Panevina A.V., Gryaznova M.V., Gureev A.P., Serzhantova O.V., Mikhailov A.A., Maslov A.Y., Popov V.N. 2019. Targeted sequencing to discover germline variants in the BRCA1 and BRCA2 genes in a Russian population and their association with breast cancer risk. Mutat Res Fund Mol Mech Mutagen, 813, pp 51-57
8. Takaoka M., Miki Y. 2018. BRCA1 gene: Function and Deficiency. International Journal of Clinical Oncology, 23, pp 36-44
9. Tan H. 2018. On the Protective Effects of Gene SNPs Against Human Cancer. EBioMedicine, 33, pp 4-5
10. World Health Organization. Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018 [Internet]. 2018. Available from: https://www.who.int/cancer/PRGlobocanFinal.pdf?ua=1
This article is prepared by Seow Qi Ng.