Many of us would probably have heard of the BRCA1 and BRCA2 genes in association with an increased risk for breast cancer.
According to the US National Breast Cancer Foundation, 55%-65% of women with a mutated BRCA1 gene will develop breast cancer before the age of 70.
Similarly, 45% of women with a mutated BRCA2 gene will develop breast cancer before the age of 70.
In comparison, a woman without either of these gene mutations has a 12% chance of developing breast cancer in her lifetime.
While these two genes are probably the most significant when it comes to breast cancer, they are not the only mutations that can affect a person’s risk of developing this disease.
There are actually hundreds of genetic variations known as single-nucleotide polymorphisms (SNPs) that are associated with breast cancer.
Although each individual SNP only carries a small increased risk for the cancer, having many of these SNPs in your genome means that their cumulative risk can add up to quite a lot.
According to a paper published in the Breast Cancer Research journal in February (2020), the interactions of these multiple gene variants (polygenic factors) are estimated to account for an additional 18% risk of developing breast cancer if you have family members with this cancer, compared to those with no family history of breast cancer.
This is why many researchers have been working on tools, commonly known as a polygenic risk score (PRS), based on these SNPs, to help estimate an individual’s breast cancer risk.
University of Nottingham Malaysia statistician Associate Professor Dr Ho Weang Kee says: “The PRS is a genetic test that focuses on certain genetic markers distributed in different parts of the genome.
“In the case of the European breast cancer PRS, there are 313 genetic markers included in the score (this means that out of the three billion “letters” in a person’s unique genome, just testing 313 “letters” enables us to determine a woman’s risk of getting breast cancer).
“Through DNA genotyping, we can determine how many of these gene variants a woman carries and we can combine the data into the PRS tool to generate a risk score that can tell each woman what is her risk of getting the disease.”
However, almost all of these tools are based on the genes of women of European descent, making the accuracy of their results in Asian women questionable.
Accurate for Asians
Explains Cancer Research Malaysia chief scientific officer Prof Datuk Dr Teo Soo Hwang: “The human population is genetically diverse, for example, Europeans are genetically more likely to be taller, and height is associated with increased risk of breast cancer.
“Before our study was conducted, it was not possible to predict whether a tool developed in one population would work in a different population.
“In addition, even within the Asian population, there is a lot of diversity and this is where our Malaysia-Singapore collaboration had a unique opportunity – we could determine whether the tool works equally well in Chinese, Malay and Indian women, the three major ethnic groups in Asia.”
Assoc Prof Ho and Prof Teo were both involved in the first large-scale study of the PRS in Asian women, which included over 45,000 women from eight Asian countries (including Malaysia), the United States and Canada.
Published in the journal Nature Communications on July 31 (2020), the study found that the PRS could indeed be used accurately in Asian women.
Says Prof Teo, who co-led the study: “Our work showed that despite being genetically distinct from Europeans, this PRS tool is applicable to Asians as long as we make adjustments to take into account the population-specific distribution of the genetic risk scores.”
She notes that all women are currently advised to undergo breast cancer screening once they hit 50 years of age.
However, some women who are at higher genetic risk of having breast cancer may develop it before that age, possibly resulting in them only being diagnosed at a later – and less curable – stage of the disease.
Others with a low risk of breast cancer might find non-life-threatening, slow-growing cancers during screening that are nonetheless treated for caution’s sake, possibly resulting in overdiagnosis and overtreatment of their condition.
Providing a woman with her own personalised risk of breast cancer may help to increase the chances of saving the lives of high-risk women through early detection, while reducing overdiagnosis for low-risk women, she says.
“Our study shows, for the first time, that the PRS can provide Asian women with an accurate estimate of their breast cancer risk, and we hope that if this test is provided for all women, we can enable them to choose the screening and prevention methods that are right for them.”
Prof Teo adds: “Using the PRS tool, we show that Asian women in the highest risk category have about a 16% lifetime risk of developing breast cancer; this means that one in six women in this risk group will develop breast cancer in their lifetime.
“These women would therefore need enhanced breast cancer surveillance to enable early detection of the disease, for instance, attending mammography screening frequently at a younger age.
“Equally, being able to provide women their risk of the disease is important and might raise awareness on the disease and encourage them to be vigilant of the changes in their breasts in between screenings.”
Universiti Malaya Cancer Research Institute head and consultant breast surgeon Prof Dr Nur Aishah Mohd Taib, who was also involved in the study, says: “Risk-based screening may be particularly important in low- and middle-resource countries that do not have population-based screening, such as Malaysia.
“Without the funding for population-based screening, identifying individuals with higher risk may be an important strategy for early detection.”
Malaysia is anticipating a 49% increase in breast cancer cases for the period of 2012 to 2025.
In addition, Malaysia has a much lower five-year survival rate at 63%, compared to other Asian countries like South Korea (92%) and Singapore (80%).
Although the tool only requires the woman to give either a blood sample or an inner cheek cell swab for genetic testing, Assoc Prof Ho, the study’s first author, notes that it is important for each person to undergo counselling beforehand.
“Before an individual considers genetic testing, we recommend that they talk to their doctor or a genetic counsellor about their personal and family history of cancer to better understand their personal and family circumstances.
“Some additional considerations include having discussions with the individual’s family about how they might respond to genetic test results (and how these may affect them), and also about health and life insurance policies,” she says.
Looking to the future, Prof Teo says that there is still much work to be done in this area, especially in the Asian population.
“Ongoing studies will enable us to continue to improve on the accuracy of our tool by incorporating not just common variants (such as the PRS), but also rare genetic variants (such as BRCA1 and BRCA2), lifestyle risk factors and other data.
“We also hope to launch a new study to evaluate whether such a risk-stratified approach is acceptable to Asian women, and to start working on wider implementation into the healthcare system.”