- Female childhood cancer survivors are at a greater
risk of developing breast cancer later in life
- Genetic profiling is a technique that can help predict
the degree of risk for developing breast cancer in young women who
survived cancer in their childhood
- Genetic profiling can predict breast cancer even
before it develops, thereby providing valuable time to institute suitable
could help identify female childhood cancer survivors who may be at a higher
risk for breast cancer, a new study suggests. The study was headed by Dr.
Zhaoming Wang, PhD, an Associate Member in the Department of Epidemiology and
Cancer Control at St. Jude Children's Research Hospital, Memphis, Tennessee,
USA. The study was published in Clinical Cancer
, a journal of the American Association for Cancer Research (AACR).
Background of the Study
Female childhood cancer
survivors have been found to be at a higher
risk of developing breast cancer than the general population. This may occur
due to radiotherapy of the chest or by the use of chemotherapeutic drugs at
It has been found
that children who have survived cancer are particularly susceptible to breast cancer
, if they carry certain mutations in their
genes. These are the so-called pathogenic or likely pathogenic (P/LP)
mutations, which include mutations in the BRCA1 gene as well as other genes.
‘Childhood cancer survivors are at a greater risk of developing breast cancer at a later age. Genetic profiling can help identify young women cancer survivors who are more prone to developing breast cancer. Early identification of these cases can help to develop adequate preventive measures.
The present study
investigated the susceptibility to breast cancer by looking at the bigger
picture of the pathogenesis of breast cancer by genetic profiling. These
include polygenic determinants, which are common genetic mutations having a
small impact or monogenic determinants such as P/LP mutations that have a
greater impact on breast cancer development.
Some of these P/LP
mutations include those in the following genes that predispose women to breast
, BRCA2, TP53,
PTEN, CDH1, STK11, NF1, PALB2, ATM, CHEK2, and NBN.
St. Jude Lifetime
Cohort Study (SJLIFE) database was accessed to analyze full genome sequencing
data of 1,133 female cancer survivors. All the cancer survivors were of
European ancestry. Of these, 47 developed breast cancer.
There were 170
common risk alleles for breast cancer in the genomes of each survivor. The
weighted sum of these 170 risk alleles were calculated and used for
constructing a polygenic risk score (PRS) for each cancer survivor. P/LP
mutations were also examined in 11 breast cancer genes that predispose an
individual to the disease. Subsequently, the relative rates of incidence of
breast cancer were estimated.
analysis revealed that survivors who belonged to the highest PRS quintile were
2.7 times more prone to developing breast cancer than those belonging to the
survivors who received chest
radiotherapy were at an even higher risk of
developing breast cancer.
For example, those in the highest PRS quintile who
received chest radiotherapy had three times the risk of developing breast
cancer than those in the lowest quintile who had undergone similar
who had P/LP mutations were at 21.8 times higher risk of subsequently
developing breast cancer than those who didn't have these mutations. Moreover,
those survivors who had P/LP mutations and also underwent chest radiotherapy
were at 10.3 times higher risk of developing breast cancer than those who
didn't have these mutations nor underwent chest radiotherapy.
Dr. Wang said: "The
PRS can identify individuals with high breast cancer risk that do not carry
known pathogenic mutations." He further added: "Our results indicate that both
polygenic determinants and large-effect rare mutations (monogenic determinants)
contribute to the risk of subsequent breast cancer independently."
It should be noted
that PRS was significantly associated with a higher propensity for developing
breast cancer only in case of women less than 45 years of age.
Dr. Wang indicated
that the data supported the hypothesis that genetic risk factors played a
crucial role in the case of younger women of subsequently developing breast
cancer. However, the observation that breast cancer was associated with the
younger age group could be due to the comparatively smaller sample size of the
older cancer survivors included in the study.
Dr. Wang said: "Our
findings suggest that polygenic screening can inform personalized breast cancer
surveillance in female childhood cancer survivors." He added: "This method can
be utilized in the clinical setting to enhance the identification of high-risk
survivors to enable the early detection and potential prevention of subsequent
Dr. Wang went on to
say: "Our results indicate that personalized breast cancer surveillance
strategies for survivors should incorporate prior exposure to specific
anti-cancer treatments, the presence of P/LP mutations, and the cumulative
presence of small-effect common variants, as represented by a polygenic risk
Limitations of the Study
A major limitation
was that the study included a relatively young cohort of childhood cancer
survivors. Moreover, the study analyses were based upon data from patients of
European ancestry. Hence, there is a need to carry out studies in other ethnic
groups around the globe.
The study was
funded by the American Lebanese Syrian Associated Charities and by the National
Institutes of Health (NIH), USA.
- Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE) - (http://clincancerres.aacrjournals.org/content/early/2018/10/23/1078-0432.CCR-18-1775)