A combined evaluation of common variants with minor effects and rare predisposing mutations among young female survivors of childhood can…
A combined evaluation of common variants with minor effects and rare predisposing mutations among young female survivors of childhood can further stratify this high risk population for subsequent breast cancer risk ( Clin Cancer Res 2018; doi: 10.1158 / 1078- 0432.CCR-18-1775).
Female childhood cancer survivors are at increased risk of developing subsequent breast cancer compared to the general population. This increased risk has been largely attributed to cancer treatment regimens, such as breast irradiation and / or exposure to highly-dose chemotherapeutic agents. Current screening of this population is dependent on treatments and doses used to treat childhood cancer, explained study writer Zhaoming Wang, doctoral student, associate member of the Department of Epidemiology and Cancer Control at St. Jude Children‘s Research Hospital in Memphis.
Wang previously found that survivors from childhood cancer are at increased risk of subsequent breast cancer if the survivors carry pathogenic or probable pathogenic (P / LP) mutations, such as mutations to the genus BRCA1 .
“Our current study tries to investigate the risks of subsequent breast cancer by considering a complete picture of breast cancer genetic sensitivity, which includes common genetic variants with small effects (polygenic determinants) in addition to P / LP mutations (monogenic determinants),” Wang explained.
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Wang and colleagues took advantage of information from St. Petersburg. Jude Lifetime Cohort Study by analyzing data from entire genetic sequences of 1,133 female cancer survivors of European ancestors. Of these survivors, 47 47 developed one or more subsequent breast cancer.
The researchers designed a polygenerative risk score (PRS) for individual survivors by calculating the weighted sum of 170 common breast cancer risk all occurring in each survivor genome. Investigators also evaluated the presence of P / LP mutations in 11 breast cancer predisposition genes. Relative frequencies of subsequent breast cancer incidence were estimated.
After multivariate analysis, researchers found that survivors in the highest PRS quintile had 2.7 times the risk of subsequent breast cancer compared with survivors in the lowest quintile. Survivors treated with radiation were even more at risk; Those who had the highest PRS quintile treated with radiation had three times the risk of subsequent cancer compared to those in the lowest quintile treated with radiation.
Survivors who had P / LP mutations had 21.8 times increased risk of subsequent breast cancer compared to those who did not have P / LP mutations. Survivors treated with breast irradiation who had P / LP mutations had 10.3 times increased risk of subsequent breast cancer compared to those who did not have P / LP mutations treated with breast irradiation.
“PRS can identify individuals with high breast cancer risk not bearing known pathogenic mutations,” noted Wang. “Our results indicate that both polygenic determinants and high effect rare mutations (monogenic determinants) contribute to the risk of subsequent breast cancer independently.”
PRS was particularly significantly associated with risk of subsequent breast cancer only in women under 45 years of age.
“Our data support the hypothesis that genetic risk factors play a more important role in the development of subsequent breast cancer in younger women,” Wang said. “However, this observed age-specific association may be due in part to the smaller sample size of elderly survivors in our study.”
P / LP mutations were defined as mutations to the following breast cancer predisposition genes: BRCA1 PTEN CDH1 STK11 NF1 PALB2 ATM CHEK2 and NBN .
“Our findings indicate that polygen screening can inform personal breast cancer surveillance in female cancer survivors,” Wang said. “This method can be utilized in the clinical environment to improve the identification of high risk survivors to enable early detection and potential prevention of subsequent breast cancer.”
In addition, “Our results indicate that personal survival breast cancer survival strategies should incorporate past exposure to specific cancer treatments, the presence of P / LP mutations, and the cumulative presence of small-acting common variants, represented by a polygenic value.”
Restrictions of the study include a relatively young cohort of survivors of childhood cancer. In addition, the analysis was limited to survivors of European ancestors. follow-up studies should be conducted in other non-European ethnic groups.