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A combined evaluation of common variants with low effects and rare predisposing mutations in women survivors of childhood cancer may better stratify this high-risk population based on the risk of subsequent breast cancer (Clin Cancer Res 2018; doi: 10.1158 / 1078-0432.CCR-18-1775).
Women survivors of childhood cancer have an increased risk of subsequently developing breast cancer compared to the general population. This increased risk has been largely attributed to cancer treatment regimens, such as chest irradiation and / or exposure to high dose chemotherapeutic agents. The current screening of this population relies on the treatments and doses used to treat cancer in the child, explained the study author, Zhaoming Wang, PhD, associate member of the department of D & # 39; 39, Epidemiology and Cancer Control St. Jude Children's Research Hospital in Memphis.
Wang had previously discovered that survivors of childhood cancer had an increased risk of subsequent breast cancer if they exhibited pathogenic or possibly pathogenic (P / LP) mutations, such as mutations in the BRCA1 gene.
"Our current study attempts to investigate contributions to subsequent breast cancer risk by taking into account the overall genetic susceptibility to breast cancer, which includes common genetic variants with small effects (polygenic determinants) as well as mutations of P / LP (monogenic determinants). Wang explained.
Specificities of the study
Wang and colleagues used the information from the St. Jude Life Cycle Cohort Study by analyzing full genome sequencing data from 1,133 women survivors of an original cancer European. Of these survivors, 47 developed one or more subsequent breast cancers.
The researchers constructed a polygenic risk score (PRS) for each survivor by calculating the weighted sum of 170 common breast cancer risk alleles present in each survivor's genome. The researchers also assessed the presence of P / LP mutations in 11 breast cancer susceptibility genes. Relative rates of subsequent incidence of breast cancer have been estimated.
After a multivariate analysis, the researchers found that survivors of the highest quintile of SRP were 2.7 times the risk of subsequent breast cancer compared to survivors of the lowest quintile. Survivors treated with thoracic irradiation had an even higher risk; those in the top quintile of SRP treated by irradiation were three times more likely to develop cancer than those in the lower quintile treated by irradiation.
Survivors with P / LP mutations were 21.8 times more likely to develop breast cancer than non-mutants P / LP. Survivors treated with chest irradiation and with P / LP mutations had a subsequent risk of breast cancer 10.3 times higher than those who did not undergo P / LP mutations treated by thoracic irradiation.
"The PRS can identify people at high risk of breast cancer who do not carry known pathogenic mutations," Wang said. "Our results indicate that polygenic determinants and rare, large-effecting mutations (monogenic determinants) independently contribute to the risk of subsequent breast cancer."
In particular, the SRP was significantly associated with the risk of subsequent breast cancer in women under 45 years of age.
"Our data support the hypothesis that genetic risk factors play a larger role in the development of subsequent breast cancers in younger women," Wang said. "However, this association observed according to age could be partly due to the smaller size of the sample of older survivors in our study."
P / LP mutations have been defined as mutations of the following breast cancer susceptibility genes: BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, NF1, PALB2, AT M, CHEK2, and NBN.
"Our findings suggest that polygenic screening may inform personalized breast cancer surveillance in women survivors of childhood cancer," said Wang. "This method can be used in a clinical setting 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 personalized breast cancer surveillance strategies for survivors should include prior exposure to specific cancer therapies, the presence of P / LP mutations, and the cumulative presence of common low-effect variants, represented by a polygenic gene. risk score. "
The limitations of the study include a relatively young cohort of childhood cancer survivors. In addition, the analysis was limited to survivors of European descent; follow-up studies should be conducted in other non-European ethnic groups.
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