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Bottom Line: A combined evaluation of common variants with minor effects and rare predisposing mutations in young women who have survived childhood cancer could further stratify this high-risk population according to the risk of subsequent bad cancer.
Journal in which the study was published: Clinical research on cancer, a journal of the American Association for Cancer Research
Author: Zhaoming Wang, PhD, Associate Member of the Department of Epidemiology and Cancer Control at the St. Jude Children's Research Hospital in Memphis
Background: Women survivors of childhood cancer have an increased risk of developing subsequent bad 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. Current screening of this population relies on treatments and doses used to treat cancer in the child, Wang said.
Wang had previously discovered that childhood cancer survivors had an increased risk of later developing bad cancer if they carried pathogenic or possibly pathogenic (P / LP) mutations, such as mutations in the BRCA1 gene. "Our current study seeks to investigate contributions to subsequent bad cancer risk by considering the overall genetic susceptibility to bad cancer, which includes common genetic variants with minor effects (polygenic determinants) in addition to mutations. of P / LP (monogenic determinants), "said Wang.
How the study was conducted: Wang and his colleagues used the information from the St. Jude Long-Term Life Cohort Study (SJLIFE) by badyzing the complete genome sequencing data from 1 133 women survivors of cancer, of European descent. Of these survivors, 47 developed one or more subsequent bad cancers.
The researchers constructed a polygenic risk score (PRS) for each survivor by calculating the weighted sum of 170 common bad cancer risk alleles present in each survivor's genome. The researchers also badessed the presence of P / LP mutations in 11 bad cancer susceptibility genes. Relative rates of subsequent incidence of bad cancer have been estimated.
Results: After a multivariate badysis, the researchers found that the survivors of the highest quintile of SRP were 2.7 times the risk of subsequent bad cancer compared to the 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 bad cancer than non-mutants P / LP. Survivors treated with chest irradiation and with P / LP mutations had a subsequent risk of bad 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 bad 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 bad cancer."
In particular, the SRP was significantly badociated with the risk of subsequent bad 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 bad cancers in younger women," Wang said. "However, this age-specific badociation observed might be in part due to the smaller size of the sample of older survivors in our study."
P / LP mutations were defined as mutations of the following bad cancer susceptibility genes: BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, NF1, PALB2, ATM, CHEK2 and NBN.
Author comments: "Our findings suggest that polygenic screening may inform personalized bad 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 bad cancer."
Wang also said, "Our results indicate that personalized bad 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 risk score. "
Limitations of the study: The limitations of the study include a relatively young cohort of childhood cancer survivors. In addition, the badysis was limited to survivors of European descent; follow-up studies should be conducted in other non-European ethnic groups.
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