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Poster De Conférence Année : 2023

Identification of rare variants involved in the risk of second cancer following radiotherapy and chemotherapy treatment of pediatric cancers

Brice Fresneau
Filippo Rosselli
  • Fonction : Auteur
  • PersonId : 1086666
Giao Vu-Bezin
Boris Schwartz
Rodrigue Allodji
Gaëlle Marenne
Thomas E Ludwig
Anne Boland-Auge
Hélène Blanché
  • Fonction : Auteur
  • PersonId : 1015002
Chiraz El-Fayech
Carole Rubino
  • Fonction : Auteur
Ibrahima Diallo
Florent de Vathaire
Nadia Haddy

Résumé

Background: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN). Exposure to radiation therapy and certain chemotherapy molecules are known risk factors for SMN development. However, there remains inter-individual variability in these treatment related SMN that is attributed to genetic variations. Objective: The aim of our study is to identify rare genetic variants associated with risk of SMN and their interactions with treatment of the primary cancer in childhood. Methods: We conducted a nested case-control study of SMN within the French Childhood Cancer Survivors Study (FCCSS) cohort with 163 cases and 287 controls. Whole exome sequencing was realized on these 450 cancer survivors. The mean radiation dose at the site of interest and doses of each chemotherapeutic agent were calculated for all the survivors. In order to have sufficient power to detect an association between rare variants and the risk of SMN, variants were grouped by genetic unit to identify genes enriched in variants in cases and controls. Three statistical methods accounting for the specific characteristics of rare variant studies were tested, all of them are gene-based association tests: a) Burden tests, more powerful when the variants are causal and in the same direction; b) Variant-component tests (e.g., SKAT), more powerful in the presence of a mixture of variants with deleterious and protective effects; c) Combined tests of the two previous approaches (e.g., SKATO). All tests were adjusted for sex, age at diagnosis and year of diagnosis of primary cancer, type of first cancer, length of follow-up, and the first 4 principal components of the PCA to account for population stratification. The results will be presented as odds ratios (ORs) with their 95% confidence intervals (CIs). Genes significantly associated with SMN status will be further analyzed for interaction with radiotherapy and chemotherapy. Results: The mean age at diagnosis of the first cancer was 7 years for cases and controls. The length of follow-up is similar for cases and controls with a median of 24 years. A total of 151 cases (92.7 %) and 194 controls (67.5 %) had received radiation therapy. Association tests identified several genes enriched in rare variants in cases with promising associations with the risk of SMN. Further analysis of these genes is underway, as well as analysis focusing on the most common SMN type (thyroid: 40.7 % and breast: 29.1 %). Interaction studies with spleen, active bone marrow radiation doses and radiation doses received at the site of the second cancer will be performed as well as with doses of selected chemotherapy drugs. Discussion: This study will provide new evidence regarding the involvement of genetics in the development of SMN in interaction with the first cancer treatment received. This could allow the identification of survivors at higher risk for SMN development in order to adapt treatment and/or follow-up.
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Dates et versions

hal-04488114 , version 1 (04-03-2024)

Identifiants

  • HAL Id : hal-04488114 , version 1

Citer

Claire Ducos, Brice Fresneau, Filippo Rosselli, Giao Vu-Bezin, Boris Schwartz, et al.. Identification of rare variants involved in the risk of second cancer following radiotherapy and chemotherapy treatment of pediatric cancers. International Society of Radiation Epidemiology and Dosimetry (ISORED) - 1st meeting, May 2023, Sitges (Barcelona), Spain. ⟨hal-04488114⟩
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