Heritable risk factors for health complications in childhood cancer.

Abstract

Childhood cancer patients and survivors suffer from serious health complications during and after treatment. The effect of heritable risk factors on health complications is still insufficiently understood. Heritable risk factors can be assessed at or early after a childhood cancer diagnosis as they do not change over time. These markers can then guide treatment, prophylactic and supportive measures, and follow-up care.

At the start of my PhD, I identified several gaps in the research on heritable conditions affecting childhood cancer patients and survivors. First, population-based data on heritable cancer predisposition syndromes were scarce. The Swiss Childhood Cancer Registry hosts a large, curated dataset of more than 10,000 people affected with childhood cancers including demographic, cancer diagnosis and treatment, follow-up, and survival data. Information on heritable conditions, i.e. cancer predisposition syndromes, had been continuously collected but not analyzed. Second, systematic nationwide collection of germline DNA in Swiss childhood cancer patients and survivors had not been established and no centralized biobank to collect, process, store, and analyze germline DNA was available. There was no structure in Switzerland to combine clinical information with germline DNA and tumor data. Third, there was a lack of data on genetic modifiers for rare outcomes. For several health complications, research on genetic modifiers had been performed, but often this information was generated from small patient samples with conflicting published results. This was the case in sinusoidal obstruction syndrome (SOS) which occurs after hematopoietic stem cell transplantation (HSCT) and some chemotherapies without HSCT. Most analyses had used a candidate-gene approach which is limited to prior knowledge for selection of candidates. Finally, as many health complications associated with childhood cancers are rare diseases and large cohorts difficult to assemble, there was a need for novel approaches to the identification of meaningful candidate genes for further genotype-phenotype analysis without relying on prior knowledge.

I addressed the first gap by analyzing data from the Swiss Childhood Cancer Registry of 8074 patients and survivors, and found that 94 were diagnosed with a second primary neoplasm (SPN) by age 21 years. I identified 304 patients with cancer predisposition syndromes (CPSs) diagnosed in regular clinical practice. I found that the incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population. The cumulative incidence of SPNs 20 years after first primary neoplasm diagnosis was 23% in patients with CPSs and 2.7% in those without. I found that CPSs were associated with an almost 8-fold increase in risk for SPNs, while chemotherapy, radiotherapy, hematopoietic stem cell20 Abstract transplantation, and older age at first primary neoplasm diagnosis each increased the risk 2-fold (Publication I, chapter 4.1).

To address the second gap, I set up the protocol for nationwide germline DNA selfcollection for childhood cancer survivors from their homes (entitled “Germline DNA Biobank Switzerland for childhood cancer and blood disorders”, BISKIDS) as part of the existing Geneva Biobank for Hematology and Oncology in Pediatrics (BaHOP). Of 928 invited eligible survivors, 463 (50%) participated. I identified foreign citizenship (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.4–0.7), older age at study invitation (OR 0.5, CI 0.4–0.8), and having a known cancer predisposition syndrome (OR 0.5, CI 0.3–1.0) to be associated with non-participation (Publication II, chapter 4.2). I then set up the genotype-phenotype research project entitled “Genetic risks for childhood cancer complications in Switzerland” (GECCOS) using samples collected through BISKIDS. We designed three sub-projects on pulmonary complications, hearing loss, and second primary neoplasms. This project will serve as a backbone for further association studies (Publication III, chapter 4.3).

To address the third gap, I performed a systematic review on sinusoidal obstruction syndrome to better understand what was known on genetic predictors for this complication (Publication IV, chapter 4.4). I found that, despite more than 20 years of research on genetic markers for this health complication, only a few genetic predictive markers were identified in more than one sample. Genetic markers that were tested in multiple studies showed often conflicting results. Only glutathione S-transferase alpha 1 (GSTA1) variants and methylenetetrahydrofolate reductase (MTHFR) variants in high-risk patients after busulfan-based conditioning regimens were repeatedly identified. Only one study performed whole-exome sequencing with replication of findings in an independent cohort. Finally, I was part of a team of researchers from the CANSEARCH research platform in pediatric oncology and hematology of the University of Geneva and the Swiss Institute of Bioinformatics of the University of Lausanne. We developed a pipeline on how to prioritize genes and genetic variants for analysis on health complications associated with specific treatment exposures (Publication V, chapter 4.5). We combined in vitro differential gene expression of lymphoblastoid cell lines after busulfan exposure with clinical whole-exome sequencing on SOS. We used a combined test statistic to prioritize genes and gene variants for further analysis. For the pipeline we used SOS after busulfan exposure during HSCT, but our model might serve other rare diseases as well.