Clinical relevance of screening checklists for detecting cancer predisposition syndromes in Asian childhood tumours

Sock Hoai Chan,Michaela Su-Fern Seng,Shao-Tzu Li,Mei Yoke Chan,Sheng Hui Tan,Enrica Ee Kar Tan,Joanne Ngeow,Ah Moy Tan,Sharon Yin Yee Low,Kenneth Chang,Amos Hong Pheng Loh,Jing Xian Teo,Tarryn Shaw,Shui Yen Soh,Winston Chew,Nur Diana Binte Ishak,Prasad Iyer,Weng Khong Lim,Yong Chen

doi:10.1038/s41525-018-0070-7

Abstract

Assessment of cancer predisposition syndromes (CPS) in childhood tumours is challenging to paediatric oncologists due to inconsistent recognizable clinical phenotypes and family histories, especially in cohorts with unknown prevalence of germline mutations. Screening checklists were developed to facilitate CPS detection in paediatric patients; however, their clinical value have yet been validated. Our study aims to assess the utility of clinical screening checklists validated by genetic sequencing in an Asian cohort of childhood tumours. We evaluated 102 patients under age 18 years recruited over a period of 31 months. Patient records were reviewed against two published checklists and germline mutations in 100 cancer-associated genes were profiled through a combination of whole-exome sequencing and multiplex ligation-dependent probe amplification on blood-derived genomic DNA. Pathogenic germline mutations were identified in ten (10%) patients across six known cancer predisposition genes: TP53, DICER1, NF1, FH, SDHD and VHL. Fifty-four (53%) patients screened positive on both checklists, including all ten pathogenic germline carriers. TP53 was most frequently mutated, affecting five children with adrenocortical carcinoma, sarcomas and diffuse astrocytoma. Disparity in prevalence of germline mutations across tumour types suggested variable genetic susceptibility and implied potential contribution of novel susceptibility genes. Only five (50%) children with pathogenic germline mutations had a family history of cancer. We conclude that CPS screening checklists are adequately sensitive to detect at-risk children and are relevant for clinical application. In addition, our study showed that 10% of Asian paediatric solid tumours have a heritable component, consistent with other populations.

Highlights

Recent genomic studies of paediatric cancer patients have suggested that 6–35% of children with cancer may harbour deleterious germline mutations associated with their disease,[3,4,5,6,7] implying an underestimation of cancer predisposition syndrome (CPS) prevalence in the paediatric population
The conundrum faced by most paediatric oncologists is navigating these complexities to identify at-risk children who will benefit from genetic testing and counselling
Multinodular goitre, N No, ND not determined, neurofibromatosis type 1 (NF1) neurofibromatosis 1, NPC nasopharyngeal cancer, NSCLC non-small cell lung cancer, P pathogenic, Pat paternally inherited, PC pheochromocytoma, PPB pleuropulmonary blastoma, RMS rhabdomyosarcoma, RCC renal cell carcinoma, SCC squamous cell carcinoma, SDR second-degree relatives, SLCT Sertoli−Leydig cell tumour, SLE/RA systemic lupus erythematosus/rheumatoid arthritis, TDR third-degree relatives, VHL von Hippel-Lindau, Y yes aZygosity status of all germline mutations was heterozygous bPatient was referred for genetic counselling but failed to follow up with the recommendation cFamily history recorded is not extensive a b

Summary

Introduction

Genetic predisposition has been estimated to account for 4–10% of childhood cancers.[1,2] recent genomic studies of paediatric cancer patients have suggested that 6–35% of children with cancer may harbour deleterious germline mutations associated with their disease,[3,4,5,6,7] implying an underestimation of cancer predisposition syndrome (CPS) prevalence in the paediatric population. Of the ten patients who screened positive and carried pathogenic germline mutations, eight fulfilled clinical criteria for CPS including Li-Fraumeni syndrome (LFS, n = 3), DICER1 syn-

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Results

Conclusion