Genetic predisposition in children with cancer – affected families' acceptance of Trio-WES

Abstract

A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). The ratio of CPSs caused by inherited versus de novo germline mutations and the risk of recurrence in other children are unknown. We initiated a prospective study performing whole-exome sequencing (WES) of parent-child trios in children newly diagnosed with cancer. We initially aimed to determine the interest in and acceptance of trio WES among affected families and to systematically collect demographic, medical, and family history data to analyze whether these point to an underlying CPS. Between January 2015 and December 2016, 83 (88.3%) of 94 families participated; only 11 (11.7%) refused to participate. Five (6.0%) children presented with congenital malignancies and three (3.6%) with tumors with a high likelihood of an underlying CPS. Two (2.5%) families showed malignancies in family members < 18 years, 11 (13.8%) showed relatives < 45 years with cancer, 37 (46.3%) had a positive cancer history, and 14 (17.5%) families had > 1 relative with cancer.Conclusions: Genetic testing in pediatric oncology is of great interest to the families, and the vast majority opts for investigation into potentially underlying CPSs. Trio sequencing provides unique insights into CPS in pediatric cancers and is increasingly becoming a common approach in modern oncology, and thus, trio sequencing needs also to be integrated routinely into the practice of pediatric oncology.

Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations

“…Whole-exome sequencing (WES) of peripheral bloodderived DNA of the parent-child trio was performed. Details on data analysis are given in the Supplemental material [11]. Taken together, we identified 461 inherited heterozygous sequence variations of probable consequences including missense (444), frameshift (9), inframe insertion and deletions (6), and start/stop-codons (2), occurring with an allele frequency of less than 5% (MAF ≤ 0.05).…”

Integrating genetic counseling and testing in the pediatric oncology setting: Parental attitudes and influencing factors

“…Research by Brozou et al demonstrated a much higher rate of uptake of ES in families of children with cancer, at 88.3%; however, this was assessed after the ES consent process. It may be that the consent process, which contains educational elements similar to those covered within a genetic counseling session, alleviated uncertainty, leading to uptake of ES . As resources permit, referral for pretest genetic evaluation and counseling is recommended to facilitate decision making regarding germline genetic testing.…”

“…Despite these considerations, research has previously demonstrated interest in genetic testing for CPS among pediatric oncology patients and their families; however, for many, this testing is not yet routinely available at the clinic . In addition, little is known about sociodemographic factors influencing interest among this population.…”

Cancer Predisposition Syndromes Associated With Pediatric High-Grade Gliomas

“…WES of parent-child trios has become a widely used strategy to identify presumably pathogenetic genetic variants in children with rare diseases. However, it has not yet been routinely implemented in pediatric oncology, with few exceptions (71). Genome-wide approaches generate huge amounts of genetic data and it remains challenging to interpret the identified variants.…”