Clinical and molecular features of pediatric cancer patients with Lynch syndrome

Abstract

Background The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD). Procedure We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies. Results There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second hits and/or increased tumor mutation burden in three of four patients with available tumor with potential implications for therapy and identification of at‐risk family members. Only one patient met current guidelines for pediatric cancer genetics evaluation at the time of tumor diagnosis. Conclusion Approximately 1% of children with cancer have Lynch syndrome, which is missed with current referral guidelines, suggesting the importance of adding MMR genes to tumor and hereditary pediatric cancer panels. Tumor analysis may provide the first suggestion of an underlying cancer predisposition syndrome and is useful in distinguishing between Lynch syndrome and CMMRD.

Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

“…Recent studies have shed light on the prevalence of adult CPS, such as LS, in children with cancer. [4][5][6][7] While for LSS tumors, clues supporting causality have been presented in multiple studies, 6,11,12 further research is required to determine whether there is an association between the underlying LS and other pediatric tumors. In this study, we present a cohort of 14 children with LS who developed 16 non-LSS tumors, which we compare to four children with LS who developed LSS tumors.…”

“…Four recent studies describing individuals with LS and childhood cancer have applied part of these techniques on malignant tumors of 17 children. Because of the small sample size and the variety of analyses applied, their combined results do not provide a definitive answer, but they do indicate that in brain tumors and CRCs there is evidence for MMR deficiency 6,11–13 . Together, these studies suggest involvement of the underlying LS in the development of LS‐spectrum (LSS) cancers.…”

Clinical impact of exome sequencing in the setting of a general pediatric ward for hospitalized children with suspected genetic disorders

“…We identified a monogenic etiology in 38% of children suspected to have undiagnosed genetic conditions. Importantly, a significant portion of the cases we identified were related to lifelong cancer risk (e.g., TP53, NF2, NRAS, PTEN , and MSH6 ), affecting both informed anticipatory follow-up and anticancer treatment regimens for these children and their families ( Zhang et al, 2015 ; Scollon et al, 2021 ). Of note, prior to every ES test, a formal explanation and conversation was made with the families during which the team has explained the possibility of secondary/incidental findings, as well as possible findings which may confer future cancer risk.…”

Combined Bioinformatic and Splicing Analysis of Likely Benign Intronic and Synonymous Variants Reveals Evidence for Pathogenicity

“…The study was approved by Baylor College of Medicine institutional review board which served as the central IRB for all six participating sites. Probands and participating parents submitted blood or saliva samples for parallel clinical germline hereditary cancer panel and exome sequencing (6), with results reported back to the medical record. Consent included permission to perform subsequent research analyses with data shared with the CSER consortium (7).…”