Landscape of germline cancer predisposition mutations testing and management in pediatrics: Implications for research and clinical care

Abstract

As germline genetic testing capacities have improved over the last two decades, increasingly more people are newly diagnosed with germline cancer susceptibility mutations. In the wake of this growth, there remain limitations in both testing strategies and translation of these results into morbidity- and mortality-reducing practices, with pediatric populations remaining especially vulnerable. To face the challenges evoked by an expanding diversity of germline cancer mutations, we can draw upon a model cancer-associated genetic condition for which we have developed a breadth of expertise in managing, Trisomy 21. We can additionally apply advances in other disciplines, such as oncofertility and pharmacogenomics, to enhance care delivery. Herein, we describe the history of germline mutation testing, epidemiology of known germline cancer mutations and their associations with childhood cancer, testing limitations, and future directions for research and clinical care.

Simultaneous Occurrence of Multiple Neoplasms in Children with Cancer Predisposition Syndromes: Collaborating with Abnormal Genes

“…Depending on the type of mutation, the presence of a genetic background is associated with the onset of the disease (sometimes indicating a better or worse prognosis) or enables its prevention [ 5 , 8 , 11 , 16 ]. The clinical cases reported in this paper exemplify the links identified between specific mutations in the genome and the induction of cancers in infancy and early childhood (at 14, 12, and 6 months of age at diagnosis, respectively).…”

“…Multiple diagnoses are extremely rare. While the exact causes of oncological diseases remain largely unknown, the role of genetic factors and the identification of syndromes that predispose individuals to cancer are gradually being identified and understood with advancements in genetics and genomics [ 5 , 6 , 7 , 8 , 9 ]. With medical advancements, targeted treatments, anticipatory screening, and the prevention of subsequent cancers are possible, which is especially important for individuals with cancer predisposition syndromes (CPSs) [ 10 , 11 , 12 , 13 ].…”

Children's Oncology Group's 2023 blueprint for research: Liver tumors

“…• the discovery of relapse therapies and interventional approaches to local control; and • the study of constitutional predisposition syndromes and germline associations. 74 Work by the COG Liver Tumor Committee over the preceding decades has laid a successful foundation for the treatment of HB. Now, in collaboration with international colleagues and consortia, we are working to further innovate and hone the therapeutic approach for HB, while advocating for the continued prospective study of pediatric patients with HCC and FLC.…”

“…Future initiatives will require ongoing international collaboration and a focus on parallel advances across the many disciplines required for the comprehensive care of patients with both HB and HCC. Specific examples include but are not limited to: the genomic characterization of tumor specimens from the AHEP1531/PHITT trial to inform “biologic risk” layered on an evolving interpretation of histopathology, immunohistochemistry, and radiographic PRETEXT staging; the use of indocyanine‐green to guide surgical approach, its sensitivity and specificity, and the role of metastatectomy in patients with lung nodules 69,70 ; the application of pixel‐level radiomics to pediatric HB and HCC tumors to further define tumor heterogeneity, as a reflection of tumor histology, and predict response to therapy and overall outcomes; the exploration of circulating tumor DNA to predict tumor genomic heterogeneity and allow a less‐invasive approach to prognostication 71–73 ; the tailoring of therapy for patients with comorbidities secondary to prematurity or other underlying developmental syndromes; the accessibility of therapy for patients of diverse ethnic and socioeconomic backgrounds; the discovery of relapse therapies and interventional approaches to local control; and the study of constitutional predisposition syndromes and germline associations 74 …”

Simultaneous Occurrence of Multiple Neoplasms in Children with Cancer Predisposition Syndromes: Collaborating with Abnormal Genes

“…remains open, as long as we discuss the very or even extremely rare genetic disorders that cause CPS. There is currently one well-known genetic disorder, Down syndrome, for which distinct diagnostic and treatment pathways have been developed, leading to early diagnosis and reduced mortality among these patients [5]. Such supportive care efforts should also be undertaken in other cases of CPS and lead to the establishment of dedicated procedures for such patients.…”