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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.

SUBMITTER: Shahani SA

PROVIDER: S-EPMC9548803 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Shahani Shilpa A SA Marcotte Erin L EL

Frontiers in pediatrics 20220926

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 ...[more]

PMID: 36225340

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Project description:BackgroundThe prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.MethodsIn 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism).ResultsMutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer.ConclusionsGermline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).

Project description:Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.

Project description:Supratentorial primitive neuroectodermal tumors while histologically similar to medulloblastoma is less curable. Gross total resection and therefore early recognition is crucial to a favorable outcome. We report our experience with a 4 year old girl whose clinical course and radiology were atypical. The patient was referred to our center for management of a seizure disorder manifesting as episodic choking, spitting, drooling and vomiting. MRI showed cortical thickening (right perisylvian fissure; right frontal operculum; insula) patchy/gyriform enhancement of the right sylvian fissure resembling angiomatous dysplasia and clusters of dysplastic meningeal vessels. There was no mass effect, midline shift, ventriculomegaly and MRV/MRA were normal. The radiological differential diagnoses offered were polymicrogyria, focal cortical dysplasia, neuronal migrational disorders, neurofibromatosis and Sturge-Webber syndrome. She had no neurological deficits and seizures were controlled with Topiramate/Levetiracetam. Brain CT 3 months later showed focal dystrophic calcification in the right perisylvian region superimposed on the cortical dysplasia again suggestive of a phakomatosis. ASA was commenced to reduce risk of stroke. MRI performed two months later showed progression of leptomeningeal enhancement involving the suprasellar cistern/perimesencephalic cistern, left sylvian fissure, ventral brainstem and cerebellar vermis. There was tumefactive material in the right pre-pontine cistern and right ventricular effacement. Spinal cord MRI done at this time showed diffuse subarachnoid spread. Throughout this period apart from episodic facial pain the patient had no neurological, speech, ocular, cerebellar or major cognitive deficits. A biopsy was performed and histopathology was consistent with supratentorial PNET. CSF was negative for malignant cells. Due to the extent /inoperability of the tumor, minimal possibility of cure/high likelihood of severe treatment related side-effects parents opted for supportive care rather than curative treatment. The patient passed away a few months later. A high index of suspicion and low threshold to biopsy is recommended for early diagnosis of these tumors.

Dataset Information

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

Publications

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

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