Developmental biology - Genetic Screening|
First genetic screening guidelines for medulloblastoma
St. Jude Children's Research Hospital identifies six genes that predispose carriers to developing the brain tumor medulloblastoma and can now screen for its carriers and possibly other cancers...
Researchers have identified six genes that predispose carriers to develop the brain tumor medulloblastoma and have used the discovery to craft genetic counseling and screening guidelines. The study appears today in the journal The Lancet Oncology.
St. Jude Children's Research Hospital, Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Germany, and The Hospital for Sick Children, Toronto, led the research.
Medulloblastoma is the most common malignant childhood brain tumor and one of the leading causes of non-accidental death in U.S. children and adolescents. The tumor includes four main molecular subgroups with different clinical and biological characteristics as well as treatment outcomes. Except in rare cases associated with genetic disorders like Li-Fraumeni syndrome or Gorlin syndrome, medulloblastoma was thought to occur by chance, usually in infants and children less than 16 years old.
After completing the largest analysis yet of genetic predisposition to a pediatric brain tumor, researchers found germline variations in six genes often play a role in the occurance of this cancer.
The genes include APC, BRCA2 and TP53, also associated with an elevated risk for breast, colon, ovarian and other cancers.
Researchers then developed screening and counseling recommendations for patients based on the medulloblastoma molecular subgroups: WNT, sonic hedgehog and group 3 and group 4.
The newly identified predisposition genes account for about 20 percent of the sonic hedgehog subgroup and about 5 percent of cases overall. Germline variations are usually inherited and carried in cells throughout the body.
"One in five patients with sonic hedgehog medulloblastoma had clear germline predispositions that put them and possibly their siblings at risk for developing medulloblastoma and other cancers later in life," explains Paul Northcott PhD, an assistant member of the St. Jude Department of Developmental Neurobiology. He and Sebastian Waszak PhD, of the European Molecular Biology Laboratory in Heidelberg, are co-first authors on the work.
Contribution of germline variations in other medulloblastoma subgroups ranged from less than 5 percent in group 3 or group 4 medulloblastoma patients, to about 10 percent of patients with WNT medulloblastoma. Overall, long-term survival is about 70 percent for patients with medulloblastoma, but ranges widely from 95 percent for WNT medulloblastoma to 50 percent for patients in group 3.
"Overall, half the patients with damaging germline variations were not identified based on their family cancer histories, which clinicians have depended on. That highlights the urgent need to make genetic counseling and testing the standard of care for some medulloblastoma patients, particularly those in the sonic hedgehog and WNT subgroups."
Paul Northcott PhD, assistant member, St. Jude Department of Developmental Neurobiology
Co-author Giles Robinson, M.D., an assistant member of the St. Jude Department of Oncology adds: "The screenings can help patients and families understand and manage their lifetime cancer risk."
Identifying predisposition genes
Along with APC, BRCA2 and TP53, the other predisposition genes identified in this study were PALB2, PTCH1 and SUFU. These gene variations are predicted to change the encoded protein and disrupt the normal function of these genes.
To find the high-risk genes, researchers compared the prevalence of rare variations in 110 known cancer predisposition genes in medulloblastoma patients from three continents to individuals without cancer. The analysis included whole genome and whole exome sequencing data of 1,022 patients with medulloblastoma. The exome is the portion of the genome that encodes instructions for protein assembly.
The samples included tumor and normal tissue from 800 of the 1,022 patients. Investigators reported no significant difference in patients screened prospectively or retrospectively. The comparison group included exome sequencing data from more than 58,000 individuals with no cancer diagnoses.
Screening and testing guidelines
The findings led to the following counseling and screening recommendations:
WNT - Genetic counseling about possible high-risk APC germline variations should be offered to certain patients with WNT medulloblastoma. Those are patients without tumor cell (somatic) mutations in the gene CTNNB1, which codes for the protein ?-catenin.
Sonic hedgehog - Genetic counseling and testing should be offered to all patients in this subgroup for some or all of the following genes: SUFU, PTCH1, TP53, PALB2 and BRCA2. The analysis also revealed that high-risk germline TP53 variations were a risk factor for medulloblastoma treatment failure.
Group 3 and Group 4 - These subgroups account for 65 to 70 percent of all medulloblastoma, but less than 5 percent of cases were associated with the cancer predisposition genes. Researchers recommend counseling and testing of PALB2 and BRCA2 in patients with family histories of breast, ovarian or other cancers associated with mutations in BRCA genes.
We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.
Authors: Senior authors are Amar Gajjar MD, co-chair of the St. Jude Department of Oncology; David Malkin MD, The Hospital for Sick Children, Toronto, Canada; Jan Korbel PhD, European Molecular Biology Laboratory; and Stefan Pfister MD, of KiTZ, and the corresponding author. Other authors are Xin Zhou and Jinghui Zhang, both of St. Jude, plus researchers in the USA, Canada, Europe, Russia, Australia and Asia.
Funding: The research was funded in part by a grant (CA21765) from the National Cancer Institute, part of the National Institutes of Health; the V Foundation; the Sontag Foundation; Pew-Stewart Scholar for Cancer; Musicians Against Childhood Cancer; and ALSAC, the fundraising and awareness organization of St. Jude. Also: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.
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May 14, 2018 Fetal Timeline Maternal Timeline News News Archive
The journal Lancet Oncology
identified six genes that predispose carriers to develop the brain tumor medulloblastoma. Image Credit: St. Jude Children's Research Hospital