Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors—a nationwide, prospective Swedish study

Tesi, Bianca; Robinson, Kristina Lagerstedt; Abel, Frida; Díaz de Ståhl, Teresita; Orrsjö, Sara; Poluha, Anna; Hellberg, Maria; Wessman, Sandra; Samuelsson, Sofie; Frisk, Tony; Vogt, Hartmut; Henning, Karin; Sabel, Magnus; Ek, Torben; Pal, Niklas; Nyman, Per; Giraud, Geraldine; Wille, Joakim; Pronk, Cornelis Jan; Norén-Nyström, Ulrika; Borssén, Magnus; Fili, Maria; Stålhammar, Gustav; Herold, Nikolas; Tettamanti, Giorgio; Maya-Gonzalez, Carolina; Arvidsson, Linda; Rosén, Anna; Ekholm, Katja; Kuchinskaya, Ekaterina; Hallbeck, Anna-Lotta; Nordling, Margareta; Palmebäck, Pia; Kogner, Per; Smoler, Gunilla Kanter; Lähteenmäki, Päivi; Fransson, Susanne; Martinsson, Tommy; Shamik, Alia; Mertens, Fredrik; Rosenquist, Richard; Wirta, Valtteri; Tham, Emma; Grillner, Pernilla; Sandgren, Johanna; Ljungman, Gustaf; Gisselsson, David; Taylan, Fulya; Nordgren, Ann

doi:10.1016/j.lanepe.2024.100881

The Lancet Regional Health - Europe

2024

DOI: 10.1016/j.lanepe.2024.100881

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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors—a nationwide, prospective Swedish study

Bianca Tesi,

Kristina Lagerstedt Robinson,

Frida Abel

et al.

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2024

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Cited by 3 publications

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Genetic testing for childhood cancer predisposition syndromes: Controversies and recommendations from the SIOPE Host Genome Working Group meeting 2022

Bakhuizen,

Bourdeaut,

Wadt

et al. 2024

EJC Paediatric Oncology

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Genetic testing for childhood cancer predisposition syndromes: Controversies and recommendations from the SIOPE Host Genome Working Group meeting 2022

Bakhuizen,

Bourdeaut,

Wadt

et al. 2024

EJC Paediatric Oncology

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Cancer risk in individuals with polydactyly: a Swedish population-based cohort study

Wachtmeister,

Tettamanti,

Nordgren

et al. 2024

Br J Cancer

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Background Polydactyly is a feature of several cancer predisposition syndromes (CPS), however, cancer risk in individuals with polydactyly is largely unknown. Methods We performed a matched cohort study using data from Swedish national registers. We included 6694 individuals with polydactyly, born in Sweden between 1970–2017. Polydactyly was categorised as thumb polydactyly, finger polydactyly, polydactyly+ (additional birth defects and/or intellectual disability) or isolated polydactyly. Each exposed individual was matched to 50 comparisons by sex, birth year and birth county. Associations were estimated through Cox proportional hazard models. Findings An increased childhood cancer risk was found in males (HR 4.24, 95% CI 2.03–8.84) and females (HR 3.32, 95% CI 1.44–7.63) with polydactyly+. Isolated polydactyly was associated with cancer in childhood (HR 1.87, 95% CI 1.05–3.33) and young adulthood (HR 2.30, 95% CI 1.17–4.50) in males but not in females. The increased cancer risk remained after exclusion of two known CPS: Down syndrome and neurofibromatosis. The highest site-specific cancer risk was observed for kidney cancer and leukaemia. Conclusions An increased cancer risk was found in individuals with polydactyly, especially in males and in individuals with polydactyly+. We encourage future research about polydactyly and cancer associations and emphasise the importance of clinical phenotyping.

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Prospective Screening of Cancer Syndromes in Patients with Mesenchymal Tumors

Öfverholm,

Lin,

Mondini

et al. 2024

Cancers

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Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed. Results: Germline pathogenic or likely pathogenic variants associated with an increased risk of tumors were detected in 24 patients (8%), of which 11 (4%) harbored a detectable second hit in the tumor. Second hits were confirmed in genes with (NF1, RB1, TP53, EXT2, and SDHC) and without (ATM, CDC73, MLH1, MSH6, POLG, and KCNQ1) known association with mesenchymal tumor predisposition. Sarcomas from two Lynch syndrome patients showed mismatch repair deficiency, predicting a treatment response to immune checkpoint inhibitors (Level 1 biomarker according to the FDA (Federal Drug Administration) and ESMO (European Society for Medical Oncology)). None of the three CHEK2 carriers had a second hit in the tumor, suggesting a weak link to sarcoma. Conclusions: We conclude that second-hit analyses can be used in standard of care to identify syndrome-related tumors. This approach can help distinguish true manifestations of tumor syndromes from unrelated germline findings and enhance the understanding of germline predisposition in soft tissue tumors. Prospective screening using germline whole genome sequencing should be considered when comprehensive somatic sequencing is introduced into clinical practice.

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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors—a nationwide, prospective Swedish study

Cited by 3 publications

References 28 publications

Genetic testing for childhood cancer predisposition syndromes: Controversies and recommendations from the SIOPE Host Genome Working Group meeting 2022

Genetic testing for childhood cancer predisposition syndromes: Controversies and recommendations from the SIOPE Host Genome Working Group meeting 2022

Cancer risk in individuals with polydactyly: a Swedish population-based cohort study

Prospective Screening of Cancer Syndromes in Patients with Mesenchymal Tumors

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