Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes

Abstract

Background: Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases.

Methods: Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants.

Results: GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk.

Conclusion: Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.

Keywords: genetic predisposition to disease; genetic variation; neoplasms.

Figure 1

Overview of the study experimental design, methods and main findings. GPV, germline pathogenic variant; LOH, loss of heterozygosity; VUS, variant of uncertain clinical significance.

Figure 2

Overview of GPV detected in 177 patients with sarcoma. Sarcomas were divided by histological subtype between bone tumours and soft tissue sarcomas. On the left, the genes included in the customised panels are represented and divided according to their association with sarcoma predisposition. # XAF1 is not included in our panel, but alterations in this gene were investigated in patients with TP53 p.Arg337His. On the right, the percentages represent the number of patients detected with GPV in the indicated gene, and at the bottom, the types of alterations are described. The results of tumour LOH analyses are also depicted. Patients are coloured according to age group. Notes: *Recessive genes: all patients were monoallelic heterozygotes. ^#Patient diagnosed with multiple subtypes of sarcomas (osteosarcoma, leiomyosarcoma and liposarcoma). ASPS, alveolar soft part sarcoma; AYA, adolescents and young adults; C, children; CS, chondrosarcoma; DFSP, dermatofibrosarcoma protuberans; ES, Ewing sarcoma; FDCS, follicular dendritic cell sarcoma; GPV, germline pathogenic variant; LMS, leiomyosarcoma; LOH, loss of heterozygosity; LS, liposarcoma; MFS, myxofibrosarcoma; MPNST, malignant peripheral nerve sheath tumours; NOS, not otherwise specified; OS, osteosarcoma; SFT, solitary fibrous tumour; SS, synovial sarcoma; WT, wild type.

Figure 3

(A) Rates of germline pathogenic variant (GPVs) according to sarcoma subtype. The light blue bars show the total number of cases of each sarcoma subtype and the dark blue bars show the percentage of GPVs identified in each subtype. The spindle cell sarcoma group includes two malignant peripheral nerve sheath tumours (MPNSTs), since both MPNSTs were initially diagnosed as spindle cell sarcomas in the routine diagnosis and were only reclassified as MPNSTs after we identified the NF1 GPVs and performed a pathological review integrating the germline findings. (B) Frequency of GPVs in genes found in this cohort (177 patients with sarcoma) compared with a cohort of healthy elderly individuals (1171 Brazilian individuals from the ABraOM database). P values are shown for Fisher’s exact test, with significant differences (p<0.05) displayed in bold.