Rare Pathogenic Germline Mutations Highlighted Among Osteosarcoma Patients

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Rare germline pathogenic or likely pathogenic variant (PV) forms of cancer-susceptibility genes may be common in patients with osteosarcoma, suggest study findings published in JAMA Oncology. 

“Our findings have important implications for the genetic testing of patients, especially younger patients, who are newly diagnosed with osteosarcoma because these patients were more likely to have a potentially clinically relevant disease-associated pathogenic/likely pathogenic variant”, say Lisa Mirabello, from the National Cancer Institute in Bethesda, Maryland, USA, and co-authors.

Whole-exome or targeted sequencing was performed for 1244 osteosarcoma patients attending one of 10 international centres or studies between 2014 and 2017, as well as 1062 control individuals without cancer participating in one of four studies, and 27,173 cancer-free individuals of non-Finnish European ancestry entered into the Exome Aggregation Consortium (ExAC) database.

Overall, 28.0% of 1004 osteosarcoma patients with European ancestry carried a PV form of one of 238 cancer-susceptibility genes, compared with just 12.1% of healthy controls and 9.3% of the ExAC cohort.

The majority (18.4%) of these osteosarcoma patients had PVs in autosomal-dominant or autosomal-dominant and autosomal-recessive cancer-susceptibility genes, as opposed to 5.3% and 5.5% of the control and ExAC groups.

The corresponding rates for variants in autosomal-recessive genes were 9.2%, 6.8% and 3.8%, respectively.

Analysis revealed that osteosarcoma patients with a PV were significantly younger than their counterparts without (mean, 15.3 vs 16.9 years), and this was especially true for the patients with autosomal-dominant gene variants where 24.5% of carriers were aged 0 to 10 years.

The most common autosomal-dominant genes with PVs in osteosarcoma patients were TP53 (4.4%) and CDKN2A (1.2%), while the most commonly affected autosomal-recessive gene was RECQL4 (1.0%).

A further 25.4% of the osteosarcoma patients had “a rare variant of uncertain significance” in an autosomal-dominant gene that was predicted by in silico analyses to be damaging in the absence of a known PV, the researchers say.

“Our data underscore the high frequency of potentially actionable cancer risk variants in patients with osteosarcoma, suggesting a need for further preventive and early detection strategies as well as a consideration of cascade genetic testing for the patient and the entire family”, Lisa Mirabello et al write.

“We note that individuals harboring Li-Fraumeni syndrome–associated TP53 mutations benefit from active screening, which could translate into improved outcomes”, they say.

“Further studies are needed to refine our observations and identify optimal approaches to genetic testing and counseling for patients with osteosarcoma.” 

Reference  

Mirabello L, Zhu B, Koster R, et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol; Advance online publication 19 March 2020. doi:10.1001/jamaoncol.2020.0197