When a child is diagnosed with osteosarcoma very young (typically below the age of 10) or has a strong family history of sarcomas/breast cancer/GBM, or when a patient relapses, genetic testing may be mentioned. There are two distinct types of genetic testing looking at distinct things. Germline testing is usually either a blood test or a saliva test and it is looking for genetic mutations in the germline which may predispose someone to cancer. The germline is the genome containing all of the genes which we have inherited from our biological parents and it appears in every cell in the body.

There are roughly 80-90 known genes in which mutations may result in strong predispositions towards cancer. Li-Fraumeni syndrome, Lynch syndrome, BRCA, and Bloom syndromes are genetic mutations in certain genes which predispose someone to very high rates of cancer and which are known to be associated with osteosarcoma.

No one knows what causes osteosarcoma, or perhaps, more accurately, what series of circumstances happen which in turn cause osteosarcoma, but the most recent research is showing that in younger osteosarcoma patients (typically under 25 at diagnosis), at least 28% and possibly as high as 50% may have germline mutations associated with osteosarcoma. This is an incredibly high rate of germline predisposition for cancer (breast cancer, by comparison has a germline genetic predisposition somewhere between 5- 10%).

Part of the reason that osteosarcoma may have high rates of germline predispositions is due to de novo germline mutations. Germline mutations can either be inherited from a parent (and are usually associated with strong family histories of cancer) or they can occur at conception as part of the random mistake which happen every day in cell division. These germline mutations which occur at conception are called “de novo” mutations. Some recent osteo research has shown that upwards of 50% of the TP53 germline mutations (Li-Fraumeni syndrome) found in osteosarcoma are de novo.
Here are some germline mutations and their names which have either been definitively or tentatively identified as being important in osteosarcoma formation:

–       TP53: Li-Fraumeni Syndrome
–       – RB1: Retinoblastoma syndrome
–        – BLM: Bloom syndrome
–        – MLH1/MSH2/3/6/PMS2: Lynch Syndrome
–        – BRCA1/2/ATM: breast cancer syndrome
–       – REQL4: Rothman-Thomson syndrome

If you are thinking about germline testing, it’s important to consult a genetic counselor who knows sarcomas well and to get a broad-spectrum germline test. Currently, germline testing isn’t going to change front-line treatment for osteosarcoma, but it will often change follow-up care (different types and/or frequency of scans), and in the case of relapse, it may also be helpful.