Following is a compilation of research into osteosarcoma, both Theresa Beech’s ¹ and other peoples, as well as some speculative thoughts. The bottom-line answer to both of these questions is that no one knows why someone gets osteosarcoma or how it develops. We just don’t know. Having said that, there are some known factors which can predispose to osteosarcoma and which correlate with it. There’s also been some basic research into how sarcomas develop and spread which we can extrapolate to osteosarcoma. And finally, in Ms. Beech’s research, she noticed certain patterns in the genetics which have sparked ideas.

According to Ms. Beech Li-Fraumeni Syndrome (LFS) or germline mutations in TP53 are known to be causal of osteosarcoma, as is Bloom Syndrome (mutations in BLM), Retinoblastoma Syndrome (mutations in RB1) and Rothman-Thomson Syndrome (mutations in the REQ4 helicases). Recent research is also showing that germline mutations in BRCA1/2, XRCC1, and potentially ATM can also predispose to osteo. Ms. Beech’s research indicates that Lynch Syndrome genes (mutations in MSH2/3/6, MLH1, or PMS3) may also be causal.

A big recent study of over 2,000 osteosarcoma patients showed that 28% have pathogenic (disease causing) germline mutations. That is a huge percentage (for comparison, breast cancer, which is thought to have a high number of germline mutations involved, only has roughly 10% of all patients with a germline mutation, and some recent genetic research out of St. Jude showed that only about 10-12% of all pediatric cancer patients have pathogenic germline mutations). These germline mutations may be inherited from one parent or they may be de novo, meaning they are newly acquired in the person and occurred at conception.

Recent research on LFS has shown that almost half of all osteosarcoma patients with LFS have a TP53 germline mutation which is de novo. General research into all sarcomas has indicated that in patients under the age of 25, germline mutations, including combinations of germline mutations, each of which individually may not be cancer-predisposing but which together may predispose, appear in roughly half of sarcoma patients.

The second point is important because these apparently “benign” combinations of germline mutations may be a big and overlooked factor. Ms. Beech sees these “benign” combinations quite frequently in osteosarcoma patients’ genetics. An example of this would be a kid has “benign” germline variants in MSH2, MSH3 and MSH6. Individually each variant is benign: it won’t predispose to cancer, but together? Who knows?

It’s important to note that Ms. Beech’s research hasn’t shown if these combinations also appear in the general population. It’s also important to point out that even if this 50% germline predisposition holds up and is further validated, that still leaves at least half of all osteosarcoma patients with no obvious germline mutation predisposing to the disease, and hence no obvious answer to the question of why they got the disease.

Research out of Minnesota (funded by the Zach Fund — thank you Laura Friedrich Sobiech) has shown that in osteosarcoma patients under the age of 30 there is about a 90% chance of having an epigenetic imprinting defect at a specific chromosomal locus: 14q32. This imprinting defect is hereditary and passed preferentially, although not exclusively, through the paternal line.

What is an epigenetic imprinting defect?

Genes can be changed directly through some sort of mutation/ abnormality. They can also be changed indirectly, or epigenetically, by another gene or messenger (miRNA) turning them on or off indirectly. As an analogy: we can turn a light on/off by using a light switch. This is the equivalent of changing a gene through a mutation or other abnormality. We can also turn a light on/off by blowing a fuse. This is the equivalent of changing a gene epigenetically. So in an epigenetic imprinting defect, something goes wrong at 14q32 which affects other genes by turning them on/off anomalously.

There are numerous miRNA which originate at 14q32 which are believed to be important in osteosarcoma. However, this imprinting defect is not enough to cause osteosarcoma because in the research they showed that while the kids had this imprinting defect and had osteosarcoma, none of the parents who had this imprinting defect also had osteosarcoma. So clearly, the imprinting defect is not enough. There is a form of secondary osteosarcoma which can occur in people who have had high dose radiation, usually for a previous cancer.

TP53 is the gene behind osteosarcoma. It is turned off somehow, either directly or indirectly, in roughly 90% of all osteosarcoma patients (the different research indicates somewhere between 74% and 99% of osteosarcoma patients have TP53 inactivated in their tumor cells). TP53 is the guardian of the human genome. It is what keeps us human, and not having it leads to intense genetic instability in the tumor cells, and an ability to mutate and change very rapidly. So this is Ms. Beech’s hypothesis for how osteosarcoma develops.

Ms. Beech stresses that this is her hypothesis and her idea. She has talked about this with various doctors. The general consensus is that it is plausible, but currently it’s just an interesting idea. We do not know how osteosarcoma develops. Given the right set of circumstances, TP53 is inactivated in a mesenchymal stem cell. These circumstances may include: the 14q32 epigenetic imprinting defect, germline mutations which predispose to osteosarcoma, high dose radiation, something else yet to be determined, and let’s not forget that utterly uncomforting phenomenon — random bad luck.

Once TP53 is inactivated, there is a rapid progression of events which unfolds something like this: TP53 inactivation ==> genetic instability ==> oncogene development ==> rapid cell growth ==> metastasis ==> more genetic instability ==> more rapid cell growth ==> more metastasis.

“In my own personal vision, what I would like to see happen someday is this: Just as all newborn babies are tested at birth for a variety of metabolic diseases (remember the heel blood tests?), I would like to see a world in which all babies are tested for the known cancer predisposing genes (aka high-penetrance genes). If they have a mutation, fix it through something like CRISPR so that they won’t face this awful beast. This won’t eradicate osteosarcoma, but I think it would significantly reduce the incidence. And if we can improve the treatments and cure rates, then maybe one day those many fewer kids who get osteosarcoma will all survive and thrive in spite of this dreadful disease. This is my vision. This is my dream.” Theresa Beech

¹ Theresa Beech is the mother of two kids, Daniel and Sara. When Daniel was 11, he was diagnosed with osteosarcoma, an extremely aggressive and deadly form of bone cancer. Two years later he was dead. While Daniel was on hospice, Theresa started doing research into osteosarcoma genetics and was able to identify two drugs which corresponded to mutations in his tumor and prolonged his life. She has continued her research since his death and is the Principal Investigator of POWR, the Patient/parent Osteosarcoma genome-Wide Registry, believed to be the largest genetic and medical registry of osteosarcoma data in the world. She is also the founder and President of “Because of Daniel”, a charitable foundation dedicated to osteosarcoma research and clinical trials. In her day job, Theresa is a space engineer (aka rocket scientist) working at NASA.