ISKS Study Links Heritable Defects With Predisposition to Sarcomas

Variants in centrosome genes were associated with malignant peripheral nerve sheath and gastrointestinal stromal tumors, and heritable defects in the shelterin complex were linked with increased susceptibility for sarcoma, melanoma, and thyroid cancers, according to findings from the International Sarcoma Kindred Study (ISKS).

For the study, investigators examined the whole-genome sequencing results of 1644 patients with sporadic sarcomas and 3205 matched healthy, elderly individuals. Data suggested that heritable defects in telomere and mitotic function increase the risk of sarcoma, compared with most epithelial cancers.

“The most tangible aspect [of this research for clinical practice] will be potentially screening patients at risk [for sarcoma]. One of the real areas where we can improve is predicting patients who are at risk,” study co-author R. Lor Randall, MD, FACS, told OncLive^®. “You could have a patient with cancer, and we could [potentially] be able to predict that there are family [members] at risk for developing sarcoma. As importantly, what we’d like to be able to find out is, if [a patient does] develop sarcoma, how at risk are [they] for progressing?”

In an interview with OncLive^®, Randall, the David Linn Endowed Chair for Orthopedic Surgery, chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California, discussed how sarcoma experts from around the world connected to collaborate on the ISKS. He also highlighted the importance of identifying and better understanding sarcoma subgroups, and how these findings could help inform prescreening for those at risk for the disease.

OncLive^®: What served as the impetus for the ISKS?

Randall: This was a monumental, heroic effort. I want to recognize the first author, Mandy L. Ballinger, MD, and the senior author, David Thomas, MD, [both from the Garvan Institute of Medical Research and the St Vincent’s Clinical School, University of New South Wales, in Sydney, Australia]. This is really their brain trust, and I am simply a collaborator [who worked] with them.

At my prior institution, the University of Utah, we were very interested in teasing out the heritable component to cancer, and in our realm, sarcomas. We did some preliminary work there, and I collaborated with Joshua Schiffman, MD, who’s still [at the University of Utah] and who is a fantastic investigator and a recognized pediatric oncologist.

I was collecting genetic material from [patients with] sarcoma, and he started to look at germline DNA. Therefore, we had germline DNA from patients and related specimens. We were asked by Drs Ballinger and Thomas to participate [in this study]. Fortunately, some other forward-thinking sarcoma investigators around the globe were also collecting this material.

We were able to generate the largest cohort of genetic material on these patients to [understand] heritable contribution to sarcomas. It has been a rigorous study, and it’s pretty exciting. In terms of [understanding the full] therapeutic implications [of the research], we’re not quite there yet. However, the science does tell us that there is a heritable contribution to some degree with sarcoma.

Could you speak to the feasibility of evaluating the biology of rare tumors, such as sarcomas? What were some of the key challenges faced?

This was a Herculean effort [originating] out of Australia [that brought] all [of us] together. [Drs Ballinger and Thomas] basically created this ISKS group [that included investigators] from around the world. We got together at one of the Connective Tissue Oncology Society meetings and started talking about this [research]. The challenge was, [we needed] all the centers that were doing this to be able to contribute germline DNA for these patients. We wanted to be able to provide this. Drs Bollinger and Thomas were able to take all those specimens from around the world and [perform] the analyses, which have [provided] us [with] clinical findings.

Could you expand on what this research revealed?

What’s amazing is that there were these cohorts of patients that had increased risk for cancer susceptibility. The clinical findings [were on] 1,644 patients recruited from sarcoma clinics through the ISKS. The average age [of these patients] was [46.7] years, and [78.2%] of those patients [had soft tissue] sarcomas. Some [patients] had multiple primary cancers, including breast, melanoma, other secondary connective tissue tumors, non-melanoma skin cancers, prostate, colorectal, and thyroid [cancers]. It was fascinating that we found that there were telomeric and centromeric mutations; [this] means that there was something going on with the cytoskeleton architecture and the ability to develop sarcomas based upon some genomic instability.

Do you feel that the model of this type of study could be used as a template for understanding the biology of other types of rare cancers?

[It is important to recognize] that this collaborative effort [was] multiple years in the making. I’ve been at UC Davis for about 4.5 years now, and we started this study before, when I was at the University of Utah. It does speak to the fact that we can collaborate and we can bring investigators [together from] around the world to answer profound questions that relate to these rare cancers.

Specifically, when we talk about sarcoma, we’re [essentially] talking about 100 different diagnoses. We will now be able to parse [diagnoses] further into their actual subtypes and get more material to pin down those particular rare cancers.

How could these findings potentially affect treatment decisions for patients with sarcoma? What are the implications of this research?

We [see] a number of patients [for] whom we can [give] surgical local control plus or minus radiation; those patients do just fine. However, there [could be] another patient who has the exact same tumor, at the exact same site, at the exact same size, [to] whom we [give] the same treatment, and they develop metastases. What would be really powerful is to be able to say to patients, ‘For you, we are going to [use] systemic treatment, as well as [provide] local control.’ Right now, we will [often] give systemic therapy; [this] is cytotoxic chemotherapy most times, but sometimes it’s bio-targeted therapy. We don’t know [which] patients [are] benefiting from that systemic therapy.

The therapeutic implications are going to be a downstream level of investigation from [these findings]. There are some targetable areas that we have been able to find. However, right now, it’s more about getting a bigger understanding about the heritable contribution.

What efforts are being made to screen patients who are at potential risk?

A test [may become] available in the clinics to screen patients for [heritable defects linked to sarcoma]. We have [prescreening tests] in certain areas [of oncology]. For example, there are tests now [that help us understand the] risk of Alzheimer [disease] and a variety of other conditions. There [are] BRCA1 and BRCA2 [mutations that we test] for [to understand] breast cancer [risk]. We may be able to screen patients who are potentially at risk and then do some surveillance for these patients to make sure that if they do develop a sarcoma, we catch it early.

Is there anything that you would like to add?

I want to give a massive shout out to [Dr Ballinger and Thomas] and their team in Australia for getting us all together. [This research effort is] a huge conglomeration of talented thought leaders in sarcoma, and it has been a real labor of love. This is just the first step in understanding the big picture of sarcomas as a group, but then drilling down on all the different subtypes, and hopefully, developing therapeutics as well as improved screening.

Reference

Ballinger ML, Pattnaik S, Mundra PA, et al.Heritable defects in telomere and mitotic function selectively predispose to sarcomas. Science. 2023;379(6629):2