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Sarcoma Susceptibility Traced to Telomere Function, Mitotic Pathways

NEW YORK – A team from the Garvan Institute of Medical Research, the University of New South Wales, and other centers has tracked down germline mutations in telomere function and mitotic pathways that increase the risk of sarcoma, a collection of rare bone or connective tissue tumors arising from tissues that develop from the embryonic mesoderm.

"Together, these data suggest that heritable defects in telomere and mitotic function increase the risk of sarcoma, in contrast to most epithelial cancers," senior and corresponding author David Thomas, a researcher affiliated with the Garvan Institute of Medical Research and the University of New South Wales St. Vincent's Clinical School, and his coauthors wrote in Science on Thursday, calling telomere maintenance and mitosis "fundamental to chromosome integrity."

Using whole-genome sequencing, the researchers searched for rare sarcoma-associated germline variants in 1,644 individuals with sporadic sarcomas, comparing patient sequences to those from more than 3,200 "wellderly" control individuals who reached 84 years old, on average, without developing cancer.

"To maximize power," the authors explained, "we applied an extreme phenotype case: control design using 3,205 healthy elderly controls [from the Medical Genome Reference Bank (MGRB)], which we previously showed are depleted in cancer-associated genetic variation relative to population-based controls."

While some of the patients included in the analysis developed sarcoma after treatment for another cancer, they noted that hundreds of patients had multiple primary cancers, including 110 patients with sarcoma as a primary diagnosis.

From these and other data, the authors reasoned that the "majority of sarcomas in individuals with multiple primary tumors are not therapy related," consistent with a "strong genetic basis for apparently sporadic sarcomas."

The team's rare variant and gene function analyses highlighted a set of almost 1,200 gene candidates that was further pared down to 968 genes with an age-corrected analysis that incorporated data for more than 400 individuals in the Australian Schizophrenia Research Bank.

After bringing in gene set enrichment, protein interaction, and pathway clues, the researchers focused on 85 proposed sarcoma susceptibility genes — a set that encompassed seven genes apiece from centromere and shelterin complexes related to mitotic and telomere functions, respectively.

The team noted that germline risk variants in genes from centromere-related pathways appeared to show enhanced ties to the risk of certain sarcomas such as malignant peripheral nerve sheath tumors (MPNSTs) and gastrointestinal stromal tumors (GISTs).

To further validate their results, the researchers considered whole-genome or exome sequence data for 839 more individuals with sarcoma and almost 4,100 control individuals before bringing in data for 4,178 cancer cases profiled for the Hartwig Foundation dataset to assess potential telomere and mitotic pathway contributions to the risk of other cancer types.

While shelterin and centromere gene alterations did not appear to be strongly enriched in other types, the authors noted that heritable changes to shelterin and telomere function are implicated in familial melanoma and thyroid cancer, potentially linking the cancer types.

In a related perspectives article in Science, Memorial Sloan Kettering Cancer Center researchers Diana Mandelker and Marc Ladanyi, who were not involved in the study, suggested that findings from the sarcoma study "should prompt further work to more firmly establish these [shelterin and centromere gene candidates] as sarcoma predisposition genes and to determine penetrance and the spectrum of cancer predisposition they confer."

"If confirmed, this will be critical to the management of individuals and families with sarcoma because it will enable more at-risk genetic testing and cancer surveillance," they wrote, noting that "this experimental design has the potential to reveal more genes that confer susceptibility to a wide variety of diseases and enhance the ability to practice individualized genetic medicine in the future."

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