Genetic Clues to ‘Devastating’ Sarcoma Diagnosis Uncovered

Genetic variants in pathways linked to mitotic and telomere cell functions appear to be associated with the risk of developing sarcoma and may increase susceptibility to other cancers, even among patients’ relatives, suggest findings from the first comprehensive genetic mapping of the disease.

The research, published in Science on January 19, involved genomic analysis of almost 1650 sarcoma patients and a series of control groups. The analysis identified two novel groups of genes associated with the cancer, one involved in protecting telomeres, and the other in centrosome formation and integrity.

Along with the previously known association between sarcoma and TP53 variants, these new genes accounted for approaching 1 in 14 cases of the rare cancer and were associated with a more than doubling of the cancer risk among relatives.

“Receiving a sarcoma diagnosis can be devastating,” commented patient advocate Jonathan Granek, who was diagnosed with a sarcoma at age 26 years. “This research offers hope to sarcoma patients” of a diagnosis at an earlier and potentially “curable” stage, he said in a statement.

Lead author Mandy Ballinger, PhD, group leader of the Genetic Cancer Risk Group, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia, agreed, adding that the results are “so important because, by understanding how individuals develop sarcomas, we move closer to earlier detection and better treatments.”

“Cancer is fundamentally a genetic disease, and genomics is the key to unlocking its secrets,” said David Thomas, PhD, head of the Genomic Cancer Medicine Laboratory at the Garvan Institute of Medical Research and CEO of Omico, a nonprofit nationwide network of cancer research and treatment centers.

“This international collaboration has developed new methods for mapping the genetic basis for cancer and identified new heritable pathways that increase cancer risk,” he noted. “These findings fill important gaps.”

Currently, less than 50% of the familial relative risk of developing cancer is accounted for by common or rare genetic variants, the authors say, “leaving the majority of heritability unexplained.”

They note that genetic studies of common epithelial cancers have offered up “major insights into the biological mechanisms underpinning specific cancer susceptibilities.”

Seeking to identify further insights, the researchers focused on sarcomas, rare malignancies arising in bone, muscle, fat, or cartilage that differ “fundamentally from epithelial cancers.”

Although rare, sarcomas account for about 20% of the cancer cases diagnosed in people younger than 20, and yet they have been “relatively understudied to date,” the authors comment.

To investigate, the team recruited 1644 sarcoma patients. Soft tissue sarcoma was the most common diagnosis, accounting for 78.2% of cases. Patients commonly had multiple primary cancers, including breast cancer, melanoma, a second connective tissue tumor, nonmelanoma skin cancer, and prostate and colorectal cancer.

Whole-genome sequencing revealed 37,820 rare single-nucleotide variants and insertions or deletions, of which 1033 were known to be or likely to be pathogenic (C5), 10,702 were new loss-of-function or protein-truncating (C4) variants, and 26,085 were potentially pathogenic (C3).

Employing a case-control design, the team evaluated 3205 healthy control persons. They found that a primary set of 1176 genes was potentially related to sarcoma risk; a further comparison with individuals from a schizophrenia database yielded a second set of 968 top-ranked genes.

From this, the researchers identified 224 genes that were in five clusters of five or more genes. From these, they selected the 85 highest-ranked genes. This yielded three groups of interest:

• the shelterin protein complex, which protects the ends of telomeres and was represented by the genes POT1, TERF1, and TINF2;

• the mitotic spindle, including CEP63, which mediates centrosome formation, and HAUS4 and HAUS5, which regulate centrosome integrity; and

• two genes, EXT1 and EXT2, which were linked to hereditary exostoses and bone sarcomas.

Comparing the results with another control group of 623 patients who mostly had epithelial cancers revealed sarcoma-specific enrichment for both the shelterin and centrosome gene sets. The latter was enriched particularly for malignant peripheral nerve sheath tumors and gastrointestinal stromal tumors.

Further analysis in an independent set of 839 patients with sarcoma and 4094 geographically matched cancer-free control persons validated their prior findings.

The researchers calculated that, in their original cohort, 3.2% of sarcoma patients carried C3 to C5 variants in the shelterin complex and related telomere genes, and 0.8% carried TP53 variants. Among control persons, the proportions were 0.03% and 0.2%, respectively.

The results also indicated that among the relatives of sarcoma patients who carry C4 or C5 variants in shelterin genes, the incidence of cancer was increased at a standardized incidence ratio (SIR) of 2.06; the risk of thyroid cancer and melanoma were particularly notable, at SIRs of 5.60 and 19.74, respectively.

This overall increased cancer risk was comparable to that seen among relatives of patients with TP53 variants, at an SIR of 2.59. In addition, a further 2.3% of sarcoma patients carried C3 to C5 variants in centrosome genes.

Discussing their findings, the team says that they have “identified genes and biologic pathways that appear specific to mesenchymal malignancies, as well as mapping the contributions of known cancer genes.”

While highlighting the notable “lack of enrichment” in BRCA1 or BRCA2, they say their research adds 14 candidates “to more than 100 known sarcoma-associated genes.”

“Biologically, these data suggest that the telomeric and mitotic pathways may play specific roles in sarcoma susceptibility, analogous to homologous recombination and mismatch repair in susceptibility to breast and colorectal cancers,” they conclude.

The study was supported by Omico, NSW Office of Medical Research, National Health and Medical Research Council, the Cancer Institute NSW, Cancer Australia, the Australian and New Zealand Sarcoma Alliance, the Liddy Shriver Sarcoma Initiative, and the Rainbows for Kate Foundation. Two authors are founders and shareholders of genomiQa Pty Ltd and are members of its board. Joshua D. Schiffman is an employee, stock option holder, and board member of PEEL Therapeutics, Inc. Other authors have relationships with Biogen, AstraZeneca, and XING Technologies.

Science. Published online January 19, 2023. Abstract

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