The following article features coverage from the Connective Tissue Oncology Society (CTOS) 2018 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

In a paper presentation during the Connective Tissue Oncology Society (CTOS) 2018 Annual Meeting in Rome, Italy, Mandy Ballinger, PhD, of the Garvan Institute of Medical Research in Australia, revealed that through the use of whole-genome sequencing, she and her colleagues had identified POT1 as a sarcoma predisposition gene.1

The researchers came to this conclusion through the examination of subjects enrolled in the International Sarcoma Kindred Study, which was established in 2008 with the goal of understanding heritable drivers of sarcoma.

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The research team analyzed 4328 blood samples and approximately 600 formalin-fixed paraffin-embedded tissue blocks from 2933 probands — patients who are thought to be the first in their family to have a particular genetic defect — and from 2623 blood relatives of the probands. Background data was collected for approximately 105,000 family members of the probands and proband feedback was taken from 4836 questionnaires.

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Among the probands, 1109 individuals underwent whole-genome sequencing using HiSeqX. Most of the probands (82%) had only had 1 primary malignancy, whereas 18% of probands had experienced more than 1 primary malignancy. Undifferentiated pleomorphic sarcoma was the most common sarcoma subtype seen across the cohort.

As controls, the researchers used genotypes from approximately 2570 healthy, elderly Australians from a publicly available repository. These individuals — which Dr Ballinger referred to as “the wellderly” — were all in their 70s at the time of blood draw. This type of comparison using extreme phenotype sampling allows for better detection of phenotype-genotype associations; one would expect a depletion of deleterious variants across control genotypes, noted Dr Ballinger, making these elderly individuals ideal controls.

The research group determined there was an increased burden of rare pathogenic variants in patients with sarcoma, with a significantly increased frequency of deleterious variants in POT1 (P < .0001). 

POT1 protein is part of the Shelterin complex, and normally protects the ends of chromosomes, maintaining telomere length by inhibiting telomerase. When the POT1 variant is pathogenic, telomeres are longer than they should be. Defects in POT1 lead to chromosomal instability and germline mutations in the POT1 gene have been linked to melanoma, gliomas, chronic lymphocytic leukemia, and cardiac angiosarcoma, according to Dr Ballinger.

The probands with sarcoma were observed to have mutations in Shelterin, suggesting that “Shelterin complex mutations are an important genetic cause of sarcomas,” noted Dr Ballinger. This finding may have clinical utility: telomere length could be a good metric for personalized risk assessments of the likelihood that an individual will develop cancer.

“Increasingly, germline information impacts treatment decisions, and that might be the case in these families,” she concluded.

Read more of Cancer Therapy Advisor‘s coverage of the CTOS 2018 meeting by visiting the conference page.


  1. Ballinger ML, Pinese M, Rath E, et al. Whole genome sequencing of 1111 sarcoma probands reveals POT1 as a sarcoma predisposition gene. Presented at: CTOS 2018 Annual Meeting; Rome, Italy: November 14-17. Paper 043.