Genomic variants, genetic testing may identify ‘sarcoma families’

More than one-half of patients with sarcoma harbored putatively pathogenic monogenic and polygenic mutations to known cancer genes, according to study results published in The Lancet Oncology.

These findings suggest the presence of inherited cancer mutations may increase the risk for cancer within families, researchers wrote.

“Sarcomas are rare types of cancer that disproportionately affect the young, have low survival rates, and in which there are currently few treatment options available,” Ian Judson, MD, FRCP, consultant medical oncologist and professor of cancer pharmacology at The Royal Marsden NHS Foundation Trust in London, said in a press release. “This important study has uncovered mutations occurring in some sarcoma patients that could potentially be targeted by precision treatments, opening up new avenues for treatment that should be investigated in clinical trials.”

Judson and colleagues conducted an international genetic study that included data from 1,162 patients (median age at diagnosis, 46 years; interquartile range, 29-58) with histologically confirmed sarcoma. These individuals served as probands for the purpose of this study.

The researchers collected thorough clinical, pathological and pedigree information. Independent verification confirmed cancer diagnoses in probands and family members.

Genetic testing involved targeted exon sequencing of blood (n = 1,114) or saliva (n = 48) samples on 72 genes associated with cancer risk and rare variants, including TP53, BRCA1, BRCA2 and ATM.

Researchers performed a case–control burden analysis with data from 6,545 white controls culled from three large datasets.

Fifteen percent (n = 170) of probands had multiple cancers. The researchers observed an increased cancer burden among first-degree relatives of probands, with 654 diagnoses observed in 3,978 first-degree relatives.

Common cancer diagnoses among first-degree relatives included sarcomas (SIR = 2.65; 95% CI, 1.6-4.4), brain tumors (SIR = 1.62; 95% CI, 1.02-2.57), breast cancer (SIR = 1.52; 95% CI, 1.25-1.84) and melanoma (SIR = 1.39; 95% CI, 1.09-1.78).

A review of 911 families with informative pedigree showed that 17% (n = 155) met recognized criteria for cancer syndromes, and an additional 87 families carried excess or unusual patterns for cancer in first-degree relatives (SIR = 1.83; 95% CI, 1.55-2.15).

The case–control rare variant analysis showed that 55% (n = 638) of sarcoma probands carried an excess of known or expected pathogenic variants (OR = 1.43; 95% CI, 1.24-1.64), representing 956 class 3 to class 5 rare variants.

Commonly mutated genes observed in this study included TP53, ATM, ATR, BRCA2 and ERCC2. A pooled analysis of all sarcoma probands showed that 240 carried multiple variants (2-6 per individual; median, 2; interquartile range, 2-3).

Probands had a higher likelihood of multiple pathogenic variants than controls (OR = 2.22; 95% CI, 1.57-3.14), as well as a higher cumulative burden of multiple variants correlating with earlier age at diagnosis (P = .0032 for trend).

An expert review showed that 66 probands carried notifiable variants about which patients should be advised. Further, 293 probands — 25% of the cohort — harbored mutations that could potentially be used for targeted treatment.

The researchers acknowledged the study was not powered to detect specific genetic or pathway interactions underlying polygenic variants.

“This study represents an important first step in mapping the heritability of sarcoma in human beings,” Judson and colleagues wrote. “There are recognized risk management strategies for individuals with several hereditary cancer syndromes, most commonly breast and bowel cancer. Sarcoma families found to be carrying high-risk genetic variants might benefit from surveillance and prevention strategies.”

In addition to new treatment options, this study may improve patient–physician communications about sarcoma, according to Robert S. Benjamin, MD, distinguished professor in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, and Andrew Futreal, PhD, interim chair of the division of genomic medicine at the same institution, wrote in a related editorial.

“These data, especially if confirmed in other series of patients with sarcoma, suggest that offering germline testing for all patients with sarcomas might be warranted, especially in the context of a comprehensive assessment of family history,” Benjamin and Futreal wrote. “Targeted therapy for sarcoma has, with few notable exceptions, been unrewarding. Although precisely how these new genetic findings could lead to improved therapeutic outcomes is not yet clear, improved understanding of the complex interactions caused by multiple genetic abnormalities could help to identify new therapeutic targets.” – by Cameron Kelsall

Disclosure: One study researcher reports an advisory board role with AstraZeneca. Judson and the other researchers report no relevant financial disclosures. Benjamin and Futreal report no relevant financial disclosures.