Germline mutations common among young adults with early-onset cancers
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Young adults with early-onset cancers appeared at increased risk for harboring specific germline mutations, according to study results presented at the American Association for Cancer Research Virtual Annual Meeting II.
“Although representing only about 4% of all cancers, young adults with cancer — defined as those diagnosed with cancer between the ages of 18 and 39 years — face unique challenges,” Zsofia K. Stadler, MD, oncologist at Memorial Sloan Kettering Cancer Center, said during a press briefing ahead of the meeting. “The identification of an inherited susceptibility to cancer in young [adults with cancer] is especially critical given the risk for a second primary cancer, the need for appropriate long-term surveillance and the potential for reproductive complications.”
Stadler and colleagues sought to determine the prevalence of genetic predisposition to cancer among 1,201 young adults aged 18 to 39 years diagnosed with cancer between 2015 and 2019. They pooled data from the Memorial Sloan Kettering IMPACT assay, which utilizes matched tumor and normal samples to analyze up to 88 genes implicated in cancer predisposition. Patient groups consisted of those with early-onset cancers (n = 877) and those with young-adult cancers (n = 324).
“Some cancers, such as sarcoma, testicular and brain tumors, are more common among young adults,” Stadler said. “However, other cancers such as prostate, pancreas and lung cancer are extremely rare in this age group and are what we classify as early-onset cancers.”
Common early-onset cancers included breast, colon, kidney, pancreatic and ovarian cancer. Among these, 21% harbored germline mutations. The most common mutations included BRCA1, BRCA2, CHEK2 and ATM.
Conversely, the most common young-adult cancer types included sarcoma and brain, testicular and thyroid cancers, of which 13% harbored germline mutations, including TP53, SDHA and SDHB.
When researchers limited their assessment to high-risk and moderate-risk cancer susceptibility genes, they found that 15% of early-onset cancers vs. 10% of young-adult cancers harbored germline variants (P = .01).
“Our study demonstrates that the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform,” Stadler said. “We found a very high prevalence of germline mutations in cancer types that typically present at later ages, which we categorized as early-onset cancers. Indeed, 21% of these patients harbored a germline variant, whereas among the remainder of young [adults with cancer], the germline mutation prevalence was only 13% [P = .002]. Both the prevalence and spectrum of mutations observed were more like pediatric cancer populations. These results suggest that the increased prevalence of germline mutations support a role for genetic testing irrespective of tumor type among patients with early-onset cancer.”
Perspective
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Elaine R. Mardis, PhD, FAACR
This retrospective study by Stadler and colleagues evaluated patient data from a next-generation sequencing panel test conducted at Memorial Sloan Kettering. The researchers describe the associations between specific inherited or germline mutations in cancer susceptibility genes and how they differ in patients with early-onset cancers, mainly among those with cancers that more commonly occur in older adults, vs. young-adult cancers that are more commonly diagnosed in young adults. The surprising finding here is that the germline prevalence of these mutations is significantly higher than we had previously thought.
Perspective
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Michael J. Hall, MD, MS
Cancers occurring at young ages are recognized for their high rates of germline mutations in hereditary cancer risk genes. Detection of pathogenic variants in genes associated with cancer risk among young persons with cancer can guide immediate therapy choices and inform survivorship through delineation of future cancer risk and prevention options. Further, genetic testing can accurately identify at-risk family members and guide risk-appropriate screening options.
Overall, these findings by Stadler and colleagues shed light on the diverse cancer risks, including gastrointestinal and genitourinary tumors, conferred by genes with pathogenic variants that are highly prevalent in the population — such as BRCA1, BRCA2, CHEK2 and ATM, which are most commonly associated with breast cancer risk. At the same time, these data adeptly demonstrate that young adults with rare cancers also have a substantial risk (13%) for having pathogenic variants in a hereditary risk gene. These findings strongly support the notion that genetic testing should be offered to any patient with cancer who is younger than 39 years, regardless of the diagnosis (excluding nonmelanoma skin cancers) and will help move the field of cancer one step closer to universal tumor and germline profiling of all patients with cancer.
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Stadler ZK, et al. Abstract 1122/4. Presented at: American Association for Cancer Research Virtual Annual Meeting II; June 22-24, 2020.
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