Higher Prevalence of Germline Mutations Identified in Young Adults With Cancer

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A new study has found that a higher-than-expected proportion of young adults with cancer harbor genetic germline mutations that have implications for treatment, surveillance, and other family members who may be at risk. Patients with “early-onset cancers”—cancers that typically do not occur in younger adults—had a significantly higher rate of germline mutations than did those with “young-adult” cancers (ie, those typically seen in this age group): 21% vs 13% (P = .002), respectively, according to results presented during a premeeting press briefing and at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.1

“Although young adults represent only about 4% of all cancers, defined as those diagnosed with cancer between the ages of 18 and 39, they face unique challenges. Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is important, as it can result in a substantial change in clinical management, such as increased cancer surveillance aimed at early detection and risk-reducing surgery to prevent new cancers, and may even have reproductive implications for young families,” stated lead author Zsofia K. Stadler, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSK), New York.

“These results suggest there is a role for genetic testing in young adults with early-onset cancer, irrespective of tumor type,” she stated.

“These results suggest there is a role for genetic testing in young adults with early-onset cancer, irrespective of tumor type.”
— Zsofia K. Stadler, MD

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For the purposes of the study, cancers in young adults (aged 18–39) were defined as early-onset (cancers not typically seen in younger patients) and young-adult cancers (those likely to occur at younger ages). Early-onset cancers, such as breast, colon, pancreatic, kidney, prostate, and ovarian, are rarely seen in young adults. Cancers commonly found in young adults include brain, testicular, and sarcoma.

Study Details

The study included 1,201 young adults diagnosed with cancer between 2015 and 2019 at MSK. The presence of germline mutations was assessed using MSK-IMPACT next-generation sequencing, which includes a panel of 88 genes known to be associated with cancer susceptibility. DNA from blood samples of these patients was analyzed.

The Surveillance, Epidemiology, and End Results Registry data were used to determine whether cancers were early-onset or young-adult, according to which cancers were more or less likely to occur by age 39. Early-onset cancers were found in 877 patients; the most commonly diagnosed cancers were colorectal (20%), breast (39%), kidney (6%), pancreatic (6%), and ovarian (6%). Young-adult cancers were diagnosed in 324 patients, and the most common cancers were sarcoma (36%), brain (23%), testicular (17%), and thyroid (9%).

Among the early-onset breast, kidney, or pancreatic cancers, the most frequent germline mutations were in BRCA1/BRCA2 (4.9%), ATM (1.6%), CHEK2 (1.7%), and Lynch syndrome–associated genes (2.2%). Germline TP53 (2.2%) and SDHA/B (1.9%) mutations were most common in patients with young-adult cancers. TP53 is consistent with Li-Fraumeni syndrome, associated with childhood cancers, including sarcoma. Dr. Stadler noted that the mutation prevalence of sarcoma in young-adult patients with cancer was 18.1%, similar to the prevalence of early-onset cancers.

Related Issues

During the question-and-answer session after Dr. Stadler’s presentation at the premeeting press briefing, she was asked whether women with known CHEK2 mutations should undergo more intensive screening. “Our data do not support that,” she answered.

Regarding insurance coverage for genetic testing, Dr. Stadler noted: “The field is changing. Patients with pancreatic cancer are now covered for germline genetic testing, and we expect guidelines will broaden coverage for early-onset and young-adult cancer populations.”

Additional Commentary

“This study was based on patient data from a next-generation sequencing panel used at MSK analyzing tumor and germline specimens. The investigators found an association between specific inherited and de novo germline mutations in cancer susceptibility genes that differed in early-onset and young-adult cancers,” explained AACR President Elaine R. Mardis, PhD, FAACR, Co-Executive Director of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, Ohio.

“The findings are surprising. The prevalence of these germline mutations is significantly higher than previously thought.”
— Elaine R. Mardis, PhD, FAACR

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“The findings are surprising. The prevalence of these germline mutations is significantly higher than previously thought. A total of 21% of early-onset patients and 13% of young-adult patients with cancer had germline pathogenic mutations, which has implications for genetic testing, surveillance, and counseling,” Dr. Mardis noted.

“It would be nice to know [the presence of mutations identified by genetic testing] before they develop cancer, but beyond that, the presence of mutations has management implications. We would want to do accelerated imaging and screening, and treatment differences would be based on diagnosis,” she added. 

DISCLOSURE: Dr. Stadler has an immediate family member who has served in a consulting or advisory role for Adverum, Alimera Sciences, Allergan, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis has served as a consultant or advisor to Interpreta Inc, Kiadis Pharma, and PACT Pharma; and has a supervisory board membership at Qiagen where she receives stock and honoraria.


1. Stadler ZK, Maio A, Padunan A, et al: Germline mutations prevalence in young adults with cancer. 2020 AACR Virtual Annual Meeting II. Abstract 1122.