Analysis of Early-Onset Cancers Suggests Need for Genetic Testing

Sharon Worcester

July 15, 2020

Patients with early onset cancers have an increased prevalence of germline pathogenic variants, suggesting that genetic testing would be worthwhile in this population, according to a presentation at the AACR virtual meeting II.

Investigators analyzed blood samples from 1,201 patients who were aged 18-39 years when diagnosed with a solid tumor malignancy.

In this group, there were 877 patients with early onset cancers, defined as cancers for which 39 years of age is greater than 1 standard deviation below the mean age of diagnosis for the cancer type.

The remaining 324 patients had young adult cancers, defined as cancers for which 39 years of age is less than 1 standard deviation below the mean age of diagnosis.

The most common early onset cancers were breast, colorectal, kidney, pancreas, and ovarian cancer.

The most common young adult cancers were sarcoma, brain cancer, and testicular cancer, as expected, said investigator Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Stadler and colleagues performed next-generation sequencing of the patient samples using a panel of up to 88 genes previously implicated in cancer predisposition. This revealed a significantly higher prevalence of germline mutations in patients with early onset cancers than in those with young adult cancers — 21% and 13%, respectively (P = .002).

In patients with only high- and moderate-risk cancer susceptibility genes, the prevalence was 15% in the early onset group and 10% in the young adult group (P = .01). "Among the early onset cancer group, pancreas, breast, and kidney cancer patients harbored the highest rates of germline mutations," Dr. Stadler said, noting that the spectrum of mutated genes differed in early onset and young adult cancer patients.

"In early onset patients, the most commonly mutated genes were BRCA1 and BRCA2 [4.9%], Lynch syndrome genes [2.2%], ATM [1.6%], and CHECK2 [1.7%]," Dr. Stadler said. "On the other hand, in young adults, TP53 mutations [2.2%], and SDHA and SDHB mutations dominated [1.9%], with the majority of mutations occurring in sarcoma patients."

These findings suggest the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform.

"We found a very high prevalence of germline mutations in young patients with cancer types that typically present at later ages," Dr. Stadler said, referring to the early onset patients.

Conversely, the young adult cancer patients had a prevalence and spectrum of mutations more similar to what is seen in pediatric cancer populations, she noted.

The findings are surprising, according to AACR past president Elaine R. Mardis, PhD, of The Ohio State University in Columbus.

Dr. Mardis said the results show that, in young adults with early onset cancers, "the germline prevalence of these mutations is significantly higher than we had previously thought."

"Although representing only about 4% of all cancers, young adults with cancer...face unique challenges," Dr. Stadler said. "Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this patient population."

Such knowledge "can significantly impact the risk of second primary cancers and the need for increased surveillance measures or even risk-reducing surgeries," Dr. Stadler explained. She added that it can also have implications for identifying at-risk family members, such as younger siblings or children who should pursue genetic testing and appropriate prevention measures.

"Our results suggest that, among patients with early onset cancer, the increased prevalence of germline mutations supports a role for genetic testing, irrespective of tumor type," Dr. Stadler said.

This study was partially funded by the Precision, Interception and Prevention Program, the Robert and Katie Niehaus Center for Inherited Cancer Genomics, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and a National Cancer Institute Cancer Center Core Grant. Dr. Stadler reported that an immediate family member serves as a consultant in ophthalmology for Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis disclosed relationships with Qiagen NV, Pact Pharma LLC, Moderna Inc., and Interpreta LLC.

SOURCE: Stadler Z et al. AACR 2020, Abstract 1122.

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