Young Adults With Cancer May Harbor Germline Mutations

Young cancer patients may benefit from germline genetic testing

PHILADELPHIA – Young patients ages 18–39 with early-onset cancer were at an especially high risk of harboring inherited genetic (germline) mutations, according to a study presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting II, held online June 22-24.

Because patients with early-onset cancer harboring germline mutations are at increased risk for second primary cancers and other health complications, they could benefit from germline genetic testing.

“Although they only represent about 4 percent of all cancers, young adults with cancer, defined as those diagnosed with cancer between the ages of 18 and 39, face unique challenges,” said Zsofia K. Stadler, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSK). “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.”

Patients with early-onset cancer are a distinct subgroup of young cancer patients, Stadler explained. “While some cancers are more typically seen in young adults, such as sarcoma, testicular cancer, and brain cancer, cancers typically diagnosed in older adults, including in breast, colon, pancreas, kidney, prostate, and ovaries, are extremely rare in this young age group, and are what we classify as ‘early-onset’ cancers.”

Stadler and colleagues studied germline mutations in 1,201 young adult patients who received a cancer diagnosis between 2015 and 2019 at MSK. The researchers used the germline genetic testing protocol of MSK-IMPACT, which utilizes a next-generation sequencing panel to study up to 88 genes known to be associated with cancer susceptibility. The analysis was performed on DNA from blood samples in these patients.

There were 877 patients with early-onset cancer, and the most common cancers were colorectal, breast, kidney, pancreatic, and ovarian cancer; 324 patients had young-adult cancers, and the most common cancers were sarcoma, and brain, testicular, and thyroid cancers.

The researchers found that 21 percent of the patients with early-onset cancer and 13 percent of the patients with young-adult cancer had an inherited genetic mutation.

Among patients with early-onset cancers, the highest rates of genetic mutations were found in those with cancer in the pancreas, breast, or kidney, with the most frequent mutations in the genes BRCA1, BRCA2, ATM, CHEK2, and the Lynch syndrome-associated genes. Among patients with young-adult cancers, germline TP53 mutations were more common, which is consistent with Li-Fraumeni syndrome, a syndrome associated with childhood cancers, including sarcomas.

“This study highlights that genetic susceptibility among young cancer patients is heterogeneous,” noted Stadler. “The distinct set of germline variants appear to suggest that patients with early-onset cancers harbor mutations similar to those also found in older individuals with cancer, but at a higher prevalence. Among patients with young-adult cancers, the mutations were more similar to those we encounter in our pediatric cancer patients.”

Stadler added, “Young cancer patients with early-onset cancer should undergo germline genetic testing given the high probability of identifying a genetic mutation with important downstream implications for cancer treatment, long-term surveillance, and at-risk family members.”

In addition to studying the germline mutations from the blood-derived DNA, the researchers are also analyzing sequencing data from tumor-derived DNA in these patients. This can help determine if a specific tumor a patient was diagnosed with is driven by the identified germline mutation, Stadler said.

Limitations to the study include that it is a single-institution study from a tertiary cancer center; therefore, some cancer types may have been over- or underrepresented, when compared with the incidence of these cancers in young adults in the general population, Stadler noted. The analysis was limited to solid tumors only and the genetic risk in young patients with hematological malignancies was not assessed.

This study was partially funded by the Precision, Interception, and Prevention Program; the Marie-Josée and Henry R. Kravis Center for Molecular Oncology; and the Robert and Kate Niehaus Center for Inherited Cancer Genomics, all at MSK. Stadler’s immediate family member holds consulting/advisory roles in ophthalmology with Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics.