JAMA NetworkRisk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients with Pancreatic Ductal Adenocarcinoma with Pathogenic or Likely Pathogenic Germline Variants

Unraveling gene-specific cancer risks in first-degree relatives of PDAC probands sheds light on a higher uptake of genetic cascade testing.

Recent data suggests that first-degree relatives of patients with pancreatic ductal adenocarcinoma (PDAC) who carry pathogenic germline variants (PGVs) in specific cancer syndrome-associated genes face heightened cancer risks. The study focuses on PDAC probands carrying PGVs in nine such genes: ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A. To date, these risks hadn’t been comprehensively analyzed.

The study analyzed 234 PDAC probands with PGVs, selected from a pool of 4,562 participants who underwent genetic testing. Findings suggest that different genes correlate to distinct types of cancer. For instance, female relatives of probands with BRCA1 and BRCA2 variants showed significantly increased risks of ovarian and breast cancer. First-degree relatives of probands with Lynch syndrome mismatch repair variants exhibited higher risks of uterine, endometrial, and colon cancer. Additionally, the risk of PDAC itself rose with variants in ATM, BRCA2, CDKN2A, and PALB2, with melanoma risk escalating for relatives of probands with CDKN2A variants.

Overall, this research underscores that gene-specific PDAC and extra-PDAC cancer risks in first-degree relatives of PDAC probands are linked with the presence of PGVs in nine cancer syndrome-associated genes. As a result, the research can help physicians to counsel their patients about the significance of genetic cascade testing.