e22638 Background: Second malignant neoplasms (SMNs) represent a major cause of non-relapse mortality among long-term cancer survivors and currently account for 15–20% of new cancer diagnoses in national registries. While lifestyle exposures and prior cytotoxic therapies contribute to SMN risk, germline pathogenic variants in cancer-predisposition genes are increasingly recognized as a key driver. Data from low- and middle-income settings, however, remain limited. Methods: We reviewed the King Hussein Cancer Center registry to identify pediatric and young adult patients diagnosed with an SMN. Individuals who subsequently underwent germline testing in the adult or pediatric genetics clinics were included. Patients were classified as children (<15 years) or adolescents/young adults (AYAs; 15–39 years). Germline evaluation was performed using targeted multigene cancer-predisposition panels. Demographic features, timing and pattern of malignancies, and genetic findings were analyzed to identify potential hereditary syndromes contributing to SMN risk. Results: Of 244 patients with SMNs, 76 (28 children; 48 AYAs) underwent germline testing. Median age at first cancer diagnosis was 29 years (0.8–38.9), at second cancer 38 years (5–80), and at third cancer 35 years (16–72). Most patients had metachronous tumors (n=53, 70%), followed by synchronous (n=20, 26%) and complex patterns (n=3, 4%). Germline variants were identified in 40 patients. Pathogenic/likely pathogenic variants were detected in 27 (35.5%) in genes including ATM, BRCA1, DICER1, LZTR1, TP53, RAD51D, MSH6, MLH1, PMS2, SDHC, NF2, VHL, and MUTYH . An additional 14 patients carried variants of uncertain significance in genes such as ALK, APC, BRCA2, BRIP1, CASR, DIS3L2, FH, KIT, MSH3, PALB2, POLE, POT1, PLCG2, RECQL4, RET, RAD51D, SMARCE1, and WT1 . Common identified syndromes included constitutional mismatch repair deficiency (CMMRD), Lynch syndrome, DICER1 syndrome, BRCA-related syndromes, and neurofibromatosis type 2. At last follow-up, 62 patients were alive with a median overall survival of 111 months (7–678). Conclusions: These findings underscore the strong association between germline cancer-predisposition variants and SMNs. Systematic genetic evaluation of cancer survivors with multiple malignancies is essential to enable early detection, tailored surveillance, and personalized therapeutic strategies, ultimately improving long-term survivorship outcomes in resource-limited settings.
Shanap et al. (Thu,) studied this question.