Pathogenic germline variants in cancer predisposition genes in patients with multiple primary cancers in an Asian population and the role of extended panel genetic testing

Background: Multiple primary cancers (MPC) are an indicator of potential hereditary cancer predisposition syndrome. There remains insufficient data on genetic testing outcomes and the optimal testing panel for MPC. We evaluated the prevalence of MPC, the spectrum of pathogenic germline variants (PGVs) and the role of extended panel testing in MPC. Methods: Cancer patients seen in a cancer genetics clinic in a tertiary cancer centre in Singapore from 2000 to 2023 were included. Clinical characteristics, PGV and patterns of cancer were analysed. Most patients were tested with 49 genes, but in a selected 156 patients with MPC, extended testing with 216 genes was carried out. Results: Of 3514 cancer patients (male = 17.9%, female = 82.1%), 668 (19%) had MPC (2 primaries, n = 570; 3 primaries, n = 81; >= 4 primaries, n = 17). The most common tumour pairs were breast-breast (33.2%), breast-ovary (8.9%), breast-endometrial (4.6%) and endometrial-ovary (4.6%). Patients with MPC had a younger median age of first cancer. Of the MPC patients, 29.4% tested positive for at least one PGV, with PGVs detected in BRCA1/2 (39.9%), other homologous recombination repair (HRR) genes (18.9%), mismatch repair (MMR) genes (11.2%) and TP53 (7%) genes. HRR genes included ATM, BARD1, BRIP1, CHEK2, PALB2, FANCL, RAD51C and RAD51D, while MMR genes included MLH1, MSH2, MSH6 and PMS2. MPC patients were more likely to have PGVs in TP53 and BARD1 compared with patients with single primary cancer. Extended testing detected more PGVs in MPC despite initial noninformative testing. It increased the number of PGVs detected in less established cancer predisposition genes, which include CFTR, SPINK1, TNFRSF13B, TET2, ADA, CDKN1C, CTNNA1, DDX41, HAX1, RECQL4 and MBD4. Conclusion: Patients with MPC were more likely to harbour a PGV. Extended testing improved PGV detection rates, particularly for less well-known cancer predisposition genes.