BackgroundDeveloping multiple cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the clinical genetic testing outcomes of these patients.MethodsWe compared cancer index patients with ≥2 primary malignancies versus 1 primary cancer who underwent clinical evaluation and testing with multi-gene panels comprising up to 49 genes from 1998-2016.ResultsAmong 1191 cancer index patients, 80.6%, 17.2%, and 2.2% respectively had 1, 2, and ≥3 primary malignancies. For patients with 2 primary cancers (n=205), the most common cancer pairs were bilateral breast (37.5%), breast-ovary (11.7%), endometrium-ovary (9.2%), colon-endometrium (3.9%) and colon-colon (3.4%). 42.3% patients underwent gene testing including 110/231 (47.6%) with multiple malignancies. Pathogenic variants were found more frequently in younger patients, in those with a family history of cancer related to the suspected syndrome, and a trend towards significance in those with multiple primary cancers (35.5% vs. 25.6%, p = 0.09). In patients with multiple cancers, pathogenic variants were most commonly identified in BRCA1 (38.5%), BRCA2 (17.9%), and the mismatch repair genes (20.5%), while 23.1% of pathogenic mutations were in other moderate- to high-penetrance cancer predisposition genes including APC, ATM, MUTYH, PALB2, RAD50 and TP53.ConclusionPatients with multiple cancers were more likely to carry pathogenic mutations than those with single cancer. About three-quarters of deleterious mutations in patients with multiple primary cancers were in BRCA1/2 and the mismatch repair genes, but multi-gene panel testing facilitated the detection of mutations in another 6 genes and is warranted in this high-risk population.
BackgroundDue to historically low uptake of genetic testing, the mutational spectrum of Asians with Hereditary Breast Cancer (HBC) is not well understood. This study sought to understand the incidence and spectrum of germline mutations in Asian patients with suspected HBC in a clinic setting.Methods1056 patients with suspected HBC were seen in our Cancer (CA) Genetics Clinic from 2000–2017, of which 460 underwent genetic testing.ResultsOf 460 probands tested, 93% were female, 61% Chinese, 90% had prior CA, with 19% (77/414) having ≥2 primary CA. Median age at CA-diagnosis was 43y (17–83); 70% had Breast CA (BC) and 25% Ovarian CA (OC). 34% had young-onset BC, 8% bilateral BC, and 4% BC/OC. Majority had family history of BC (53%) or OC (20%). 57% underwent multigene testing (14–49 genes), 34% targeted testing, and 8% predictive testing. 30% were found to have a pathogenic mutation: 80% in BRCA1/2 (8 novel mutations noted). Of 33 non-BRCA1/2 pathogenic mutations detected, 61% were in 11 BC genes while 39% were in non-BC genes suggestive of alternative CA syndromes. Testing beyond BRCA1/2 impacted management for 15.9% (22/138) of carriers, but extensive testing identified variants of uncertain significance (VUS) in up to 44.5% of probands. Restricting multigene panel testing to a guideline-based 20-gene panel including Lynch Syndrome genes was found to be most optimal, detecting 94.6% of mutation carriers while reducing VUS rate to 21.5%.ConclusionsEvolution of CA Genetics testing strategy to a multigene approach facilitated detection of pathogenic mutations in non-BRCA1/2 genes and aided management. Guideline-based panel testing is feasible and can be offered in Asians with suspected HBC.
Background
Hereditary paraganglioma (PGL) and pheochromocytoma (PCC) syndromes are rare conditions, with limited data on spectrum of causative gene variants of these syndromes in Asian patients.
Methods
We describe the clinical characteristics and genetic testing outcomes of patients with suspected hereditary PGL/PCC who were referred to a tertiary cancer genetics clinic in Singapore.
Results
Among 2196 patients with suspected hereditary cancer syndrome evaluated at the cancer genetics clinic from 2000 to 2019, 13/2196 (0.6%) patients fulfilled clinical suspicion for hereditary PGL/PCC syndrome. After genetic counselling, 10 patients underwent multi-gene next generation sequencing and deletion/duplication analysis, including SDHAF2, SDHA, SDHB, SDHC, SDHD, VHL, NF1, RET, MAX, and TMEM127. Seven of 10 patients (70%) were identified to carry pathogenic variants, including 3 unrelated Chinese patients with head and neck PGL who carried the same SDHD: c.3G > C (p.Met1Ile) variant that was previously reported to be a possible founder variant in Chinese, and 3 patients with urogenital PGL and 1 patient with retroperitoneal PGL who carried different SDHB variants. Variant carriers were younger, more likely to present with multiple tumours, or have family history of paraganglioma or pheochromocytoma, than non- variant carriers.
Conclusion
Hereditary PGL/PCC accounts for only 0.6% of patients seen in an adult cancer genetics clinic in Asia. SDHD and SDHB genes remain the most important causative genes of hereditary PGL/PCC in Asia even when patients are tested with multi-gene NGS panel.
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