Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers

Abstract

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.

Int22h1/Int22h2 ‐mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features

“…Intriguingly, the development of RCC before the age of 47 years, which was the case of Proband 6, is regarded as one of the findings suggestive of VHL syndrome (van Leeuwaarde et al, 1993). VBP1 is not included in most commercial multigene panels routinely performed when assessing for genetic cancers (Chan et al, 2018; Hampel et al, 2015). The observation that no culprit genes could be identified through cancer multipanel screen for Proband 6, and his early development of RCC, possibly suggests a possible role of VBP1 in his oncogenesis.…”

Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer

“…Nevertheless, multigene panel testing in clinical settings represents a considerable challenge as these panels include moderate or less well‐defined genes as well as high‐penetrant genes 36‐38 . Lack of clear management guidelines for variants in genes with undefined cancer risks or P/LP variants in genes can be problematic.…”

Case Report: Novel RPGRIP1L Gene Mutations Identified by Whole Exome Sequencing in a Patient With Multiple Primary Tumors

“…These advances have contributed to more satisfactory survival times and higher incidence of MPTs. It is generally accepted that inherited genetic defects are most likely to cause MPTs (Chan et al, 2018 ). A recent paper reported a rare variant within a PARP4 pseudogene (PARP4P2) in a patient with MPTs and familial cancer history.…”