Abstract
Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73–1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.
Highlights
Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown
Together with Endometrial cancer (EC)—another cancer characterized by MSI16—Gastric cancer (GC) and colorectal cancer (CRC) are the main cancer types associated with Lynch Syndrome (LS), caused by pathogenic variants in mismatch repair (MMR) genes, resulting in up to an 80% lifetime risk of c ancers[17,18]
We investigated the prevalence of loss of function (LoF) variants in cancer predisposition genes using a cohort of 71 patients with MPCs
Summary
Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Along with early-onset cancer, MPC have been regarded as high-risk of heritability[7] and those patients represent excellent candidates for genetic screening. Together with Endometrial cancer (EC)—another cancer characterized by MSI16—GC and CRC are the main cancer types associated with Lynch Syndrome (LS), caused by pathogenic variants in MMR genes, resulting in up to an 80% lifetime risk of c ancers[17,18]. MPCs with cancer types in the spectrum of LS represent some of the strongest candidates for genetic screening, as the prevalence of LS among MPC is unknown
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