Abstract
BackgroundExtensive clinical and genetic heterogeneity of inherited cancers has allowed multi-gene panel testing to become an efficient means for identification of patients with an inherited predisposition to a broad spectrum of syndromic and nonsyndromic forms of cancer. This study reports our experience with a 27-gene inherited cancer panel on a cohort of 630 consecutive individuals referred for testing at our laboratory with the following objectives: 1. Determine the rates for positive cases and those with variants of uncertain clinical significance (VUS) relative to data published in the recent literature, 2. Examine heterogeneity among the constituent genes on the panel, and 3. Review test uptake in the cohort relative to other reports describing outcomes for expanded panel testing.MethodsClinical and genomic data were reviewed on 630 individuals tested on a panel of 27 genes selected on the basis of high (≥ 40%) or moderate to low (≤ 40%) lifetime risk of hereditary cancer. These patients were not enriched for adherence to the National Comprehensive Cancer Network (NCCN) criteria for Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) and constitute a referral laboratory cohort.ResultsSixty-five individuals with variants classified as pathogenic or likely pathogenic across 14 genes were identified for an overall positive rate of 10.3%. Although a family history of cancer constituted a major reason for referral, accounting for 84% of our cohort, excluding patients with a known familial variant did not have a significant impact on the observed positive rate (9% vs 10.3%). More than half (58%) of the pathogenic or likely pathogenic variants were observed in high or moderate to low risk genes on the panel, while only 42% occurred in classic HBOC or LS-associated genes.ConclusionThese results provide the actual percentage of family or personal history of cancer that can be attributed to pathogenic or likely pathogenic variants in one or more of the genes on our panel and corroborate the utility of multi-gene panels over sequential testing to identify individuals with an inherited predisposition to cancer.
Highlights
Extensive clinical and genetic heterogeneity of inherited cancers has allowed multi-gene panel testing to become an efficient means for identification of patients with an inherited predisposition to a broad spectrum of syndromic and nonsyndromic forms of cancer
Further evaluation of the cancer phenotypes revealed that 74% (n = 467) reported a family history of Hereditary Breast and Ovarian Cancer (HBOC)-associated cancers and 59% (n = 359) reported a family history of Lynch Syndrome (LS)-associated cancers, with 50% (n = 313) reporting a family history of cancers associated with both syndromes (Fig. 1)
A personal history of HBOC-associated cancers accounted for 34% (n = 217) of the cohort, while a personal history of LS-associated cancers accounted for 10% (n = 64)
Summary
Extensive clinical and genetic heterogeneity of inherited cancers has allowed multi-gene panel testing to become an efficient means for identification of patients with an inherited predisposition to a broad spectrum of syndromic and nonsyndromic forms of cancer. Hereditary Cancer Syndromes, including Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS), can result in various forms of cancer due to germline mutations in cancer predisposition genes. Between 30 and 50% of families fulfill stringent criteria for LS and test negative for germline mismatch repair gene mutations [2]. Adding complexity to these disorders is the significant overlap in the spectrum of cancers observed between various hereditary cancer syndromes, including many cancer susceptibility syndromes. LS-spectrum cancers include colorectal cancer, as well as uterine (endometrial), ovarian, gastric, and other rare forms of cancer [5]
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