Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome (BRCA...)

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Consistent with prior studies, the following were considered LS-associated cancers: CRC, endometrial cancer (EC), ovarian cancer, gastric cancer, pancreatic cancer, small intestine cancer, urinary tract cancer, hepatobiliary cancer, sebaceous adenomas/carcinomas, and brain tumors.12 

Prior studies have shown no increased CRC risk in BRCA1/2 probands, and traditional thinking thus has been that LS and HBOC are phenotypically distinct syndromes, aside from both conferring increased risks of ovarian cancer.⁴⁴ In this study, however, BRCA1/2 probands had phenotypes that were markedly more “Lynch-like” than “HBOC-like,” suggesting that standard clinical evaluation would not have identified most of these individuals as needing BRCA1/2 testing...... 

.... Furthermore, with expanded use of panel testing, the question as to how patients with unexpected, high-penetrance germline mutations identified by panel testing (eg, BRCA1/2 mutations in individuals with a clinical history suggestive of hereditary colorectal cancer) should be managed is likely to become an increasingly common dilemma for practicing clinicians.....

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 Article Outline
    Materials and Methods
        Study Population
        Clinical Data
        Germline Sequencing/Interpretation
        Statistical Methods
    Results
        Clinical Characteristics
        Germline Findings
        PREMM1,2,6 Scores and NCCN Criteria
    Discussion

    Supplementary Materials and Methods
        NCCN Guideline Classification
        Design of Custom Primer Library for NGS Target Enrichment
        Sample Preparation and Next-Generation Sequencing
        NGS Data Analysis
        Pathogenicity Classification
        Validation of the Multigene Panel

Background & Aims
Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome.


Methods
We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome–associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients’ personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing.
Results
Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing. Multigene panel testing identified 114 probands with Lynch syndrome mutations and 71 with mutations in other cancer predisposition genes. Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis. An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS.
Conclusions
In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients’ histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.

.....The growing availability of multigene panels provides clinicians with the option of broad-based genetic analysis for hereditary cancer risk assessment, rather than traditional, phenotype-driven genetic testing. The benefits of such comprehensive testing strategies have been debated and are only beginning to be evaluated scientifically.7, 35 Clinical guidelines, such as NCCN criteria, and prediction models, such as PREMM1,2,6, have been developed to select individuals for LS evaluation, based on their personal/family histories.9, 12 Our study, in which the vast majority of both LS and non-LS mutation carriers fulfilled NCCN criteria for LS and had a PREMM1,2,6 score of 5% or higher, shows that such criteria, although very useful for identifying which individuals should be referred for genetic evaluation, ultimately may not be specific for underlying LS.