The impact of hereditary cancer gene panels on clinical care and lessons learned

Abstract

Mutations in hereditary cancer syndromes account for a modest fraction of all cancers; however, identifying patients with these germline mutations offers tremendous health benefits to both patients and their family members. There are about 60 genes that confer a high lifetime risk of specific cancers, and this information can be used to tailor prevention, surveillance, and treatment. With advances in next-generation sequencing technologies and the elimination of gene patents for evaluating genetic information, we are now able to analyze multiple genes simultaneously, leading to the widespread clinical use of gene panels for germline cancer testing. Over the last 4 years since these panels were introduced, we have learned about the diagnostic yield of testing, the expanded phenotypes of the patients with mutations, and the clinical utility of genetic testing in patients with cancer and/or without cancer but with a family history of cancer. We have also experienced challenges including the large number of variants of unknown significance (VUSs), identification of somatic mutations and need to differentiate these from germline mutations, technical issues with particular genes and mutations, insurance coverage and reimbursement issues, lack of access to data, and lack of clinical management guidelines for newer and, especially, moderate and low-penetrance genes. The lessons learned from cancer genetic testing panels are applicable to other clinical areas as well and highlight the problems to be solved as we advance genomic medicine.

Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels

“…Granting we can now generate large amounts of sequence data, our ability to accurately interpret this information, is still limited, creating a significant increase in the numbers of VOUS 19 . Possibly the greatest worry is the likelihood of reporting a false positive unsolicited finding to a patient, due to its potential negative impact.…”

“…The secondary analysis used the Illumina MiSeq Reporter 2.6.2.3 platform, incorporating FASTQ alignment (using Burrows-Wheeler Align version 0.7.9a-isis-1.0.0) 12 , and variant extraction (using SAMtools 0.1.18 13 and GATK 1. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Sequences were mapped to GRCh37 ("hg19"), retaining reads with a median quality score genotype quality (GQ) greater than 30, variant frequency greater than 20%, variant depth greater than 20 and strand bias less than −10.…”

Which came first: validity or clinical testing? The example of long QT genes

“…While identifying the underlying molecular diagnosis could provide guidance to patients and their treating clinicians, providing an erroneous diagnosis could lead to harms in over treatment (false positive) or failing to make the correct diagnosis (false negative). These difficulties of weighing the harms and benefits of rapid bench discovery to clinical market and increasing size and clinical scope of multi-gene panel tests have been a concern noted by investigators in a variety of diseases with genetic heterogeneity including cancers and vascular disease [26][27][28] .…”

Cancer genetics: An approach to suspected hereditary breast or colorectal cancer

“…For earlier-onset conditions or in affected individuals, genetic testing is offered at a younger age. [12,14] Carriers of a pathogenic variant in certain genes are also at an increased risk of having children with specific severe autosomal recessive conditions, if their partner carries a variant in the same gene. [4] Testing of partners may therefore require consideration.…”

“…2). [12,14] In some situations, it is reasonable first to test for founder mutations in the BRCA1, BRCA2 or MLH1 and MSH2 genes that are common in specific SA populations. These tests are relatively cheap (ZAR1 500 -3 000), but are population specific and do not exclude all pathogenic variants.…”