incidental findings in NGS testing of hereditary cancer patients

Mosaicism refers to the presence of two genetically distinct populations of cells within an individual, derived from a single zygote. Mosaicisim events have been implicated in diseases (most often in cancers) and can be transmitted to the next generation as constitutional variants (1-5). These mosaicism events (sequence variants) occur at a low level (<25%) in the human body and thus are often go unnoticed by traditional detection method (e.g. Sanger sequencing). The advent of next-generation sequencing (NGS) technologies allows sensitive detection of low level of sequence variants (6). Over the past five years, mosaicism has been reported in a number of genes in a variety of hereditary cancers, including colorectal adenomatous polyposis (7), neurofibromatosis type 1 (8), and Li-Fraumeni syndrome (9, 10). These low-level sequence variants detected in the peripheral blood samples might be either germline mosaicism that occurs in the egg or sperm or somatic mosaicism resulted from age-related clonal hematopoiesis (Jaiswal S et al, 2014; Genovese G et al, 2014). If they were derived from germline mosaicism, they can potentially be passed to next generation as constitutional variants. If they were somatic mosaicism, they will not pass to next generation, but may increase the risk of hematologic malignancies (11, 12). Therefore, understanding of the nature of these mosaic variants has important role in providing proper genetic counseling and clinical management. So far, nearly all the studies in hereditary cancers were limited to one gene, and no such study has been done in Canada. It should be noted that the criteria for genetic testing of hereditary cancers differ from one country to another. Our study will be helpful for Canadian cancer geneticists and genetic counsellors to provide better counseling and clinical follow up for patients with hereditary cancer syndromes.