Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic

Abstract

Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients’ cancer genetic risks.

Implementation of “clinical sequencing” in cancer genome medicine in Japan

“…The clinical relevance of sequencing tests will also be enhanced by the development of therapies for gene alterations that are frequent but currently “undruggable”, such as deleterious mutations in the chromatin regulator genes . Functional annotation of mutations that are currently classified as variants of unknown significance will also facilitate clinical sequencing by prioritizing further actionable mutations …”

“…[27][28][29] Functional annotation of mutations that are currently classified as variants of unknown significance will also facilitate clinical sequencing by prioritizing further actionable mutations. 30,31 Of course, finding actionable mutations in a patient's tumor does not imply that the patient will respond to a therapeutic agent against that target. It is important to examine whether or not a treatment based on the gene profile of an individual patient can really improve the clinical course of his or her disease.…”

Defining the Clinical Value of a Genomic Diagnosis in the Era of Next-Generation Sequencing

“…The yield of genome-scale sequencing has been evaluated in cohorts of patients with specific disorders, ranging from cancer to intellectual disability to rare diseases such as Joubert syndrome (34,40,43,114,124). These initial studies clearly illustrate that some conditions are good candidate diseases for genome-scale testing; ophthalmological disorders, for example, have a diagnostic yield over 50% (18,69).…”

Hypomethylating Agents in Oncohematology

“…Результаты демонстрируют, что метод точно выявил около 90 % клини-чески значимых мутаций, кроме того, были открыты новые мутации в онкогенах. Эти данные свидетельствуют о том, что метод позволит усовершенствовать лечение пациентов с онкологическими заболеваниями, а также поможет найти новые онкогены [5].…”