Is KRAS mutation associated with interval colorectal cancers?

BACKGROUND: Colorectal cancers diagnosed in the interval after a complete colonoscopy may occur due to rapid tumor growth. Interval colorectal cancers are associated with microsatellite instability (MSI). AIMS: Our aim was to study the association of KRAS mutation with interval colorectal cancers and MSI. METHODS: We searched our institution's cancer registry for interval colorectal cancers, defined as colorectal cancers that developed within 5 years of a complete colonoscopy. These were frequency matched to patients with non-interval colorectal cancers. Archived cancer specimens were evaluated for KRAS mutations in codons 12 and 13 using sequencing, and MSI by sequencing microsatellite loci. Multivariable logistic regression was used to analyze the association between KRAS mutation status, MSI status and interval colorectal cancers. RESULTS: There were 63 interval and 131 non-interval colorectal cancers. KRAS mutation was present in 12.9% of interval cancers compared to 28.9% of non-interval cancers (P = 0.03). In multivariable logistic regression model, KRAS was inversely associated with interval cancers (OR 0.36; 95% CI 0.15-0.90). In Cox proportional hazards model, adjusting for age, tumor grade, TNM Stage and MSI status, we found no association between KRAS mutation and 5-year survival compared to cancers without KRAS mutation (HR 0.84; 95% CI 0.4-1.46; P = 0.5). CONCLUSIONS: KRAS mutation is inversely associated with interval cancers and with MSI, suggesting that it is a marker of the chromosomal instability pathway associated with slow tumor growth, and distinct from MSI rapidly growing cancers. Molecular characterization of colorectal cancers is helpful in determining underlying pathway and may determine therapy.

Next generation sequencing for clinical diagnostics: Five year experience of an academic laboratory.

Clinical laboratories have adopted next generation sequencing (NGS) as a gold standard for the diagnosis of hereditary disorders because of its analytic accuracy, high throughput, and potential for cost-effectiveness. We describe the implementation of a single broad-based NGS sequencing assay to meet the genetic testing needs at the University of Minnesota. A single hybrid capture library preparation was used for each test ordered, data was informatically blinded to clinically-ordered genes, and identified variants were reviewed and classified by genetic counselors and molecular pathologists. We performed 2509 sequencing tests from August 2012 till December 2017. The diagnostic yield has remained steady at 25%, but the number of variants of uncertain significance (VUS) included in a patient report decreased over time with 50% of the patient reports including at least one VUS in 2012 and only 22% of the patient reports reporting a VUS in 2017 (p = .002). Among the various clinical specialties, the diagnostic yield was highest in dermatology (60% diagnostic yield) and ophthalmology (42% diagnostic yield) while the diagnostic yield was lowest in gastrointestinal diseases and pulmonary diseases (10% detection yield in both specialties). Deletion/duplication analysis was also implemented in a subset of panels ordered, with 9% of samples having a diagnostic finding using the deletion/duplication analysis. We have demonstrated the feasibility of this broad-based NGS platform to meet the needs of our academic institution by aggregating a sufficient sample volume from many individually rare tests and providing a flexible ordering for custom, patient-specific panels.