Cancer is thought to arise through the accumulation of genomic aberrations evolving under Darwinian selection. However, it remains unclear when the aberrations associated with metastasis emerge during tumor evolution. Uveal melanoma (UM) is the most common primary eye cancer and frequently leads to metastatic death, which is strongly linked to BAP1 mutations. Accordingly, UM is ideally suited for studying the clonal evolution of metastatic competence. Here we analyze sequencing data from 151 primary UM samples using a customized bioinformatic pipeline, to improve detection of BAP1 mutations and infer the clonal relationships among genomic aberrations. Strikingly, we find BAP1 mutations and other canonical genomic aberrations usually arise in an early punctuated burst, followed by neutral evolution extending to the time of clinical detection. This implies that the metastatic proclivity of UM is “set in stone” early in tumor evolution and may explain why advances in primary treatment have not improved survival.

undreds of individuals apply for ophthalmology residency positions each year using the Centralized Application Services (CAS), administered by San Francisco Residency and Fellowship Matching Services (SF Match). Although the match rate remains relatively stable at approximately 75%, the mean number of applications submitted has risen from 48 in 2008 to 75 in 2019. 1,2 In 2010, highly qualified applicants were advised to apply to between 10 and 20 residency programs, 3 but more recent studies suggested a target of 45 applications for these applicants and more than 80 for applicants with less competitive qualification. 2 The application process represents a considerable financial burden for applicants; in 2018-2019, the CAS application alone cost $685 to apply to 45 programs, which increased to $1910 for 80 pro-grams. These high costs are not unique to ophthalmology. In emergency medicine, the cost of securing a residency position was estimated at $8312 in 2016. 4 These trends also come with increasing administrative burden for residency programs tasked with reviewing rising numbers of applications. As a result, many programs have increasingly emphasized quantifiable cognitive measures, such as clinical grades and the US Medical Licensing Examination (USMLE) board scores. 3 The USMLE Step 1 scores and Alpha Omega Alpha Honors Medical Society membership are factors with statistically significant associations with matching into an ophthalmology residency. 5 Although USMLE Step 1 scores have been correlated with in-training examination scores and board-certification pass rates, they are not associated with IMPORTANCE The ophthalmology residency application process is critical for applicants and residency programs, and knowledge about the preferences of applicants would assist both groups in improving the process.OBJECTIVE To evaluate the experiences and preferences of ophthalmology residency applicants. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional, nonvalidated survey was conducted online. All applicants to the Bascom Palmer Eye Institute ophthalmology residency program during the 2018-2019 application cycle were invited to complete the survey. Data collection occurred from April 1, 2019, to April 30, 2019.MAIN OUTCOMES AND MEASURES Applicant demographics, application submissions, interview experiences, financial considerations, match results, and suggestions for improvement of the application process. RESULTSResponses were received from 185 applicants (36.4%), including 77 women (41.6%). A successful match into an ophthalmology residency was achieved by 172 respondents (93.0%). There was a mean (SD) US Medical Licensing Examination Step 1 score of 245.8 (13.3) points. Respondents applied to a mean (SD) of 76.4 (23.5) ophthalmology residency programs, received 14.0 (9.0) invitations to interview, and attended 10.3 (4.4) interviews. Choices regarding applications and interviews were based mostly on program reputation, location, and advisor recommendation. A usual lead time of at least 3 weeks between the invit...

In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.