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PURPOSE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.
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Predisposición Genética a la Enfermedad , Humanos , Femenino , Persona de Mediana Edad , Adulto , Masculino , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Secuenciación del Exoma , Guías de Práctica Clínica como Asunto , Anciano , Pruebas Genéticas/métodos , Adulto Joven , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/diagnóstico , HeterocigotoRESUMEN
Tumors frequently arise as a result of an acquired genomic instability and the subsequent evolution of neoplastic populations with variable genomes. A barrier to the study of the somatic genetics of human solid tumors in vivo is the presence of admixtures of non-neoplastic cells with normal genomes in patient samples. These can obscure the presence of somatic aberrations including mutations, homozygous deletions, and breakpoints in biopsies of interest. Furthermore, clinical samples frequently contain multiple neoplastic populations that cannot be distinguished by morphology. Consequently, it is difficult to determine whether mutations detected in a sample of interest are concurrent in a single clonal population or if they occur in distinct cell populations in the same sample. The advent of targeted therapies increases the selection for preexisting populations. However the asymmetric distribution of therapeutic targets in clonal populations provides a mechanism for the rapid evolution of resistant disease. Thus, there is a need to not only isolate tumor from normal cells, but to also enrich distinct populations of clonal neoplastic cells in order to apply genome technologies to identify clinically relevant genomic aberrations that drive disease in patients in vivo. To address this we have applied single and multiparameter DNA content based flow assays to the study of solid tumors. Our work has identified examples of clonal resistance to effective therapies. This includes androgen withdrawal in advanced prostate cancer. In addition we demonstrate examples of co-existing clonal populations with highly aberrant genomes and ploidies in a wide variety of solid tumors. We propose that clonal analysis of tumors, based on flow cytometry and high resolution genome analyses of purified neoplastic populations, provides a unique approach to the study of therapeutic responses and the evolution of resistance.
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BACKGROUND: Whether time between biopsy and surgery for malignant melanoma affects clinical outcomes is sparsely defined. This study evaluated factors influencing surgical interval and surgical interval effect on outcomes. METHODS: We performed a review of a prospective 10-year, single-institution database. RESULTS: There were 473 patients treated for 478 malignant melanomas. The mean surgical interval was 30.5 days. The mean thickness was 2.1 mm; 46% of patients had a surgical interval of more than 28 days whereas 8% had a surgical interval of more than 56 days. Residual melanoma was found at excision in 170 (36%) patients. Age, sex, and referral source significantly affected surgical interval, however, lesion thickness, sentinel lymph node status, ulceration, and residual melanoma at excision did not. In univariate Cox models, neither a surgical interval of 28 or less nor less than 56 days showed better overall survival (OS) or disease-free survival (DFS). In multivariate Cox models of OS and DFS including lesion thickness, sentinel lymph node status, ulceration, and residual melanoma at excision, neither a surgical interval of 28 days or fewer nor a surgical interval of 56 days or fewer significantly affected outcomes. CONCLUSIONS: Age, sex, referral source, and lesion thickness were associated with surgical interval. Immediate surgery for malignant melanoma does not significantly impact OS or DFS.