Hereditary mixed polyposis syndrome is a rare colon cancer predisposition syndrome caused by a duplication of a noncoding sequence near the gremlin 1, DAN family BMP antagonist gene (GREM1) originally described in Ashkenazi Jews. Few families with GREM1 duplications have been described, so there are many questions about detection and management. We report 4 extended families with the duplication near GREM1 previously found in Ashkenazi Jews; 3 families were identified at cancer genetic clinics in Israel and 1 family was identified in a cohort of patients with familial colorectal cancer. Their clinical features include extracolonic tumors, onset of polyps in adolescence, and rapid progression of some polyps to advanced adenomas. One family met diagnostic criteria for Lynch syndrome. Expansion of the hereditary mixed polyposis syndrome phenotype can inform surveillance strategies for carriers of GREM1 duplications.

The molecular drivers of thymoma are poorly understood. Outside of the identification of rarely occurring epidermal growth factor receptor and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog mutations via candidate gene sequencing, mutations in common cancer genes have yet to be observed. Only a single thymoma genome sequence has been previously reported, with no mutations in known cancer genes identified. Thus, we attempted to identify somatic driver mutations in a cytogenetically normal thymoma. A stage IVB type B3 thymoma from a 47-year-old male of Asian descent with no history of myasthenia gravis or other autoimmune condition was genomically evaluated. Exome sequencing and low-pass whole-genome sequencing was performed to identify somatic point mutations, copy number changes and structural variants. Mutations in known tumor suppressors DNMT3A (p.G728D) and ASXL1 (p.E657fs), consistent with mutations of known consequence in acute myeloid leukemia, were identified. Contrary to a previous report, this finding suggests the genetic etiology of thymomas may not be fundamentally distinct from other tumor types. Rather, these findings suggest that further sequencing of cytogenetically normal thymoma samples should reveal the specific molecular drivers of thymoma.

OBJECTIVES: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A . We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

BackgroundControversy exists as to whether disparities in colorectal cancer (CRC) outcomes in African Americans (AAs) are best resolved by screening at age 45 or by proper use of existing guidelines. In 2004, an aggressive colonoscopy-based CRC screening program was implemented throughout New York City. Our goal was to determine the effect of that program on CRC outcomes in our mostly AA population.MethodsCRC cases entered into Harlem Hospital’s tumor registry from January 1992 to December 2011 were divided into two cohorts: 1992-2003, the pre-intensive screening era (PSE), and 2004-2011, the intensive screening era (ISE). Each cohort was reviewed for demographics, indication for colonoscopy, tumor location, tumor stage, and mortality. Multivariate analysis was applied to the pooled cohorts to determine factors associated with survival.ResultsInclusion criteria were met by 379 patients: 207 PSE and 172 ISE. Racial distribution, gender, age at presentation, and tumor location were not different during the two eras. Over 75% of patients were AA. During the ISE, 84% were insured compared to 34% in the PSE (P<0.0001). Fewer patients died during the ISE (21%) than during the PSE (67%) (P<0.0001). The ISE patients were diagnosed with earlier stages of CRC compared to the PSE. Increased survival was associated with being insured (hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.30-2.81), distal tumors (HR 1.43, 95%CI 1.05-1.95), and being female (HR 1.36, 95%CI 1.01-1.850).ConclusionsA multifaceted program reduced CRC outcome disparities in a poor AA community. Aggressive implementation of current colonoscopy screening guidelines still has unrealized potential to reduce CRC mortality disparities in AAs.