The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants.

BACKGROUND: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance. METHODS: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC. RESULTS: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance. CONCLUSIONS: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.

Inflammatory bowel disease in families with four or more affected first-degree relatives.

BACKGROUND: Family history increases the risk for inflammatory bowel diseases (IBDs). However, data on differences in phenotypic characteristics among patients with a strong family history of IBD are scarce and controversial. The aim of the study was to compare the phenotypic features of IBD patients with four or more affected first-degree relatives with sporadic cases of IBD. METHODS: Patients with familial and sporadic IBD were identified from the institutional IBD database. IBD patients from families with at least four first-degree affected relatives were selected for analysis and were compared to non-matched sporadic cases with IBD chosen randomly. Comparison for type of IBD (Crohn's disease (CD) vs. ulcerative colitis (UC)), age at onset as well as for disease extent, behavior, extraintestinal manifestations and indicators of severe disease were analyzed. RESULTS: Thirty-five patients with familial IBD (28 CD, seven UC) were compared to 88 sporadic IBD patients (61 CD, 24 UC and three IBDU). Disease duration was 10.3 ± 8.2 in the familial and 8.0 ± 7.2 years in the sporadic cases, p=.13. The familial cases were younger at diagnosis (19.3 ± 8.6 vs. 25.7 ± 11.8, p=.004). Patients with familial compared to sporadic IBD were significantly more likely to require steroid treatment (80% vs. 54.5%, p=.009), biological treatment (94.3%, vs. 63.6%, p<.001) or surgery (25.7%, vs. 11.4%, p=.048). CONCLUSIONS: IBD with a very strong positive family history is associated with younger age at onset and a more adverse IBD phenotype compared to sporadic IBD.

Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance.

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.

Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A.

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.

A decade of improved access to screening is associated with fewer colorectal cancer deaths in African Americans: a single-center retrospective study.

BACKGROUND: Controversy 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. METHODS: CRC 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. RESULTS: Inclusion 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). CONCLUSIONS: A 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.