Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients.

BACKGROUND/OBJECTIVES: BRCA1, BRCA2, ATM, and CHEK2 are known cancer predisposition genes (CPGs), but tumor risk in patients with simultaneous pathogenic variants (PVs) in CPGs remains largely unknown. In this study, we describe six patients from five families with multiple cancers who coinherited a combination of PVs in these genes. METHODS: PVs were identified using NGS DNA sequencing and were confirmed by Sanger. RESULTS: Families 1, 2, and 3 presented PVs in BRCA2 and ATM, family 4 in BRCA2 and BRCA1, and family 5 in BRCA2 and CHEK2. PVs were identified using NGS DNA sequencing and were confirmed by Sanger. The first family included patients with kidney, prostate, and breast cancer, in addition to pancreatic adenocarcinomas. In the second family, a female had breast cancer, while a male from the third family had prostate, gastric, and pancreatic cancer. The fourth family included a male with pancreatic cancer, and the fifth family a female with breast cancer. CONCLUSIONS: The early age of diagnosis and the development of multiple cancers in the reported patients indicate a very high risk of cancer in double-heterozygous patients associated with PVs in HR-related CPGs. Therefore, in families with patients who differ from other family members in terms of phenotype, age of diagnosis, or type of cancer, the cascade testing needs to include the study of other CPGs.

Outcomes of esophagectomy after noncurative endoscopic resection of early esophageal cancer.

BACKGROUND: Current guidelines recommend performing esophagectomy after endoscopic resection for early esophageal cancer when the risk of lymph node metastasis or residual cancer is found to be significant and endoscopic treatment is therefore noncurative. Our aim was to assess the safety and oncological outcomes of esophagogastric resection in this specific clinical setting. PATIENTS AND METHODS: A retrospective review from 2012 to 2018 was performed at four tertiary referral centers. All patients had a noncurative endoscopic resection of a clinical T1 esophageal cancer, followed by esophagectomy. Outcome measures were the rates of T0N0 specimens, overall survival, disease-free and cancer-specific survival, postoperative morbidity and mortality. RESULTS: A total of 30 patients (13 with squamous cell carcinoma and 17 with adenocarcinoma) were included. The reasons for noncurative endoscopic resection were: positive vertical margins (n = 12), squamous cell carcinoma with muscularis mucosae or submucosal layer invasion (n = 3 and 9), adenocarcinoma with deep submucosal invasion (n = 11), poorly differentiated tumor (n = 6) and lymphovascular invasion (n = 6). Overall, 63% of the esophagi were T0N0: most residual lesions were T1a metachronous lesions, and four (13%) patients had advanced pT status (n = 3) or lymph node metastases (n = 2). Overall survival, disease-free survival and cancer-specific survival were 83%, 75%, and 90% respectively. A total of 43% of patients had severe postoperative complications, and postoperative mortality was 7%. CONCLUSION: In this cohort, esophagectomy allowed the resection of residual advanced cancer or lymph node metastases in 13% of cases, at the cost of 43% severe morbidity and 7% mortality. Therefore, the possibility of close follow up needs to be balanced with a highly morbid surgical management in these patients.

Endoscopic findings in case of incidental colonic uptake in PET-CT how to improve PET-CT specificity?

Unexpected colonic 18FDG focal uptakes (UCFU) in PET CT occur in 1.3-3.3% of cases in retrospective study and are often associated with significant colorectal findings in endoscopy, especially neoplastic lesions. The purpose of our prospective study was to evaluate the significance of UCFU and to assess criteria improving PET CT specificity for advanced adenoma and neoplasia. This study was conducted in a single institution from April 2012 to September 2013. In the 2904 patients who benefit from PET CT, 52 had an UCFU and 43 were referred for colonoscopy. After endoscopy, 8 examinations showed no colonic abnormality (18.6%), 7 showed benign lesion (16.3%), 18 showed advanced adenoma (42.9%) and 10 showed carcinoma (23.3%). There were more false positives results in the proximal colon compared to distal colon. Eighteen patients had UCFU and tomodensitometric abnormalities in the same colonic area. This pathological combination was strongly associated to the diagnosis of malignancy. Comparing standardized uptake values (SUV), we showed statistically significant difference between the adenocarcinoma and advanced adenoma groups and a difference at the margin of statistical significance between adenocarcinoma and benign lesion groups. Any cut off value could be determined. In conclusion, we confirmed that UCFU are often associated to endoscopic findings and neoplastic lesions and justify systematic endoscopic exploration. Considering the fragility of oncologic patients, criteria improving PET CT specificity are needed to select endoscopies which should be performed quickly from those who could be delayed. We showed that associated tomodensitometric abnormality and high focal FDG activity are more predictive of a neoplastic lesion.

Distinctive patterns of p53 protein expression and microsatellite instability in human colorectal cancer.

Although evidence suggests an inverse relationship between microsatellite instability and p53 alterations in colorectal cancer, no study has thoroughly examined the use of p53 immunohistochemistry in phenotyping colorectal cancers. We investigated the value of p53 immunohistochemistry in microsatellite instability-positive colorectal cancers prescreening and attempted to clarify the relationship between DNA mismatch repair system and p53 pathway. In a series of 104 consecutive colorectal cancers, we performed p53 immunohistochemistry, TP53 mutational analysis, DNA mismatch repair system efficiency evaluation (DNA mismatch repair system immunohistochemistry, microsatellite instability status, MLH1/MSH2 germ line, and BRAF, murine double minute 2, and p21 immunohistochemistry. Microsatellite instability high was observed in 25 of 104 colorectal cancers, with DNA mismatch repair system protein loss (24/25) and germ line (8/25) or BRAF mutations (8/25). p53 immunohistochemistry revealed 3 distinct patterns of expression: complete negative immunostaining associated with truncating TP53 mutations (P < .0001), diffuse overexpression associated with missense TP53 mutations (P < .0001), and restricted overexpression characterized by a limited number of homogenously scattered strongly positive tumor cells in 36.5% of colorectal cancers. This latest pattern was associated with wild-type TP53 and microsatellite instability high colorectal cancers (P < .0001) including all Lynch tumors (8/8), but its presence among 22% of DNA mismatch repair system-competent colorectal cancers decreased its positive predictive value (55.2% [95% confidence interval, 45%-65%]). It was also correlated with murine double minute 2 overexpression (P < .0001) and inversely with p21 loss (P = .0002), independently of microsatellite instability status. In conclusion, a restricted pattern of p53 overexpression is preferentially associated with microsatellite instability high phenotype and could, therefore, be of clinical use as signal for microsatellite instability analysis in a large-scale tumor screening. Its association with concomitant murine double minute 2 overexpression suggests an alternative mechanism of p53 pathway deregulation.

Frequent mutations of hepatocyte nuclear factor 1 in colorectal cancer with microsatellite instability.

BACKGROUND & AIMS: The TCF1 gene encoding hepatocyte nuclear factor 1 alpha (HNF1), a transcription factor germline mutated in patients with maturity-onset diabetes of the young type 3, was recently found to be frequently inactivated by biallelic alterations in liver adenoma and in rare hepatocellular carcinomas. The impact of HNF1 in colorectal carcinogenesis has not been studied until now. Colorectal cancer is characterized by the existence of different molecular mechanisms known as microsatellite stable or unstable tumors. METHODS: At first, a series of 10 adenomas and 29 colon cancers regardless of microsatellite instability status were screened for TCF1 mutations on the entire coding sequence. RESULTS: Three mutations in microsatellite instability high (MSI-H) tumors were found in the exon 4 polymorphic poly-cytosin (C)(8) or (C)(9) tract and consisted of a cytosin deletion at position 291. To further characterize the prevalence of TCF1 mutations in the subgroup of MSI-H tumors, 52 additional MSI-H samples were screened for exon 4 alterations; 23% of MSI-H tumors (95% confidence interval, 14%-36%) were found to harbor frameshift at the poly-cytosin tract. The (C)(9) allele was significantly more frequently mutated than the (C)(8) allele (22% vs. 8%; P = 0.03), showing a higher instability of the longer repetition. CONCLUSIONS: These results show a role for HNF1 in MSI-H colorectal carcinogenesis.

Epidemiology of inflammatory bowel diseases in the elderly in the province of Liège.

OBJECTIVE: Inflammatory bowel diseases (IBD) are heterogeneous diseases which affect preferentially young adults. The late onset could represent a particular form of expression of these diseases. The aim of our prospective study was to describe the incidence of IBD in patients older than 60 years as well as their clinical pattern in comparison with a population younger than 60. METHODS: A standardized questionnaire for each new case diagnosed in the province of Liège between 01/06/1993 and 31/05/1996 was completed. RESULTS: During the three years, 270 patients were enrolled. In group IBD > 60 years old, there were 60 new cases, including 23 cases with Crohn's disease (CD) (38%), 30 with ulcerative colitis (UC) (50%), and 7 with undetermined colitis (IC) (12%). The proportion of CD was significantly lower in the group IBD > 60 years old than in the group<60 (114 CD (54%), 81 UC (39%) and 15 IC (7%); P=0.04). The annual incidence tended to be higher for UC than for CD in group IBD > 60 (4.5 and 3.5 per 100,000, respectively) while it was the contrary in younger patients (3.4 and 4.8 per 100,000, respectively). There was no striking difference in the clinical features for both diseases in the two groups, except more frequent diarrhea, weight loss and extraintestinal symptoms in CD patients<60 years old. CONCLUSIONS: In the province of Liège, the incidence of IBD in people older than 60 years is high. IBD in the elderly is characterized by a lower proportion of CD than in the younger population. Clinical features tend to be the same whatever the age at diagnosis for each disease.