Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer.

Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy.

Gastrointestinal stromal tumors in a cohort of Chinese patients in Hong Kong.

AIM: To investigate the prevalence and clinical pattern of gastrointestinal stromal tumors (GISTs) in Hong Kong Chinese, and to assess the impact of introduction of CD117 on the disease incidence. METHODS: From the database of the Department of Pathology of Yan Chai Hospital, 47 patients, with GISTs from September 1995 to December 2003 were included in this study. Ten GISTs were diagnosed before the introduction of CD117. The clinical features, tumor characteristics, and treatment were analyzed. Factors predicting tumor related death or recurrence were studied with Cox proportional hazard model. RESULTS: The patients included 26 males and 21 females, with a mean age of 66.6 years (SD 13.1, range 29-87 years). The estimated prevalence of GISTs was 13.4-15.6 per 100,000 people, with an annual incidence of 1.68-1.96 per 100,000 people. The annual incidence of GISTs before and after the introduction of CD117 was 1.1 per 100,000 people and 2.1 per 100,000 people respectively. Stomach (34 patients, 72.3%) was the most common location for the tumor, followed by the small intestine (8 patients, 17.0%), esophagus (2 patients, 4.3%), omentum (2 patients, 4.3%) and colon (1 patient, 2.1%). Thirty-one patients (66%) had complete tumor resection. Eleven out of 16 deaths (23%) were tumor-related. The median survival time was 26 mo. Five-year survival rate was 61.3%. The significant factors associated with tumor-related death or recurrence were incomplete resection, tumor size 5 cm or above, invasion to the adjacent organ or presence of metastasis. CONCLUSION: The incidence of GIST in Hong Kong is comparable to that in the United States but lower than that in Finland. The true incidence of GISTs could be underestimated before the introduction of CD117. Incomplete resection, tumor size 5 cm or above, invasion to the adjacent organ or presence of metastasis are factors predicting tumor-related death or recurrence.

Emphysematous pyelonephritis: an 8-year retrospective review across four acute hospitals.

OBJECTIVE: To retrospectively review our experience of managing patients with emphysematous pyelonephritis (EPN). METHODS: Case notes of patients with EPN were reviewed. The patients' demographic data, clinical presentation, investigation findings, treatment, and outcome were studied. RESULTS: Twelve patients were diagnosed with EPN. Majority (66.7%) of them had diabetes mellitus. All patients had been evaluated by computed tomography (CT). Using the classification proposed by Wan et al, five patients had type 1 EPN, whereas six, two, and four patients had Huang and Tseng CT class 2, 3a, and 3b EPN, respectively. Immediate nephrectomy was performed in six patients, whereas conservative treatment was adopted in the other six. In the nephrectomy group, one patient died of disseminated sepsis after a protracted course. Conservative treatment failed in three patients, who succumbed despite salvage nephrectomy in two of them. Analysis revealed that severe hyperglycemia and radiological CT class (both Wan and Huang systems) were significant predictors of mortality from EPN. CONCLUSION: Severe hyperglycemia and CT class of EPN are significant risk factors for death. CT is the investigation of choice for correct diagnosis of EPN. Additional intervention should be offered to EPN patients with Wan type 1 and Huang and Tseng class 3 CT features.

Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1.

Lynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including MSH2 (ref. 1). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of TACSTD1, a gene directly upstream of MSH2 encoding Ep-CAM. Due to these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation.

Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma.

BACKGROUND: There are controversies on the benefits of elective neck dissection (END) for oral tongue carcinoma. METHOD: This is a prospective randomized study of elective selective I, II, III neck dissection versus observation for N0 neck of stage I to II oral tongue carcinoma. There were 35 patients on the observation arm and 36 patients on the END arm. The main outcome assessment parameters are node-related mortality and disease-specific survival rate. RESULTS: There were 11 patients in the observed arm and 2 patients in the END arm who developed nodal recurrence alone without associated local or distant recurrence. All 13 patients were salvaged, and no patient died of nodal recurrence. The 5-year disease-specific survival rate was 87% for the observation arm and was 89% for the END arm; the 2% difference was not significant. CONCLUSION: Observation may be an acceptable alternative to END if strict adherence to a cancer surveillance protocol is followed.