Springer Science and Business Media LLC

Một bệnh nhân nữ 25 tuổi mắc chứng polyp đại tràng gia đình (FAP) đã được chẩn đoán có một khối u ở bụng ngay dưới vết sẹo do phẫu thuật cắt đại tràng thực hiện 15 tháng trước. Khối u này (khối u A) có kích thước 7 cm, được chẩn đoán là khối u desmoid ở thành bụng và đã được cắt bỏ. Mặc dù sau đó đã đưa ra điều trị với sulindac (300 mg mỗi ngày trong 1 năm), nhưng khối u desmoid đã tái phát tại cùng vị trí. Cắt bỏ lại đã được thực hiện khi khối u có kích thước 8 cm, và kết quả kiểm tra cho thấy khối u bao gồm một khối u lớn (B) và một khối u nhỏ (C) nhô lên từ khối u B. Phân tích gen APC qua dòng đời cho thấy có một sự thiếu hụt C tại codon 1460 dẫn đến sự hình thành codon dừng. Hai đột biến somatic đã được quan sát thấy trong khối u A: một sự thiếu hụt TCAA tại codon 1068 và sự thiếu hụt một codon tại bp 1192–2097. Trong khối u B, một đột biến somatic đã được tìm thấy tại codon 1041 thay đổi CAA thành TAA. Chúng tôi không thể phát hiện bất kỳ đột biến somatic nào trong khối u C. Chúng tôi kết luận rằng phân tích đột biến somatic của gen APC có thể được sử dụng để xác định xem khối u desmoid tái phát ở bệnh nhân mắc FAP là khối u nguyên phát mới hay là tái phát từ những di tích vi mô của khối u ban đầu.

Positive familial history (first or second degree relative) for colorectal carcinoma (CRC) can be found in approximately 30% of all newly diagnosed cases, but less than 5% will be due to a defined genetic category of hereditary CRC. Pathologic examination of the biopsy or resection specimen can help in identification of unsuspected cases of certain forms of hereditary CRC due to the characteristic morphologic findings. Additional immunohistochemical and molecular studies can then provide a definitive diagnosis. The most common form of hereditary CRC is Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) which is characterized by proximally located tumors frequently showing mucinous and medullary type histologic features. The syndrome results from a germline mutation in genes for mismatch repair (MMR) proteins leading to insufficient DNA repair and development of tumors characterized by high levels of instability in short tandem repeat DNA sequences (microsatellites) or “microsatellite instability-high” (MSI-H). The presence of intra-epithelial lymphocytes is single most helpful morphologic feature in identification of CRC caused by deficiency in MMR proteins, for which MSI-H status is a good marker but morphologic features and MSI-H do not differentiate tumors caused by germline mutations in one of the MMR genes (Lynch syndrome) from sporadic CRC due to inactivation of MLH-1 through promoter methylation. Hereditary CRC may also arise in various familial polyposis syndromes which include familial adenomatous polyposis (FAP), attenuated FAP and other multiple adenomas syndromes as well as various hamartomatous polyposis syndromes. All of these rare conditions have characteristic clinical presentation and histopathologic features of polyps and most of them have defined genetic abnormality. Furthermore, due to the germline nature of mutations in these syndromes, various extracolonic manifestations may be the first sign of the disease and knowledge of such associations can greatly improve the quality of care for these patients. The role of pathologist is to recognize these characteristics and initiate appropriate follow up with clinicians and genetic counselors.

The spectrum of BRCA1/2 mutations demonstrates significant interethnic variations. We analyzed for the first time the entire BRCA1/2 coding region in 340 Belarusian cancer patients with clinical signs of BRCA1/2-related disease, including 168 women with bilateral and/or early-onset breast cancer (BC), 104 patients with ovarian cancer and 68 subjects with multiple primary malignancies involving BC and/or OC. BRCA1/2 pathogenic alleles were detected in 98 (29%) women, with 67 (68%) of these being represented by founder alleles. Systematic comparison with other relevant studies revealed that the founder effect observed in Belarus is among the highest estimates observed worldwide. These findings are surprising, given that the population of Belarus did not experience geographic or cultural isolation throughout history.

Microsatellite instability (MSI) in colorectal tumours is the hallmark of defective DNA mismatch repair (MMR) and high level MSI can be detected in up to 15% of incident colorectal cancers. MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1 while MSI is almost universal in tumours from HNPCC family members due to germline MMR gene mutation with loss or mutational inactivation of the second copy as a somatic event. There is evidence that tumour MSI is associated with a better outcome than the generality of large bowel malignancy. However, although MSI occurs in both sporadic colorectal cancer and in tumours arising in patients with germline MMR gene mutations, cancer survival should not be considered to be equivalent for these two groups with MSI tumours simply because both exhibit similarities in molecular phenotype. Here, we review the evidence on prognosis in patients with sporadic MSI tumours compared to those who have inherited a germline DNA MMR repair gene defect. In addition, we explore whether there are variables that afford opportunity to distinguish three groups on the basis of MSI status, namely: sporadic MSI tumours; MSI tumours in carriers of germline MMR gene defects; microsatellite stable (MSS) tumours. Differences in prognosis between these three groups is important because it underpins the rationale for surveillance and early identification of tumours in MMR gene carriers, as well as refining understanding of the influence of MSI on cancer progression. Furthermore, we discuss the effect of MSI on the effectiveness of chemotherapy regimens.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract. Polyps are most common in the colorectum (98 % of patients) and the stomach (14 %). Causative mutations for JPS have been identified in two genes to date, SMAD4 and BMPR1A. SMAD4 mutations are associated with a higher incidence of gastric polyposis. In this case report, we describe two patients with massive gastric polyposis associated with a SMAD4 mutation. Both presented with anaemia and both had colonic polyps. Initial endoscopic findings revealed giant rugal folds suggestive of Ménétrier disease. However, as other possible gastropathies could not be differentiated on the basis of histology, a definitive diagnosis of JPS required additional mutation analysis. In patients with polyposis predominant in or limited to the stomach, establishing a diagnosis based solely on the pathological features of polyps can be challenging due to difficulties in differentiating JPS from other hypertrophic gastropathies. Mutation analysis should be considered early in the diagnostic process in cases of suspected juvenile polyposis, thus facilitating rapid diagnosis and adequate follow-up.

Inactivating mutations in the CDH1 (E-cadherin) gene are the predisposing cause of gastric cancer in most families with hereditary diffuse gastric cancer (HDGC). The lifetime risk of cancer in mutation positive members is more than 80 % and prophylactic total gastrectomy is recommended. Not all mutations in the CDH1 gene are however pathogenic and it is important to classify mutations before this major operation is performed. Probands from two Danish families with gastric cancer and a history suggesting HDGC were screened for CDH1 gene mutations. Two novel CDH1 gene mutations were identified and found pathogenic. In silico and mini-gene assay were used to predict the functional consequence in one of them. Mutation carriers were offered endoscopy and total gastrectomy. The gastric specimens were completely sectioned and examined histologically. Seven asymptomatic mutation carriers were operated. Hospital stay was 6–8 days and there were no complications. Small foci of diffuse gastric cancer were found in all patients—intramucosal in six and advanced in one. Preoperative endoscopic biopsies had revealed a microscopic cancer focus in two of the patients. Our data confirmed the pathogenic nature of both mutations and strongly support the recommendation of total gastrectomy in asymptomatic CDH1 gene mutation carriers. The functional consequences of novel CDH1 gene mutations with uncertain effects should be tested before correct advice and treatment can be given.