Medico-genetic and cytogenetic investigation in family with high predisposition to diffuse intestine polyposis

We revealed a family consisting of 25 persons which displayed high predisposition to malignant diseases of the gastrointestinal tract (GIT): rectal cancer (RC) was diagnosed in 2 patients, large intestine malignant polyposis (LIMP) in 1 patient, large intestine diffuse polyposis (LIDP) in 3 and uterus fibromyoma in 1 patient. Six members of the family were examined cytogenetically with the methaphase method on blood lymphocytes following G-banding of chromosomes. In 2 patients with LIDP was detected 8.7 and 16.7% of hyperaneuploid cells, respectively, and 20% of cells with double minute chromosomes (DMS) were detected in 1 LIDP patient. We suppose, that LIDP development in members of the family is related to the significant increase of proportion of hyperaneuploid and DMS-containing cells.     

Genetics of primary brain tumors: a review

Summary In this review we provide evidence for the existence of genes associated with primary malignant brain tumors. We summarize the current knowledge from studies of familial cancer aggregation, hereditary syndromes, and molecular and cytogenetic studies. The epidemiologic evidence is suggestive but inconclusive for an association between brain tumors and cancers in other family members, including cancers of the breast, lung and colon. Central nervous system (CNS) tumors have been associated with several hereditary syndromes including the Li-Fraumeni cancer family syndrome, neurofibromatosis (types 1 and 2), tuberous sclerosis, nevoid basal cell carcinoma syndrome, familial polyposis, and von Hippel-Lindau disease. Significant studies leading to the recognition of molecular and cytogenetic abnormalities in malignant gliomas are described in detail. The genetic studies conducted thus far suggest a role for inherited susceptibility in some CNS tumors.     

The real face of juvenile polyposis syndrome

Colorectal cancers are mostly sporadic; some cases of familial clustering and autosomal dominant conditions are also known to occur. Juvenile polyposis syndrome (JPS) is an autosomal dominant condition caused by the mutation of the SMAD4 or the BMPR1A genes. JPS is characterized by hamartomatous polyps developing in the upper and lower intestine. Contradicting previous studies, many of these polyps can go through malignant transformation.This paper reports the case of a male patient who was continuously treated for juvenile polyposis. During the eighteen years of treatment, more than hundred polyps were endoscopically removed from his gastrointestinal tract. The patient’s care was interrupted for eight years due to insufficient compliance. He was subsequently referred to our Department of Gastroenterology in severe clinical condition caused by metastatic colorectal cancer. He died after a short palliative therapy at the age of 31. His first-degree accessible relatives were further examined for juvenile polyposis syndrome. Several gastrointestinal polyps of different histological origin were observed in the deceased patient’s brother, who subsequently had to undergo a left lateral hemicolectomy. Genetic analyses revealed mutations of the BMPR1A gene in the clinically affected brother, the brother’s daughter, and in the deceased proband’s daughter.Indebt genetic analyses helped customize and deliver care to a very specific group of individuals. We were able to identify potential family members on whom preventive care and treatment could be focused and simultaneously prevented unnecessary clinical and invasive procedures on those who were healthy. Furthermore, these analyses helped prevent future unnecessary trauma or distress on the analyzed family.Key Words: Juvenile polyposis syndrome (JPS), malignant transformation, BMPR1A gene mutation, mutation-carrier     

Free urinary amino acid excretion in patients with familial polyposis of the colon

The free urinary amino acids excretion per 24 hr of the neutral and acidic amino acids did not reveal any diagnostic abnormality in five patients with familial polyposis of the colon with or without associated desmoid tumors and osteomas. One patient with Klinefelter's syndrome and familial polyposis had a urinary acid excretion pattern indistinguishable from his brother, who had familial polyposis and normal chromosomes. It is suggested that patients with familial polyposis deserve intensive biochemical study as this represents a prototype hereditary malignant disease.     

Hereditary colon cancer syndromes

Colon cancer is associated with a family history in up to 25% of cases. As many as 5% are associated with an established hereditary syndrome, demonstrating the profound influence of inheritable genetic mechanisms in the development of this disease. These syndromes confer a diverse spectrum of risk, age of presentation, endoscopic and histological findings, extracolonic manifestations, and modes of inheritance. As the molecular characteristics of these disorders become better described, enhanced genotype-phenotype correlations may offer a more targeted approach to diagnosis, screening, and surveillance. While the strategies for diagnosis and management of familial adenomatous polyposis (FAP) and Lynch syndrome are more established, the approach to newly recognized syndromes such as MUTYH-associated polyposis (MAP) and hyperplastic polyposis syndromes continues to evolve. Effective cancer prevention in affected individuals and at-risk family members first requires timely recognition of these hereditary colon cancer syndromes followed by integration of genetic testing and clinical examinations.     

A Peutz–Jeghers syndrome family associated with sinonasal adenocarcinoma: 28 years follow up report

Peutz–Jeghers syndrome (PJS) is a rare hereditary disorder characterized by hamartomatous polyps in both of the gastrointestinal tract and mucosal pigmentation. It could increase in risk of intestinal and extra-intestinal neoplasms. We here described three cases of sinonasal polyposis in a PJS family and two developed sinonasal type adenocarcinoma. Genetic study revealed a germline STK11/LKB1 mutation on codon 179 (c.C536G, p.P179R) of exon 4. LOH analysis of the LKB1 locus confirms this to be a deleterious mutation. Sinonasal polyposis with malignant transformation could be encountered in PJS patients. Regular follow-up was recommended for the risk of malignant changes in nasal polyps.     

A new frameshift MEN1 gene mutation associated with familial malignant insulinomas

MEN-1 is an autosomal dominant familial cancer syndrome characterized by involvement of parathyroid, enteropancreatic endocrine tissues and the anterior pituitary gland. Malignant insulinomas are rare, and therefore, there are few data regarding their clinical presentation and long-term prognosis. In this report we present a large family with malignant insulinoma and hyperparathyroidism with MEN-1 gene mutation analysis. A large family (three generations) with several members affected were evaluated for clinical and biochemical characteristic of MEN-1 syndrome. Genetic analysis for MEN1 gene was carried out in all family members using PCR amplification of coding regions followed by direct sequencing. In three brothers that presented with hypoglycemia, insulinoma was confirmed and two were malignant according to pathology and surgery report. Two of them had hyperparathyroidism too. Mutation screening revealed the presence of a two nucleotide deletion in the exon 2 (c199_200del2). In the current study, the deletion happens early in the sequence, and obviously results in a non-functional gene product. However, it will be helpful to further examine somatic mutations and other genetic markers for a more precise study of genotype-phenotype correlation.     

恶性肿瘤住院患者家属疾病不确定感的现状及影响因素

 目的　调查恶性肿瘤患者家属的疾病不确定感现状， 探讨影响肿瘤患者家属疾病不确定感的因素，为临床医护人员对患者家属实施有效的干预措施提供临床依据。方法　采用中文版疾病不确定感家属量表（MUIS-FM）和自制的家属一般情况调查表、患者疾病资料问卷调查恶性肿瘤住院患者家属的疾病不确定感水平，分析其相关因素。结果　恶性肿瘤患者家属疾病不确定感得分为（82.71±9.93）分，大于总分最高分（75分）的50 %，在家属的受教育程度、家庭收入、居住地以及患者的入院次数方面不同组别的恶性肿瘤患者家属疾病不确定感总分差异有统计学意义（F值分别为8.06、3.14、3.99、4.85，均P＜0.05）。结论　恶性肿瘤患者家属疾病不确定感水平较高，文化程度、家庭收入、居住地以及患者的入院次数对恶性肿瘤患者家属的疾病不确定感水平有一定影响。     

Molecular and clinical study of familial adenomatous polyposis for genetic testing and management

Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenomatous polyps, predominantly in the colorectal region. Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis. We examined germline mutations of the APC gene and clinical features among eighty-seven individuals who consisted of thirty-nine FAP-patients, thirty-seven of their family members with a 1 in 2 risk of predisposition to this disease, and eleven normal persons. We accurately identified nine heterozygotes, among individuals with a 1 in 2 risk by genetic testing, without the uncertainty of the recurrence risk calculated by Bayes' theorem. Six of the nine heterozygotes were confirmed to have colorectal polyps by colonoscopic examination. Since they were diagnosed at 12.7 years-of-age on average, and were no more than 20 years old, they could be treated to prevent colorectal cancer. Based on the genotype-phenotype correlation, we concluded that the germline mutations responsible for the sparse polyps phenotype of FAP-patients tend to locate from codon 1055 in the proximal region of the APC gene, while those for the profuse type locate from codon 1102 in the distal region. Among the thirty-nine FAP-patients, we found that those with the germline mutations within codon 1055 and codon 1262 had colorectal carcinomas of an advanced stage, at a high rate (71.4%). Special attention and aggressive intervention is needed in these patients and relatives at risk. With reasonable and appropriate management, it should be possible to prolong and improve the quality of life of those family members both affected and at risk.     

CD27-CD70 Interaction: Unravelling its Implication in Normal and Neoplastic B-Cell Growth

Members of the Tumour Necrosis Factor-Receptor (TNFR) family play an essential role in the control of lymphoid cell growth and differentiation. The ligand of one of its lymphoid-specific members, CD27, was recently characterized as CD70, a type II transmembrane molecule with homology to TNF that is expressed on activated T and B cells. Ligation of CD27 by its natural ligand generates a potent costimulatory signal for cytokine production and proliferation of activated T cells. In contrast to normal B cells, where CD27 expression is confined to germinal centre cells and to a small subset of circulating B lymphocytes, CD27 expression is found on a large array of distinct B-cell neoplasia. Here, we review recent data on the expression and function of TNFR family members on normal and malignant lymphocytes and propose a role for CD27-CD70 interaction in B-cell development.     

The isolation and characterization of colorectal epithelial cell lines at different stages in malignant transformation from familial polyposis coli patients

The genetic disease familial polyposis coli (hereditary adenomatosis of the colon and rectum) provides an excellent model for the study of tumour progression in the large bowel. We have isolated and characterized four epithelial cell lines from colorectal tumours from polyposis coli patients. These cell lines are grown on collagen-coated Petri dishes in the presence of mouse 3T3 feeder cells in medium containing 20% foetal bovine serum. Of these cell lines three were isolated from premalignant adenomas and one from an adenocarcinoma. All four lines have a characteristic cuboidal epithelial morphology, and their epithelial origin was confirmed by positive staining with a monoclonal antibody which reacts specifically with the keratin filaments of simple epithelia. The adenoma-derived lines display ultrastructural features characteristic of colonic epithelium including desmosomes, microvilli and mucin droplets. One of the adenoma-derived cell lines, designated PC/AA, has retained differentiated functions in culture, namely mucin production, after 21 in vitro passages. PC/AA has a karyotype of 46, XY with no detectable chromosome rearrangements. The adenoma-derived lines could be passaged from clumps of cells but not from single cells even in the presence of 3T3 feeder cells. The carcinoma-derived line, designated PC/JW, could however grow from single cells in the presence of a feeder layer. The one premalignant adenoma-derived line tested so far, PC/AA, did not produce tumours in athymic nude mice. In contrast, the carcinoma-derived line, PC/JW was tumorigenic in athymic nude mice. PC/JW produced moderately well-differentiated tumours which were histologically similar to the adenocarcinoma from which the cell line was isolated. PC/JW has a near-diploid chromosome number with an isochromosome (1q), an isochromosome (14q) and an (Xp; 17q) translocation. Unidentified marker chromosomes were present in a few cells. The features at present which distinguish the carcinoma-derived line from the adenoma-derived lines are tumorigenicity, growth from single cells and chromosomal abnormalities. The isolation and characterization of differentiating human epithelial cell lines at different stages in malignant transformation provide an opportunity to examine the cellular and molecular mechanisms controlling tumour progression in the large intestine, and to obtain an insight into the multistep process of human epithelial carcinogenesis.     

An unusual case of familial adenomatous polyposis with very early symptom occurrence

We report the clinical case of a patient who showed an “accelerated” form of polyposis, with development of major lesions within the first decade of life. The patient belongs to a familial adenomatous polyposis family—already described in 2001—featured by profuse polyposis at an early age of onset and desmoid tumors in the majority of affected individuals (of both sexes). The family was characterized by an uncommon mutation of the APC gene (c.4391_4700del310insCACCTACTGCTGAAA, previously defined as c.4394ins15del310) consisting in a large deletion of 310 bp at codon 1,464 with duplication of the breakpoint leading to a stop codon at position 1,575. The proband was affected by desmoids tumors at the age of 3 years. In the same year (2004) numerous polyps in the large bowel and a hepatoblastoma developed. After several months new desmoids appeared in the surgical scar. In 2010, at age 9, the patient was operated of total colectomy and endorectal pull-through of the small intestine owing to profuse colorectal adenomatosis. New desmoids developed in 2011 and 2012, and required chemotherapy. Further analysis of the APC gene in the proband revealed several polymorphisms. One of these (c.398A>G) had not been previously reported, nor was present in two other affected members of the family. The clinical case, and the practical implications for therapy, are discussed according to the most recent theories of colorectal cancer development. Long-term treatment with Cox-2 inhibitors might represent a good option for this patient.     

Quantitative cytochemical detection of malignant and potentially malignant cells in the colon

It was found to be possible to distinguish malignant cells from normal cells by using an oxygen-sensitive tetrazolium salt (neotetrazolium) for the histochemical demonstration of glucose-6-phosphate dehydrogenase activity in cryostat sections of human colon. We have studied 12 cases of established adenocarcinoma of the colon in addition to 4 of ulcerative colitis and 4 of adenomatous polyposis (polyposis coli). In a nitrogen atmosphere the activities of malignant and normal cells were similar. However, after incubation in an atmosphere of pure oxygen, only malignant cells gave a positive reaction after 5 min. Three of the four cases of adenomatous polyposis gave a positive reaction for glucose-6-phosphate dehydrogenase activity in oxygen in a manner similar to that of specimens with severe dysplasia. In general, positive foci were histologically indistinguishable from the neighboring tubuli. However, foci of severely dysplastic epithelium usually showed a positive reaction. All three patients eventually developed clear-cut severe dysplasia. The other patient, who showed a negative reaction in oxygen, was diagnosed after 3 years as not suffering from dysplasia. All cases of ulcerative colitis gave a reaction in oxygen comparable with that of normal cells. Therefore, the areas with a positive reaction are considered to be either in the process of malignant transformation or malignant. An explanation for the oxygen insensitivity of cancer cells appeared to be a decrease in the activity of superoxide dismutase (EC 1.15.1.1), as addition of exogenous superoxide dismutase to malignant cells caused a normal reaction. We wish to suggest that this test in combination with the routine histology may be exploited for the diagnosis of polyps in premalignant conditions.     

Tumor spectrum in cancer family syndrome (hereditary nonpolyposis colorectal cancer)

The distribution of different malignant tumors was studied in 40 cancer family syndrome (CFS) families with 315 affected family members and a total of 472 separate tumors or malignant diseases. Only families with three or more first-degree family members with colorectal carcinoma were included and other CFS characteristics were required in at least two cases. Colorectal (63%), endometrial (8%), gastric (6%), biliopancreatic (4%), and uroepithelial carcinomas (2%) were the most frequent, and represent the tumors typical of CFS. Families with endometrial cancer (23, 57%) and those without endometrial cancer (17, 43%) did not differ in frequencies of other extracolonic carcinomas. Families with endometrial cancer has more affected members and especially more affected female members than those without endometrial cancer (means, 9.7 and 4.9 versus 5.5 and 1.6 per family, respectively). The authors conclude, therefore, that the occurrence of one or more types of extracolonic tumors in members of CFS families does not provide a firm basis for subdividing the CFS (or hereditary nonpolyposis colorectal carcinoma syndrome.     

Clinical management of familial adenomatous polyposis

Familial adenomatous polyposis is a generalized growth disorder. It manifests itself in a catastrophic way with the inevitable development of colorectal cancer if left untreated. The aim of clinical management should be to detect this disease at its earliest possible stage by treatment of the family as a unit and identification of those at risk with appropriate screening. Early surgical intervention with, most commonly, colectomy with ileorectal anastomosis or, in more advanced cases, with colectomy, rectal mucosectomy and ileoanal pouch procedure is appropriate. Following colorectal cancer the major risks of death from this disease include upper gastrointestinal cancer, desmoid tumour and a number of other malignancies throughout the body. The exact magnitude of the risk of malignant degeneration of these extracolonic manifestations is as yet uncertain. Surveillance is required particularly for upper gastrointestinal adenomas, as there is a significant risk for the development of duodenal carcinoma and it is obvious that prophylactic colectomy alone does not cure this disease predictably. The role of a familial polyposis registry in managing these patients is important not only in maintaining compliance with surveillance and therefore early detection of the disease but also in educating the family members and gaining long-term follow-up data on these cases to more accurately define the risk of death from extracolonic malignancy.     

Increased in vitro tetraploidy: tissue specific within the heritable colorectal cancer syndromes with polyposis coli

In vivo expression of human hereditary tumors are known to be tissue specific; in familial polyposis coli the genotype is expressed solely as colonic polyps that become malignant and in the Gardner syndrome as extracolonic connective tissue tumors and related neoplasms in addition to such colonic lesions. In vitro such tissue specificity was also seen in these 2 syndromes. Increased tetraploidy has been observed only in those cultures derived from tissues, which although appearing normal in the patient, were known to undergo malignant transformation in vivo based on clinical phenotypes and family histories: colonic mucosa in familial polyposis coli, skin and colonic mucosa in the Gardner syndrome. Cultures established from tissues known not to show neoplastic growth or from benign tumors (fibromas, sebaceous cysts and lipomas) did not show increased tetraploidy. Increased tetraploidy in cultures established from these 2 syndromes did not identify all cultured cells with either mutant genotype or those cells showing abnormal benign growths in vivo but rather only in those that are known to undergo malignant transformation in vivo in both syndromes. Such observations suggested that in these 2 syndromes there was a population of tetraploid cells, at least in culture, constantly present which may be relevant to the multi-step process of carcinogenesis.     

Inherited colorectal cancer syndromes

Colorectal cancer is the most common gastrointestinal malignancy and the second leading cause of cancer death in both men and women in the United States. Most colorectal cancer cases diagnosed annually are due to sporadic events, but up to 5% are attributed to known monogenic disorders including Lynch syndrome, familial adenomatous polyposis, MYH-associated polyposis, and the rare hamartomatous polyposis syndromes. These inherited colorectal cancer syndromes confer a markedly increased risk for the development of multiple cancers, and predictive genetic testing is available to identify mutation carriers and at-risk family members. Through personalized strategies for diagnosis and management, a substantial reduction in morbidity and mortality has been appreciated among patients at highest risk for the development of colorectal cancer.     

Sensitive detection of tumour cells in effusions by combining cytology and fluorescence in situ hybridisation (FISH)

Diagnosis of malignant cells in effusions is important for staging procedures and resulting therapeutic decisions. Cytodiagnostics in effusions is sometimes difficult since reactive mesothelial cells can mimic malignant cells. We used fluorescence in situ hybridisation (FISH) in single-colour or if appropriate in dual-colour evaluation to detect chromosomal aberrations in effusion cells as markers of malignancy, to raise the diagnostic yield. Cytologic and FISH evaluations--by using probes representing several chromosomes always including chromosomes 11 and 17--were performed in 358 effusion fluids. Cytology was positive for malignancy in 44.4% of all effusions, whereas FISH was positive in 53.9% (P=0.0001). The combination of cytology and FISH was diagnostic for malignancy in 60.9% of effusions. Diagnostic superiority of FISH was demonstrated in effusions from breast cancer, lung cancer, pancreatic cancer, and in effusions from the entire group of gynaecological and gastrointestinal carcinomas. In transudates (effusion protein <2.5 g dl(-1)), malignant cells were detectable by cytology, FISH, and combined use of both methods in 18.6, 30, and 37.1% of effusions, respectively, suggesting that cytologic and molecular analysis should be performed also with transudates. In conclusion, FISH in combination with conventional cytology is a highly sensitive and specific diagnostic tool for detecting malignant cells in effusions.