|
| ||
|
|
||
Cancer Syndrome (cancer + syndrome)
Kinds of Cancer Syndrome Selected AbstractsHereditary Breast Cancer: Part I. Diagnosing Hereditary Breast Cancer SyndromesTHE BREAST JOURNAL, Issue 1 2008Henry T. Lynch MD Abstract:, Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15,20% of those affected with BC will have one or more first- and/or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20,25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and genotypic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis. [source] Keratoacanthoma: A Clinico-Pathologic EnigmaDERMATOLOGIC SURGERY, Issue 2004Robert A. Schwartz MD Background. Keratoacanthoma (KA) is an extraordinary entity. Once considered a benign neoplasm that resembled a highly malignant one (pseudomalignancy), it is now viewed in an opposite light as a cancer that resembles a benign neoplasm (pseudobenignity). Objective. The goal was to delineate the malignant potential of this neoplasm based on the author's experience and a review of recent data and research and to emphasize the KA as a possible part of an autosomal dominant familial cancer syndrome, the Muir,Torre syndrome. Methods. This is a review of the literature. Results. In this work, the KA is reviewed with recent advances emphasized. Conclusion. KA is an abortive malignancy that rarely progresses into an invasive SCC. The KA may serve as a marker for the important autosomal dominant familial cancer syndrome, the Muir,Torre syndrome, as a result of a defective DNA mismatch repair gene. [source] MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay,HUMAN MUTATION, Issue 2 2010Sara Molatore Abstract MUTYH -associated polyposis (MAP) is a colorectal cancer syndrome, due to biallelic mutations of MUTYH. This Base Excision Repair gene encodes for a DNA glycosylase that specifically mitigates the high mutagenic potential of the 8-hydroxyguanine (8-oxodG) along the DNA. Aim of this study was to characterize the biological effects, in a mammalian cell background, of human MUTYH mutations identified in MAP patients (137insIW [c.411_416dupATGGAT; p.137insIleTrp]; R171W [c.511C>T; p.Arg171Trp]; E466del [c.1395_1397delGGA; p.Glu466del]; Y165C [c.494A>G; p.Tyr165Cys]; and G382D [c.1145G>A; p.Gly382Asp]). We set up a novel assay in which the human proteins were expressed in Mutyh,/, mouse defective cells. Several parameters, including accumulation of 8-oxodG in the genome and hypersensitivity to oxidative stress, were then used to evaluate the consequences of MUTYH expression. Human proteins were also obtained from Escherichia coli and their glycosylase activity was tested in vitro. The cell-based analysis demonstrated that all MUTYH variants we investigated were dysfunctional in Base Excision Repair. In vitro data complemented the in vivo observations, with the exception of the G382D mutant, which showed a glycosylase activity very similar to the wild-type protein. Our cell-based assay can provide useful information on the significance of MUTYH variants, improving molecular diagnosis and genetic counseling in families with mutations of uncertain pathogenicity. Hum Mutat 30:1,8, 2009. © 2009 Wiley-Liss, Inc. [source] Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis,,HUMAN MUTATION, Issue 10 2006Sophie Lejeune Abstract Familial adenomatous polyposis has been linked to germline mutations in the APC tumor suppressor gene. However, a number of patients with familial adenomatous polyposis (with either classical or attenuated phenotype) have no APC mutation. Recently, germline mutations in the Wnt pathway component gene AXIN2 have been associated with tooth agenesis-colorectal cancer syndrome. Moreover, biallelic mutations in the base excision repair gene MUTYH have been associated with polyposis and early-onset colorectal cancer. The aim of this study was to further assess the contribution of AXIN2 and MUTYH to hereditary colorectal cancer susceptibility. AXIN2 and MUTYH genes were screened for germline mutations by PCR and direct sequencing in 39 unrelated patients with multiple adenomas or colorectal cancer without evidence of APC mutation nor mismatch repair defect. Two novel AXIN2 variants were detected in one patient with multiple adenomas, but no clearly pathogenic mutation. In contrast, nine different MUTYH mutations were detected in eight patients, including four novel mutations. Biallelic MUTYH mutations were only found in patients with multiple adenomatous polyposis (7 out of 22 (32%)). Interestingly, five MUTYH mutation carriers had a family history consistent with dominant inheritance. Moreover, one patient with biallelic MUTYH mutations presented with multiple adenomas and severe tooth agenesis. Therefore, germline mutations are rare in AXIN2 but frequent in MUTYH in patients with multiple adenomas. Our data suggest that genetic testing of MUTYH may be of interest in patients with pedigrees apparently compatible with autosomal recessive as well as dominant inheritance. © 2006 Wiley-Liss, Inc. [source] Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndromeINTERNATIONAL JOURNAL OF CANCER, Issue 4 2007Laura Renkonen-Sinisalo Abstract The estimated lifetime risk for endometrial carcinoma (EC) in hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is 32,60%, thus supporting surveillance. The survival rate of EC patients is, however, favourable questioning the need for surveillance. Yet, the effectiveness of gynecological surveillance remains to be shown. The 2 previously published studies were based on transvaginal ultrasound (TVUS) alone. Intrauterine biopsy has not been tested in surveillance for EC in HNPCC families. The effect of gynecological surveillance was evaluated among 175 Finnish mutation carriers. During 759 person years at risk, there were 503 surveillance visits including TVUS and intrauterine biopsy of endometrium at 94% and 74% of the visits, respectively. EC occurred in 14 cases, 11 of which were diagnosed by surveillance, 8 by intrauterine biopsies. TVUS indicated only 4 EC patients but missed 6 other cases. Intrauterine sampling detected 14 additional cases of potentially premalignant hyperplasia. The stage distribution and survival tended to be more favorable in the 14 EC cases of the surveilled group (no deaths) than in the group of 83 symptomatic mutation carriers of whom 6 died of EC, but with no statistical significance. Four cases of ovarian cancer occurred but none was detected by surveillance in TVUS examinations. In conclusion, EC surveillance in HNPCC seems more effective with endometrial biopsies than with TVUS alone. A definite improvement in survival remains to be shown. The detection of early cancer stages and premalignant lesions offers the opportunity to avoid extensive adjuvant treatment. © 2006 Wiley-Liss, Inc. [source] Hereditary Breast Cancer: Part I. Diagnosing Hereditary Breast Cancer SyndromesTHE BREAST JOURNAL, Issue 1 2008Henry T. Lynch MD Abstract:, Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15,20% of those affected with BC will have one or more first- and/or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20,25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and genotypic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis. [source] Hereditary diffuse gastric cancer: A manifestation of lost cell polarityCANCER SCIENCE, Issue 7 2009Bostjan Humar Hereditary diffuse gastric cancer is a cancer syndrome caused by germline mutations in the gene for the cell adhesion protein E-cadherin (CDH1). E-cadherin plays a central role in the maintenance of cell polarity and its loss during tumorigenesis is associated with poorly differentiated cancers and a poor prognosis. Hereditary diffuse gastric cancer is dominated by diffuse-type gastric adenocarcinoma, often with signet ring cell morphology. Large numbers of stage T1a signet ring cell carcinomas exist in the stomachs of CDH1 mutation carriers from a young age, and these foci sometimes show enrichment to the transition zone between the body and antrum. Generally these signet ring cell carcinomas are hypoproliferative, lack Wnt pathway activation, and are relatively indolent. However, a small proportion of the T1a foci contain cells that are poorly differentiated, display mesenchymal features, and express activated c-Src and its downstream targets. These same features are observed in more advanced stages of hereditary diffuse gastric cancer progression, suggesting that an epithelial,mesenchymal transition is required for tumor invasion beyond the muscularis mucosae. Hereditary diffuse gastric cancer initiation requires somatic down-regulation of the second CDH1 allele, which in most cases is caused by DNA promoter hypermethylation. Subsequent to CDH1 down-regulation, lost polarity in gastric stem or progenitor cells would be predicted to interfere with mitotic spindle orientation and the segregation of cell fate determinants. We predict that this disruption of cell division results in daughter cells being deposited in the lamina propria where their population expands and partially differentiates, resulting in the formation of foci of signet ring cells. (Cancer Sci 2009; 100: 1151,1157) [source] DNA repair and cancer: Lessons from mutant mouse modelsCANCER SCIENCE, Issue 2 2004Takatoshi Ishikawa DNA damage, if the repair process, especially nucleotide excision repair (NER), is compromised or the lesion is repaired by some other error-prone mechanism, causes mutation and ultimately contributes to neoplastic transformation. Impairment of components of the DNA damage response pathway (e.g., p53) is also implicated in carcinogenesis. We currently have considerable knowledge of the role of DNA repair genes as tumor suppressors, both clinically and experimentally. The deleterious clinical consequences of inherited defects in DNA repair system are apparent from several human cancer predisposition syndromes (e.g., NER-compromised xeroderma pigmentosum [XP] and p53 -deficient Li-Fraumeni syndrome). However, experimental studies to support the clinical evidence are hampered by the lack of powerful animal models. Here, we review in vivo experimental data suggesting the protective function of DNA repair machinery in chemical carcinogenesis. We specifically focus on the three DNA repair genes, O6 -methylguanine-DNA methyltransferase gene (MGMT), XP group A gene (XPA) and p53. First, mice overexpressing MGMT display substantial resistance to nitrosamine-induced hepatocarcinogenesis. In addition, a reduction of spontaneous liver tumors and longer survival times were evident. However, there are no known mutations in the human MGMT and therefore no associated cancer syndrome. Secondly, XPA mutant mice are indeed prone to spontaneous and carcinogen-induced tumorigenesis in internal organs (which are not exposed to sunlight). The concomitant loss of p53 resulted in accelerated onset of carcinogenesis. Finally, p53 null mice are predisposed to brain tumors upon transplacental exposure to a carcinogen. Accumulated evidence in these three mutant mouse models firmly supports the notion that the DNA repair system is vital for protection against cancer. [source] Constitutive deficiency in DNA mismatch repairCLINICAL GENETICS, Issue 6 2007KEA Felton Mutations in the DNA mismatch repair (MMR) genes are associated with the inheritance of hereditary non-polyposis colorectal cancer, also known as Lynch syndrome, a cancer syndrome with an average age at onset of 44. Individuals presenting with colorectal cancer are diagnosed with Lynch I, whereas individuals who present with extra-colonic tumors (such as endometrial, stomach, etc.) are identified as patients with Lynch syndrome II. Recently, 30 families have been reported with inheritance of biallelic mutations in the MMR genes. Here we summarize the phenotype of individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein or greatly compromised protein function. In contrast to individuals with Lynch syndrome I and II, individuals with no MMR function present with childhood onset of hematological and brain malignancies, whereas residual MMR function can also result in gastrointestinal cancers and an age of onset in the second to fourth decade. Individuals with biallelic MMR mutations often present with café-au-lait spots, regardless of the level of MMR function remaining. Thus, the inheritance of two MMR gene mutations is a separate entity from Lynch I or II or the subtypes Turcot and Muir,Torre. [source] Colorectal carcinoma in young adults: a retrospective study on Indian patients: 2000,2008COLORECTAL DISEASE, Issue 10Online 2010S. Gupta Abstract Aim, To highlight an increased incidence of colorectal cancer (CRC) amongst young Indian adults. Method, A retrospective study of 305 cases of CRC admitted to SSKM Hospital, Kolkata, India during 2000,2008 was carried out. Results, The ratio (0.64) of under-40 to above-40 CRC patients reported in this study is comparable to those from premier Oncology Centers in India (,0.52) and is higher than those in the Indian National Cancer Registry (,0.20) and international average (0.07). Distinctive tumour characteristics in younger patients including left-sided lesion (69.7%), presentation at an advanced (III/IV) stage (60%), poor histological differentiation (50%) and predominance of mucin-secreting adenocarcinoma (80%) are similar to those reported in the international literature. Some features are suggestive of hereditary non polyposis colorectal cancer syndrome, which may be a possible reason for the high proportion of young CRC patients. Conclusion, A high index of suspicion for CRC among young Indian adults is necessary. [source] High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families,HUMAN MUTATION, Issue 8 2009George Chong Abstract Lynch syndrome is one of the most common autosomal dominantly inherited cancer syndromes. Mutations in MLH1, MSH2, MSH6, and PMS2 account for greater than 98% of reported mutations in Lynch syndrome families. It has been reported that large genomic deletions in MLH1 and MSH2 are a frequent cause of Lynch syndrome in certain populations. Using a multimodal approach, we have identified mutations in MLH1, MSH2, and MSH6 in French Canadian families fulfilling the Amsterdam criteria for Lynch syndrome and who displayed abnormal staining for at least one of the Lynch syndrome proteins. Mutations were identified in 28 of our 29 French Canadian probands (97%). A total of 18 distinct mutations (nine in MLH1, seven in MSH2, two in MSH6) were identified, of which six (33%) were genomic exon deletions. Another four (22%) resulted in exon deletions in cDNA alone. Three (17%) are novel mutations. Five of these 18 mutations were detected in more than one distinct family (four in MLH1, one in MSH2) and haplotype analysis suggests the possibility of founder effects. Fifteen of the 29 (52%) families carried one of these five putative founder mutations. These findings may simplify genetic testing for Lynch syndrome in French Canadians. © 2009 Wiley-Liss, Inc. [source] Risk of cancer among children of cancer patients,a nationwide study in FinlandINTERNATIONAL JOURNAL OF CANCER, Issue 5 2010Laura-Maria S. Madanat-Harjuoja Abstract Cancer treatments have the potential to cause germline mutations that might increase the risk of cancer in the offspring of former cancer patients. This risk was evaluated in a population-based study of early onset cancer patients in Finland. Using the nationwide registry data, 26,331 children of pediatric and early onset cancer patients (diagnosed under age 35 between 1953 and 2004) were compared to 58,155 children of siblings. Cancer occurrence among the children was determined by linkage with the cancer registry, and the standardized incidence ratios (SIRs) were calculated comparing the observed number of cancers with that expected, based on rates in the general population of Finland. Among the 9,877 children born after their parent's diagnosis, cancer risk was increased (SIR 1.67; 95% CI 1.29,2.12). However, after removing those with hereditary cancer syndromes, this increase disappeared (SIR 1.03; 95% CI 0.74,1.40). The overall risk of cancer among the offspring of siblings (SIR 1.07; 95% CI 0.94,1.21) was the same as among the offspring of the patients with nonhereditary cancer. Risk of cancer in offspring, born before their parents cancer diagnosis, was elevated (SIR 1.37, 95% CI 1.20-1.54), but removing hereditary syndromes resulted in a diminished and nonsignificant association (SIR 1.08, 95% CI 0.93-1.25). This study shows that offspring of cancer patients are not at an increased risk of cancer except when the patient has a cancer-predisposing syndrome. These findings are directly relevant to counseling cancer survivors with regard to family planning. [source] All in the family: Using inherited cancer syndromes to understand de-regulated cell signaling in brain tumorsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2007S. Sean Houshmandi Abstract The cell signaling pathways that are tightly regulated during development are often co-opted by cancer cells to allow them to escape from the constraints that normally limit cell growth and cell movement. In this regard, de-regulated signaling in cancer cells confers a number of key tumor-associated properties, including increased cell proliferation, decreased cell death, and increased cell motility. The identification of some of these critical signaling pathways in the nervous system has come from studies of inherited cancer syndromes in which affected individuals develop brain tumors. The study of brain tumors arising in patients with neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and tuberous sclerosis complex (TSC) has already uncovered several key intracellular signaling pathways important for modulating brain tumor growth. An in-depth analysis of these intracellular signaling pathways will not only lead to an improved understanding of the process of brain tumorigenesis, but may also provide important molecular targets for future therapeutic drug design. J. Cell. Biochem. 102: 811,819, 2007. © 2007 Wiley-Liss, Inc. [source] Hereditary Breast Cancer: Part I. Diagnosing Hereditary Breast Cancer SyndromesTHE BREAST JOURNAL, Issue 1 2008Henry T. Lynch MD Abstract:, Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15,20% of those affected with BC will have one or more first- and/or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20,25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and genotypic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis. [source] Dermatological features of inherited cancer syndromes in adultsCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 5 2010A. Al Fares Summary Many syndromes predisposing to cancer have dermatological features, which, although often subtle, will alert the clinician to the possibility of systemic malignancy. Many of these conditions are hereditary and are therefore also of relevance to the families of these patients. Early detection and appropriate genetic counselling is vital, as this will allow the patient and their relatives to be screened appropriately. This review will provide an overview of dermatological features of several cancer-predisposing syndromes divided according to organ system, describing the main clinical features and presentation of the selected syndromes. [source] Putative common origin of two MLH1 mutations in Italian-Quebec hereditary non-polyposis colorectal cancer familiesCLINICAL GENETICS, Issue 2 2004I Thiffault Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3,5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin. [source] | |||||||||||||||||||||||||