Correlations between germline APC mutation sites and colorectal pathophenotypes, as evaluated by the direct count of adenomas at colectomy, were investigated analysing colectomy specimens from 29 FAP patients carrying one mis-sense (codon 208) and 14 frame-shift or non-sense APC mutations (codons 232, 367, 437, 623, 876, 995, 1061, 1068, 1075, 1112, 1114, 1309, 1324, 1556). The mis-sense mutation at codon 208 was associated with a relatively mild colorectal pathophenotype. The mutation at codon 367, subject to alternative splicing, was associated with attenuated FAP. The mutation at codon 1309 was associated with the profuse colorectal adenomatosis. For 13 mutations, predicted to result in null alleles or truncated APC proteins, we correlated density and distribution of colorectal adenomas with the predicted functional effects of the mutation. The most severe colorectal pathophenotype was significantly associated with the truncating mutation at codon 1309, which is located downstream to the I β-catenin binding domain but upstream II β-catenin-binding domain. Mutations between codons 867 and 1114, which affect the I β-catenin binding domain, as well as mutations occurring in exons 6 and 9, predicted to result in null alleles, were associated with a less severe colorectal pathophenotype. Overall, the highest number of adenomas was detected in the right colon, followed by the left colon, transverse colon sigma and rectum. However, the highest density of adenomas was observed in the left colon, followed by the right colon, sigma, transverse colon and rectum. Colorectal carcinomas, observed in only five patients, were all in the left colon. © 2000 Cancer Research Campaign

BackgroundThe spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history.MethodsThe study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2).DiscussionWe found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component.This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-1-20) contains supplementary material, which is available to authorized users.

The etiology of breast cancer in Africa is scarcely investigated. Breast cancer was responsible for 456/2,233 cancer patients (20.4%) ascertained between 1999 and 2004 at Gezira University, Central Sudan. Male breast cancer accounted for 16/456 patients (3.5%), 275/440 female patients (62.5%) were premenopausal and 150/440 cases (34%) occurred in women with > or =5 childbirths. We characterized for germline BRCA1/2 mutations a one-year series of patients (34 females, 1 male) selected by diagnosis within age 40 years or male gender. Overall 33/35 patients were found to carry 60 BRCA1/2 variants, of which 17 (28%) were novel, 22 (37%) reported in populations from various geographic areas and 21 (35%) reported worldwide. Detected variants included 5 truncating mutations, one of which (in BRCA2) was in the male patient. The 55 non-truncating variants included 3 unclassified variants predicted to affect protein product and not co-occurring with a truncating mutation in the same gene. Patients were from different tribes but AMOVA showed that most BRCA1/2 variation was within individuals (86.41%) and patients clustered independently of tribe in a phylogenetic tree. Cluster analysis based on age at cancer diagnosis and reproductive variables split female patients in two clusters that, by factor analysis, were explained by low versus high scores of the total period occupied by pregnancies and lactation. The cluster with low scores comprised all 4 patients with truncating mutations and 3 of the 4 carriers of unclassified variants predicted to affect protein product. Our findings suggest that in Central Sudan BRCA1/2 represent an important etiological factor of breast cancer in males and young women less exposed to pregnancy and lactation. Factors other than BRCA1/2 may contribute to breast cancer in young highly multiparous women who breast-fed for prolonged periods.

The analysis of APC and MYH mutations in adenomatous polyposis coli patients should provide clues about the genetic heterogeneity of the syndrome in human populations. The entire coding region and intron-exon borders of the APC and MYH genes were analyzed in 60 unrelated Italian adenomatous polyposis coli patients. APC analysis revealed 26 point mutations leading to premature termination, one missense variant and one deletion spanning the entire coding region in 32 unrelated patients. Novel truncating point mutations included c.1176_1177insT (p.His393_PhefsX396), c.1354_1355del (p.Val452_SerfsX458), c.2684C>A (p.Ser895X), c.2711_2712del (p.Arg904_LysfsX910), c.2758_2759del (p.Asp920_CysfsX922), c.4192_4193del (p.Ser1398_SerfsX1407), c.4717G>T (p.Glu1573X) and a novel cryptic APC exon 6 splice site. MYH analysis revealed nine different germline variants in nine patients, of whom five were homozygotes or compound heterozygotes. The mutations included 4 novel MYH missense variants (c.692G>A, p.Arg231His; c.778C>T, p.Arg260Trp; c.1121T>C, p.Leu374Pro; and c.1234C>T, p.Arg412Cys) affecting conserved amino acid residues in the ENDO3c or NUDIX domains of the protein and one novel synonymous change (c.672C>T, p.Asn224Asn). Genotype-phenotype correlations were found in carriers of APC mutations but not in carriers of biallelic MYH mutations, except for a negative correlation with low number of polyps. A distinctive characteristic of patients negative for APC and MYH mutations was a significantly (p<0.0001) older age at diagnosis compared to patients with APC mutations. Moreover, the proportion of cases with an attenuated polyposis phenotype was higher (p = 0.0008) among patients negative for APC and MYH mutations than among carriers of APC or biallelic MYH mutations.

Hepatoblastoma, a rare embryonic tumor that may arise sporadically or in the context of hereditary syndromes (familial adenomatous polyposis and Beckwith-Wiedemann's) is the most frequent liver cancer of childhood. Deregulation of the APC/b-catenin pathway occurs in a consistent fraction of hepatoblastomas, with mutations in the APC and b-catenin genes implicated in familial adenomatous polyposis-associated and sporadic hepatoblastomas, respectively. Alterations in other cancer-related molecular pathways have not been reported. We investigated a series of 21 sporadic paraffin-embedded hepatoblastoma cases for mutations in the p53 (exons 5-8) and b-catenin (exon 3) genes, loss of heterozygosity at APC, microsatellite instability and immunohistochemical expression of b-catenin and of the two main mismatch repair proteins, MLH1 and MSH2. No loss of heterozygosity at APC was detected. We found mutations in b-catenin and p53 in 4/21 (19%) and 5/21 (24%) cases respectively, b-catenin protein accumulation in 14/21 cases (67%), microsatellite instability in 17/21 cases (81%), of which eight resulted positive for high-level of microsatellite instability (in four cases associated with loss of MLH1/MSH2 immunostaining). No correlations between involved molecular pathway(s) and hepatoblastoma histotype(s) emerged. This study confirms that b-catenin deregulation is involved in sporadic hepatoblastoma and also suggests that mismatch repair defects and p53 mutations contribute to this rare liver cancer. Sporadic hepatoblastoma appears to be molecularly and phenotypically heterogeneous and may reflect different pathways of liver carcinogenesis.

The development of colorectal cancer (CRC) is a multistep process initiated by a benign polyp that has the potential to evolve into in situ carcinoma through the interactions between environmental and genetic factors. CRC incidence rates are constantly increased for young adult patients presenting an advanced tumor stage. The majority of CRCs arise from colonic adenomas originating from aberrant cell proliferation of colon epithelium. Endoscopic polypectomy represents a tool for early detection and removal of polyps, although the occurrence of cancers after negative colonoscopy shows a significant incidence. It has long been recognized that the aberrant regulation of Wingless/It (Wnt)/β-Catenin signaling in the pathogenesis of colorectal cancer is supported by its critical role in the differentiation of stem cells in intestinal crypts and in the maintenance of intestinal homeostasis. For this review, we will focus on the development of adenomatous polyps through the interplay between renewal signaling in the colon epithelium and reactive oxygen species (ROS) production. The current knowledge of molecular pathology allows us to deepen the relationships between oxidative stress and other risk factors as lifestyle, microbiota, and predisposition. We underline that the chronic inflammation and ROS production in the colon epithelium can impair the Wnt/β-catenin and/or base excision repair (BER) pathways and predispose to polyp development. In fact, the coexistence of oxidative DNA damage and errors in DNA polymerase can foster C>T transitions in various types of cancer and adenomas, leading to a hypermutated phenotype of tumor cells. Moreover, the function of Adenomatous Polyposis Coli (APC) protein in regulating DNA repair is very important as therapeutic implication making DNA damaging chemotherapeutic agents more effective in CRC cells that tend to accumulate mutations. Additional studies will determine whether approaches based on Wnt inhibition would provide long-term therapeutic value in CRC, but it is clear that APC disruption plays a central role in driving and maintaining tumorigenesis.

Mutations in the BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185) genes account for only a fraction of breast cancer susceptibility, thus the role of other predisposing genes is currently being investigated [Wooster and Weber, 2003]. Recent reports have implicated the cell-cycle-checkpoint kinase CHEK2 gene (MIM# 604373; also known as CHK2) in the susceptibility to breast and other cancers [Dong et al.,

In our experience fewer than 10 rectal polyps at presentation can predict a favorable outcome after IRA. Identification of specific germ-line APC or MYH mutation can address the choice of surgical treatment.