Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor . The adenomatous polyposis coli ( APC ) tumour-suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta ( GSK-3beta ) , axin / conductin and betacatenin . Complex formation induces the rapid degradation of betacatenin . In colon carcinoma cells , loss of APC leads to the accumulation of betacatenin in the nucleus , where it binds to and activates the Tcf-4 transcription factor ( reviewed in [ 1 ] [ 2 ] ) . Here , we report the identification and genomic structure of APC homologues . Mammalian APC2 , which closely resembles APC in overall domain structure , was functionally analyzed and shown to contain two SAMP domains , both of which are required for binding to conductin . Like APC , APC2 regulates the formation of active betacatenin-Tcf complexes , as demonstrated using transient transcriptional activation assays in APC - / - colon carcinoma cells . Human APC2 maps to chromosome 19p13 . 3 . APC and APC2 may therefore have comparable functions in development and cancer .	0

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Identification of APC2 , a homologue of the adenomatous polyposis coli tumour suppressor . 
The adenomatous polyposis coli ( APC ) tumour - suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta ( GSK - 3beta ) , axin / conductin and betacatenin . 
Complex formation induces the rapid degradation of betacatenin . 
In colon carcinoma cells , loss of APC leads to the accumulation of betacatenin in the nucleus , where it binds to and activates the Tcf - 4 transcription factor ( reviewed in [ 1 ] [ 2 ] ) . 
Here , we report the identification and genomic structure of APC homologues . 
Mammalian APC2 , which closely resembles APC in overall domain structure , was functionally analyzed and shown to contain two SAMP domains , both of which are required for binding to conductin . 
Like APC , APC2 regulates the formation of active betacatenin - Tcf complexes , as demonstrated using transient transcriptional activation assays in APC - / - colon carcinoma cells . 
Human APC2 maps to chromosome 19p13 . 
3 . 
APC and APC2 may therefore have comparable functions in development and cancer . 

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Identification of APC2 , a homologue of the adenomatous polyposis coli tumour suppressor .
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Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor . The adenomatous polyposis coli ( APC ) tumour-suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta ( GSK-3beta ) , axin / conductin and betacatenin . Complex formation induces the rapid degradation of betacatenin . In colon carcinoma cells , loss of APC leads to the accumulation of betacatenin in the nucleus , where it binds to and activates the Tcf-4 transcription factor ( reviewed in [ 1 ] [ 2 ] ) . Here , we report the identification and genomic structure of APC homologues . Mammalian APC2 , which closely resembles APC in overall domain structure , was functionally analyzed and shown to contain two SAMP domains , both of which are required for binding to conductin . Like APC , APC2 regulates the formation of active betacatenin-Tcf complexes , as demonstrated using transient transcriptional activation assays in APC - / - colon carcinoma cells . Human APC2 maps to chromosome 19p13 . 3 . APC and APC2 may therefore have comparable functions in development and cancer .	0
A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer . The frequency , origin , and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated . The mutation ( A-- > T at nt943 + 3 ) disrupts the 3 splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported . Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England , more extensive analysis has reduced the frequency to four of 52 ( 8 % ) English HNPCC kindreds analysed . In contrast , the MSH2 mutation was identified in 10 of 20 ( 50 % ) separately identified colorectal families from Newfoundland . To investigate the origin of this mutation in colorectal cancer families from England ( n = 4 ) , Newfoundland ( n = 10 ) , and the United States ( n = 3 ) , haplotype analysis using microsatellite markers linked to MSH2 was performed . Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families . In contrast , a common haplotype was identified at the two flanking markers ( CA5 and D2S288 ) in eight of the Newfoundland families . These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families . We calculated age related risks of all , colorectal , endometrial , and ovarian cancers in nt943 + 3 A-- > T MSH2 mutation carriers ( n = 76 ) for all patients and for men and women separately . For both sexes combined , the penetrances at age 60 years for all cancers  and for colorectal cancer were 0 . 86 and 0 . 57 , respectively . The risk of colorectal cancer was significantly higher ( p  0 . 01 ) in males than females ( 0 . 63 v 0 . 30 and 0 . 84 v 0 . 44 at ages 50 and 60 years , respectively ) . For females there was a high risk of endometrial cancer ( 0 . 5 at age 60 years ) and premenopausal ovarian cancer ( 0 . 2 at 50 years ) . These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers .	0
Age of onset in Huntington disease : sex specific influence of apolipoprotein E genotype and normal CAG repeat length . Age of onset ( AO ) of Huntington disease ( HD) is known to be correlated with the length of an expanded CAG repeat in the HD gene . Apolipoprotein E ( APOE ) genotype , in turn , is known to influence AO in Alzheimer disease , rendering the APOE gene a likely candidate to affect AO in other neurological diseases too . We therefore determined APOE genotype and normal CAG repeat length in the HD gene for 138 HD patients who were previously analysed with respect to CAG repeat length . Genotyping for APOE was performed blind to clinical information . In addition to highlighting the effect of the normal repeat length upon AO in maternally inherited HD and in male patients , we show that the APOE epsilon2epsilon3 genotype is associated with significantly earlier AO in males than in females . Such a sex difference in AO was not apparent for any of the other APOE genotypes . Our findings suggest that subtle differences in the course of the neurodegeneration  in HD  may allow interacting genes to exert gender specific effects upon AO.	1


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BRCA1 is secreted and exhibits properties of a granin. Germline mutations in BRCA1 are responsible for most cases of inherited breast and ovarian cancer . However , the function of the BRCA1 protein has remained elusive . We now show that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family . Interestingly , BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein . Both BRCA1 and the granins localize to secretory vesicles , are secreted by a regulated pathway , are post-translationally glycosylated and are responsive to hormones . As a regulated secretory protein , BRCA1 appears to function by a mechanism not previously described for tumour suppressor gene products . . 	0
Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Women who carry a mutation in the BRCA1 gene ( on chromosome 17q21 ) , have an 80 % risk of breast cancer and a 40 % risk of ovarian cancer by the age of 70 ( ref . 1 ) . The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals . The HRAS1 variable number of tandem repeats ( VNTR ) polymorphism , located 1 kilobase ( kb ) downstream of the HRAS1 proto-oncogene ( chromosome 11p15 . 5 ) is one possible genetic modifier of cancer penetrance . Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers , including breast cancer ( 2-4 ) . To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer , we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique . The risk for ovarian cancer was 2 . 11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles , compared to carriers with only common alleles ( P = 0 . 015 ) . The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer ( 5 ) . Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles . This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome 	0
A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. Myotonic dystrophy ( DM ) is associated with a ( CTG ) n trinucleotide repeat expansion in the 3-untranslated region of a protein kinase-encoding gene , DMPK , which maps to chromosome 19q13 . 3 . Characterisation of the expression of this gene in patient tissues has thus far generated conflicting data on alterations in the steady state levels of DMPK mRNA , and on the final DMPK protein levels in the presence of the expansion . The DM region of chromosome 19 is gene rich , and it is possible that the repeat expansion may lead to dysfunction of a number of transcription units in the vicinity , perhaps as a consequence of chromatin disruption . We have searched for genes associated with a CpG island at the 3 end of DMPK . Sequencing of this region shows that the island extends over 3 . 5 kb and is interrupted by the ( CTG ) n repeat . Comparison of genomic sequences downstream ( centromeric ) of the repeat in human and mouse identified regions of significant homology . These correspond to exons of a gene predicted to encode a homeodomain protein . RT-PCR analysis shows that this gene , which we have called DM locus-associated homeodomain protein ( DMAHP ) , is expressed in a number of human tissues , including skeletal muscle , heart and brain .	1


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Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Ataxia-telangiectasia ( A-T ) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 ( ref . 3 ) . The risk of cancer , especially lymphoid neoplasias , is substantially elevated in A-T patients and has long been associated with chromosomal instability . By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia ( T-PLL ) , a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T , we demonstrate a high frequency of ATM mutations in T-PLL . In marked contrast to the ATM mutation pattern in A-T , the most frequent nucleotide changes in this leukaemia were missense mutations . These clustered in the region corresponding to the kinase domain , which is highly conserved in ATM-related proteins in mouse , yeast and Drosophila . The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition . Two of seventeen mutated T-PLL samples had a previously reported A-T allele . In contrast , no mutations were detected in the p53 gene , suggesting that this tumour suppressor is not frequently altered in this leukaemia . Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkins lymphomas ( B-NHL ) and a B-NHL cell line . The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor . As constitutional DNA was not available , a putative hereditary predisposition to T-PLL will require further investigation . . 	0
Myotonic dystrophy protein kinase is involved in the modulation of the Ca2+ homeostasis in skeletal muscle cells. Myotonic dystrophy ( DM ) , the most prevalent muscular disorder in adults , is caused by ( CTG ) n-repeat expansion in a gene encoding a protein kinase ( DM protein kinase ; DMPK ) and involves changes in cytoarchitecture and ion homeostasis . To obtain clues to the normal biological role of DMPK in cellular ion homeostasis , we have compared the resting [ Ca2 + ] i , the amplitude and shape of depolarization-induced Ca2 + transients , and the content of ATP-driven ion pumps in cultured skeletal muscle cells of wild-type and DMPK [ - / - ] knockout mice . In vitro-differentiated DMPK [ - / - ] myotubes exhibit a higher resting [ Ca2 + ] i than do wild-type myotubes because of an altered open probability of voltage-dependent l-type Ca2 + and Na + channels . The mutant myotubes exhibit smaller and slower Ca2 + responses upon triggering by acetylcholine or high external K + . In addition , we observed that these Ca2 + transients partially result from an influx of extracellular Ca2 + through the l-type Ca2 + channel . Neither the content nor the activity of Na + / K + ATPase and sarcoplasmic reticulum Ca2 + -ATPase are affected by DMPK absence . In conclusion , our data suggest that DMPK is involved in modulating the initial events of excitation-contraction coupling in skeletal muscle . . 	1
Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. In most patients with isolated unilateral retinoblastoma , tumor development is initiated by somatic inactivation of both alleles of the RB1 gene . However , some of these patients can transmit retinoblastoma predisposition to their offspring . To determine the frequency and nature of constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma , we analyzed DNA from peripheral blood and from tumor tissue . The analysis of tumors from 54 ( 71 % ) of 76 informative patients showed loss of constitutional heterozygosity ( LOH ) at intragenic loci . Three of 13 uninformative patients had constitutional deletions . For 39 randomly selected tumors , SSCP , hetero-duplex analysis , sequencing , and Southern blot analysis were used to identify mutations . Mutations were detected in 21 ( 91 % ) of 23 tumors with LOH . In 6 ( 38 % ) of 16 tumors without LOH , one mutation was detected , and in 9 ( 56 % ) of the tumors without LOH , both mutations were found . Thus , a total of 45 mutations were identified in tumors of 36 patients . Thirty-nine of the mutations-including 34 small mutations , 2 large structural alterations , and hypermethylation in 3 tumors-were not detected in the corresponding peripheral blood DNA . In 6 ( 17 % ) of the 36 patients , a mutation was detected in constitutional DNA , and 1 of these mutations is known to be associated with reduced expressivity . The presence of a constitutional mutation was not associated with an early age at treatment . In 1 patient , somatic mosaicism was demonstrated by molecular analysis of DNA and RNA from peripheral blood . In 2 patients without a detectable mutation in peripheral blood , mosaicism was suggested because 1 of the patients showed multifocal tumors and the other later developed bilateral retinoblastoma . In conclusion , our results emphasize that the manifestation and transmissibility of retinoblastoma depend on the nature of the first mutation , its time in development , and the number and types of cells that are affected . . 	2