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Breast cancer genes snared
Breast snared
cancer
patients developed colorectal cancer within 3 years after the last negative colonoscopic examination. In the Finnish series
Screening for hereditary
genes
colorectal
cancer
2 "interval"
Three papers on major advances in familial breast cancer research are soon to be : published. The studies were done by international multilaboratory groups, in collaboration with Mark H Skolnick of : Salt Lake City, Utah. Inherited suscepti- : bility accounts for about 5% of all breast cancer cases, and about 25% of early- : onset cases. The breast cancer susceptibility gene BRCA1, mapped 4 years ago to the long arm of chromosome 17, has been isolated, and a report by Miki et al will appear in Science, Oct 7. BRCAl accounts for nearly half of familial breast cancer cases. From genetic evidence the gene is a cancer suppressor, and from sequence evidence it is a DNA-binding protein. Made up of 23 exons spread over 100 kb of genomic DNA, the gene encodes a predicted product of 1863 aminoacids. This large size, and the variety of mutations found in the families studied, mean that development of a genetic test will be very difficult. RRC47 is also expressed in ovary, thymus, and testis; some kindreds with mutations in BRCA also have high rates of ovarian cancer. A second susceptibility locus, BRCA2, has been mapped to a 6-centimorgan region (very roughly 6 million bp) on chromosome 13q 12-13, as will be reported by Wooster et al in Science, Sept 30, putting BRCA2 research approximately where BRCA research was 4 years ago. The BRCA2 locus accounts for about as many familial breast cancer cases as does BRCA1, leaving a small minority of inherited susceptibility cases assignable to other genes. (Some of those other cases are related to mutations in genes that are not specific for breast cancer, such as TP53, and some are presumably related to genes unknown.) BRCA2 seems less associated with ovarian cancer than is BRCAl but perhaps more strongly associated with male breast cancer. : Futreal et al, in a companion paper to Miki et al, have examined the possible role of BRCA1 mutants in 32 breast and 12 ovarian tumours, selected without regard to family history of cancer. All of these tumours were hemizygous for the BRCAl region. But only 4 of those 44 tumours had mutations in &RC/47, and all of those mutations were inherited rather than somatic. Thus, although inherited mutations in BRCA] are important in familal breast and ovarian cancer, somatic mutations in BRCA do not seem to be important in breast cancer in general. Nevertheless, researchers hope that the study of BRCAl will lead them to other components of the tumour suppression pathway in mammary epithelium, and eventually to clinically useful findings. :
i
Paul M Rowe
cancers were detected within 3 years. All the surveillance protocols being applied by the members of the group included colonoscopy. Most members recommend that screening start at to predisposition hereditary non-polyposis 20-25 years of age. The screening protocolorectal cancer (HNPCC), it is premature to offer testing to large groups of cols recommend a 2 or 3 year interval high-risk family members until several between examinations. The group recomcrucial questions have been addressed. mends an interval of 2 years for proven gene carriers. Most members of the group They include the number of genes responsible for HNPCC and how often they are recommend surveillance for other associated cancers (eg, cancer of the endometriinvolved; the types of mutations responsium or urinary tract), but there was no ble and their nature; the false-positive and consensus on the screening protocol. The false-negative rates of DNA testing; how education about the complexities of DNA group recognised the urgent need for contesting can be provided to large numbers trolled trials to assess the effect of surveilcancer for colorectal and of potentially at-risk individuals; and the lance cancer and to determine the endometrial effectiveness of an array of pos-sible prointerval. It therefore : appropriate screening phylactic interventions. Several of these issues were addressed ’. decided to conduct such studies in proven at the sixth meeting of the International gene carriers. It also hopes to collect all Collaborative Group on HNPCC, held in mutation data from HNPCC families and Milan, Italy, on Sept 11. The members of to publish them in a regular newsletter. this group are involved in the manageThe address of the ICG-HNPCC secretariat is: ment of about 900 HNPCC families in Foundation for the Detection of Hereditary specialist centres. DNA-mutation analysis Tumours, c/o University Hospital, Rijnsburgerweg 10, Bldg 50, 2333 AA Leiden, at 15 of these centres has shown productNetherlands. inactivating mutations in at least 23 families (17 mutations in hMSH2, 4 in H F A Vasen, J-P Mecklin, P Meera Khan, hMHLl, 1 in PMS’7, and 1 in hPMS2). : H T Lynch All the mutations reported so far are unique to the family. It has been suggested that missense mutations segregating Youth as for antiwith HNPCC may cause misleading intertobacco efforts pretations of a cause-and-effect relation between the mutation and HNPCC. : 8 centres have started to counsel family The US Congress and the state legislamembers on the results of DNA-testing. tures should enact tough new legislation to discourage the use of tobacco products Most centres use a protocol that is genersimilar to that used for ally by children and youth, says a report disease and hereditary breast cancer. Lack (Growing up tobacco free) issued by the of information on the incidence of National Academy of Sciences’ Institute HNPCC and, thereby, on the frequency of Medicine.’I The panel noted that from 1964, when of the HNPCC-genes (estimates vary from 1/200-1/2000), makes it impossible the first official warning of the health hazards of tobacco was issued, to 1991, to predict accurately how many individuals require testing. The only way to solve the percentage of Americans smoking this difficulty is to do mutation screening fell from 40% to 20%. But since then in a population-based series of colorectal the percentage of smokers has remained : stable, in part because tobacco compatients. The group also discussed the effectivepanies successfully recruit new smokers ness of surveillance programmes in among children and teens by inundatHNPCC patients and families. Data from ing them with pro-tobacco images and Finland obtained from a 10-year screenmessages that lead young people to ing programme implemented among 22 believe that tobacco smoking is the HNPCC families (colonoscopy every 2-3 social norm among "attractive, vital, years) resulted in 63% fewer colorectal successful people who seek to express cancers in the screening group compared their individuality, who enjoy life, and with the control group (individuals who who are socially secure". An estimated refused surveillance or could not be 3000 young people become regular traced). Moreover, there was no colorectal smokers each day, roughly 1 million a cancer-related mortality among the group year. screened. A similar programme in 43 famTo prevent nicotine addiction among ilies in the Netherlands with a mean folthe young, society should seek to establish low-up of 6 years has shown that cancer a "tobacco-free social norm", the panel was detected at an earlier stage in the said. Just such a tobacco-free social norm screened group than in the symptomatic . seems to be taking root among Africanpatients. Disappointingly, however, 3 American youth, whose daily smoking has
advances in the genetics Although of colorectal cancer have raised the possibility of widespread DNA testing to detect recent
i
targets
Huntington’s
877
cancer
patients developed colorectal cancer within 3 years after the last negative colonoscopic examination. In the Finnish series
Screening for hereditary
genes
colorectal
cancer
2 "interval"
Three papers on major advances in familial breast cancer research are soon to be : published. The studies were done by international multilaboratory groups, in collaboration with Mark H Skolnick of : Salt Lake City, Utah. Inherited suscepti- : bility accounts for about 5% of all breast cancer cases, and about 25% of early- : onset cases. The breast cancer susceptibility gene BRCA1, mapped 4 years ago to the long arm of chromosome 17, has been isolated, and a report by Miki et al will appear in Science, Oct 7. BRCAl accounts for nearly half of familial breast cancer cases. From genetic evidence the gene is a cancer suppressor, and from sequence evidence it is a DNA-binding protein. Made up of 23 exons spread over 100 kb of genomic DNA, the gene encodes a predicted product of 1863 aminoacids. This large size, and the variety of mutations found in the families studied, mean that development of a genetic test will be very difficult. RRC47 is also expressed in ovary, thymus, and testis; some kindreds with mutations in BRCA also have high rates of ovarian cancer. A second susceptibility locus, BRCA2, has been mapped to a 6-centimorgan region (very roughly 6 million bp) on chromosome 13q 12-13, as will be reported by Wooster et al in Science, Sept 30, putting BRCA2 research approximately where BRCA research was 4 years ago. The BRCA2 locus accounts for about as many familial breast cancer cases as does BRCA1, leaving a small minority of inherited susceptibility cases assignable to other genes. (Some of those other cases are related to mutations in genes that are not specific for breast cancer, such as TP53, and some are presumably related to genes unknown.) BRCA2 seems less associated with ovarian cancer than is BRCAl but perhaps more strongly associated with male breast cancer. : Futreal et al, in a companion paper to Miki et al, have examined the possible role of BRCA1 mutants in 32 breast and 12 ovarian tumours, selected without regard to family history of cancer. All of these tumours were hemizygous for the BRCAl region. But only 4 of those 44 tumours had mutations in &RC/47, and all of those mutations were inherited rather than somatic. Thus, although inherited mutations in BRCA] are important in familal breast and ovarian cancer, somatic mutations in BRCA do not seem to be important in breast cancer in general. Nevertheless, researchers hope that the study of BRCAl will lead them to other components of the tumour suppression pathway in mammary epithelium, and eventually to clinically useful findings. :
i
Paul M Rowe
cancers were detected within 3 years. All the surveillance protocols being applied by the members of the group included colonoscopy. Most members recommend that screening start at to predisposition hereditary non-polyposis 20-25 years of age. The screening protocolorectal cancer (HNPCC), it is premature to offer testing to large groups of cols recommend a 2 or 3 year interval high-risk family members until several between examinations. The group recomcrucial questions have been addressed. mends an interval of 2 years for proven gene carriers. Most members of the group They include the number of genes responsible for HNPCC and how often they are recommend surveillance for other associated cancers (eg, cancer of the endometriinvolved; the types of mutations responsium or urinary tract), but there was no ble and their nature; the false-positive and consensus on the screening protocol. The false-negative rates of DNA testing; how education about the complexities of DNA group recognised the urgent need for contesting can be provided to large numbers trolled trials to assess the effect of surveilcancer for colorectal and of potentially at-risk individuals; and the lance cancer and to determine the endometrial effectiveness of an array of pos-sible prointerval. It therefore : appropriate screening phylactic interventions. Several of these issues were addressed ’. decided to conduct such studies in proven at the sixth meeting of the International gene carriers. It also hopes to collect all Collaborative Group on HNPCC, held in mutation data from HNPCC families and Milan, Italy, on Sept 11. The members of to publish them in a regular newsletter. this group are involved in the manageThe address of the ICG-HNPCC secretariat is: ment of about 900 HNPCC families in Foundation for the Detection of Hereditary specialist centres. DNA-mutation analysis Tumours, c/o University Hospital, Rijnsburgerweg 10, Bldg 50, 2333 AA Leiden, at 15 of these centres has shown productNetherlands. inactivating mutations in at least 23 families (17 mutations in hMSH2, 4 in H F A Vasen, J-P Mecklin, P Meera Khan, hMHLl, 1 in PMS’7, and 1 in hPMS2). : H T Lynch All the mutations reported so far are unique to the family. It has been suggested that missense mutations segregating Youth as for antiwith HNPCC may cause misleading intertobacco efforts pretations of a cause-and-effect relation between the mutation and HNPCC. : 8 centres have started to counsel family The US Congress and the state legislamembers on the results of DNA-testing. tures should enact tough new legislation to discourage the use of tobacco products Most centres use a protocol that is genersimilar to that used for ally by children and youth, says a report disease and hereditary breast cancer. Lack (Growing up tobacco free) issued by the of information on the incidence of National Academy of Sciences’ Institute HNPCC and, thereby, on the frequency of Medicine.’I The panel noted that from 1964, when of the HNPCC-genes (estimates vary from 1/200-1/2000), makes it impossible the first official warning of the health hazards of tobacco was issued, to 1991, to predict accurately how many individuals require testing. The only way to solve the percentage of Americans smoking this difficulty is to do mutation screening fell from 40% to 20%. But since then in a population-based series of colorectal the percentage of smokers has remained : stable, in part because tobacco compatients. The group also discussed the effectivepanies successfully recruit new smokers ness of surveillance programmes in among children and teens by inundatHNPCC patients and families. Data from ing them with pro-tobacco images and Finland obtained from a 10-year screenmessages that lead young people to ing programme implemented among 22 believe that tobacco smoking is the HNPCC families (colonoscopy every 2-3 social norm among "attractive, vital, years) resulted in 63% fewer colorectal successful people who seek to express cancers in the screening group compared their individuality, who enjoy life, and with the control group (individuals who who are socially secure". An estimated refused surveillance or could not be 3000 young people become regular traced). Moreover, there was no colorectal smokers each day, roughly 1 million a cancer-related mortality among the group year. screened. A similar programme in 43 famTo prevent nicotine addiction among ilies in the Netherlands with a mean folthe young, society should seek to establish low-up of 6 years has shown that cancer a "tobacco-free social norm", the panel was detected at an earlier stage in the said. Just such a tobacco-free social norm screened group than in the symptomatic . seems to be taking root among Africanpatients. Disappointingly, however, 3 American youth, whose daily smoking has
advances in the genetics Although of colorectal cancer have raised the possibility of widespread DNA testing to detect recent
i
targets
Huntington’s
877