Search PubMed⌕ Search

Biomedical subjects

J Peto

Publications and source records attributed to J Peto.

At least 37 records · Page 2Linked to original sources
PubMed2000

High constant incidence in twins and other relatives of women with breast cancer.

The incidence of breast cancer rises steeply between ages 25 and 50, and more slowly thereafter. In contrast, the incidence in the unaffected (contralateral) breast of women who have had breast cancer remains constant at about 0.7% per year for at least the next 20 years after diagnosis, irrespective of age at first diagnosis. The incidence in relatives of the patients seems to show a similar pattern. The incidence in a prospective study of monozygotic twins of patients was approximately constant at 1.3% per year (77 cases), again about 0.7% per breast. At ages older than a patient's age at diagnosis, her mother and sisters have an incidence of 0.3-0.4% per year. Above the index patient's age at diagnosis, the rate in relatives shows no temporal trend and is independent of the patient's age at diagnosis. A statistically simple explanation is that incidence in susceptible women increases to a high constant level by a predetermined age that varies between families, but this seems inconsistent with conventional models of carcinogenesis and susceptibility. The very high incidence in monozygotic twins of patients indicates that a high proportion, and perhaps the majority, of breast cancers arise in a susceptible minority of women.

Adult↗
PubMed2000

Completeness of cancer registration: a new method for routine use.

We report a new method of estimating the completeness of cancer registration, in which the proportions of unregistered patients are derived from the time distributions of three probabilities, each of which can be directly estimated from the registry's own data--the probabilities of survival, of registration of the cancer during the patient's life, and of the mention of cancer on the death certificate of a cancer patient who dies. This method allows completeness to be assessed routinely by factors such as age, sex, geographical area and tumour type.

Death Certificates↗
PubMed2000

Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort.

To distinguish risk factors for acquisition of cervical human papillomavirus (HPV) infection from the determinants of neoplasia among infected individuals we have conducted a three-arm case-control study nested within a large population-based cohort of women (the Manchester cohort) screened for HPV at entry using L1 consensus primer PCR. The study includes 181 HPV-positive controls who did not develop high-grade cervical intraepithelial neoplasia (CIN3) during follow-up, 203 HPV-negative controls, and 199 HPV-positive cases with histologically confirmed CIN3. Detailed information on sexual, reproductive and gynaecological history, oral contraceptive use and smoking was obtained at face-to-face interview. There was a striking division between risk factors for infection and those predictive of disease. Comparing the HPV-positive against the HPV-negative controls, the only risk factors for infection were number of sexual partners (OR for six or more = 3.89; 95% Cl = 1.99-7.62), a relatively recent new sexual relationship (OR for a new partner within the previous 2 years = 4.17; 95% Cl = 2.13-8.33), and a history of previous miscarriage (OR = 2.59; 95% Cl = 1.28-5.21). The determinants of CIN3 among infected women were, in contrast, early age at first intercourse (OR for 16 years old or less = 3.23; 95% Cl = 1.33-7.69), a long time since starting a new sexual relationship (OR for 6 years or more = 4.94; 95% Cl = 2.51-9.71), and cigarette smoking, with strong evidence for a dose- response (OR for current smoking habit 20+ per day = 2.57; 95% Cl = 1.49-4.45). Oral contraceptive use was not significantly associated with either HPV infection or CIN3.

Adult↗
PubMed2000

The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2.

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families. Breast cancers in non-BRCA1/2 families were of lower grade (P = 0.0018), showed fewer mitoses (P < 0.0001), less nuclear pleomorphism (P = 0.0014), less lymphocytic infiltrate (P < 0.0001), a lesser extent of the tumor with a continuous pushing margin (P = 0.004), a lesser extent of the tumor composed of solid sheets of cells (P = 0.0047), less necrosis (P = 0.002), and wereparison with BRCA2 tumors, non-BRCA1/2 tumors were lower grade (P = 0.017) and exhibited less pleomorphism (P = 0.01) and more tubule formation (P = 0.05). In comparison with control breast cancers unselected for a family history of the disease, non-BRCA1/2 tumors were of significantly lower grade (P = 0.001), showed less pleomorphism (P = 0.0002), and had a lower mitotic count (P = 0.003). The results indicate that non-BRCA1/2 breast cancers differ histologically from both BRCA1 and BRCA2 breast cancers and are overall of lower grade. They also suggest that non-BRCA1/2 breast cancers differ from nonfamilial breast cancers, but these differences may be attributable to various types of bias.

BRCA2 Protein↗
PubMed2000

An age, period and cohort analysis of pleural cancer mortality in Europe.

Death certification data from pleural cancer in eight European countries providing data to the World Health Organization database over the period 1970-1994 were analysed using a log-linear Poisson model to disentangle the effects of age, birth cohort and period of death. The age effect reached values between 10 and 15/100,000 males at age 80-84 in most countries, except Hungary (6.7), Switzerland (18.0), France (20.6) and the Netherlands (36.5). Cohort effects were steadily and appreciably upwards in all countries up to the generations born in 1940 or 1945, and levelled off for the 1950 cohort, except in Hungary, where persistent rises were observed. Thus, most rises in pleural cancer mortality in Europe were on a cohort of birth basis. Since most pleural cases were asbestos-related mesotheliomas, and since asbestos has an early-stage effect on subsequent mesothelioma risk, exposure early in life is important for determining the subsequent mesothelioma risk of each generation. Consequently, the data indicate that the peak mortality from pleural cancer in most western European countries will be reached in the first decades of the 21st century, i.e. around 2010-2020, when the generations born between 1940 and 1950 will reach the peak age for mesothelioma incidence and mortality. This contrasts with US data, where the peak of pleural cancer incidence has been reached at the end of the 20th century, and reflects a delay in adopting adequate prevention measures since the 1940-1945 generations entered the workforce in the 1960s, when cancer risk from asbestos exposure was already recognized.

Adult↗
PubMed1999

Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.

BACKGROUND: Mutations in the BRCA1 and BRCA2 genes are found in most families with cases of both breast and ovarian cancer or with many cases of early-onset breast cancer. However, in an outbred population, the prevalence of BRCA1 and BRCA2 mutations in patients with breast cancer who were unselected for a family history of this disease has not been determined. METHODS: Mutations in the BRCA1 and BRCA2 genes were detected in blood samples from two population-based series of young patients with breast cancer from Britain. RESULTS: Mutations were detected in 15 (5.9%) of 254 women diagnosed with breast cancer before age 36 years (nine [3.5%] in BRCA1 and six [2.4%] in BRCA2) and in 15 (4.1%) of 363 women diagnosed from ages 36 through 45 years (seven [1.9%] in BRCA1 and eight [2.2%] in BRCA2). Eleven percent (six of 55) of patients with a first-degree relative who developed ovarian cancer or breast cancer by age 60 years were mutation carriers, compared with 45% (five of 11) of patients with two or more affected first- or second-degree relatives. The standardized incidence ratio for breast cancer in mothers and sisters was 365 (five observed and 1.37 expected) for 30 mutation carriers and 199 (64 observed and 32.13 expected) for 587 noncarriers. If we assume recent penetrance estimates, the respective proportions of BRCA1 and BRCA2 mutation carriers are 3.1% and 3.0%, respectively, of patients with breast cancer who are younger than age 50 years, 0.49% and 0.84% of patients with breast cancer who are age 50 years or older, and 0.11% and 0.12% of women in the general population. CONCLUSIONS: Mutations in the BRCA1 and BRCA2 genes make approximately equal contributions to early-onset breast cancer in Britain and account for a small proportion of the familial risk of breast cancer.

Adult↗
PubMed1999

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.

Antibodies, Viral↗
PubMed1999

The European mesothelioma epidemic.

Projections for the period 1995-2029 suggest that the number of men dying from mesothelioma in Western Europe each year will almost double over the next 20 years, from 5000 in 1998 to about 9000 around 2018, and then decline, with a total of about a quarter of a million deaths over the next 35 years. The highest risk will be suffered by men born around 1945-50, of whom about 1 in 150 will die of mesothelioma. Asbestos use in Western Europe remained high until 1980, and substantial quantities are still used in several European countries. These projections are based on the fit of a simple age and birth cohort model to male pleural cancer mortality from 1970 to 1989 for six countries (Britain, France, Germany, Italy, The Netherlands and Switzerland) which together account for three-quarters of the population of Western Europe. The model was tested by comparing observed and predicted numbers of deaths for the period 1990-94. The ratio of mesothelioma to recorded pleural cancer mortality has been 1.6:1 in Britain but was assumed to be 1:1 in other countries.

Adult↗
PubMed1999

Low frequency of germline E-cadherin mutations in familial and nonfamilial gastric cancer.

Little is known about the relative contributions of genetic and environmental factors to the development of gastric cancer. Mutations in the cell adhesion molecule E-cadherin are recognized to be associated with the development of undifferentiated, diffuse and invasive gastric cancers. A recent study of two gastric cancer families has shown that germline mutations in the E-cadherin gene can be causative (Guilford P et al, Nature 1998; 26: 402-405). We have examined the E-cadherin gene for constitutive mutations in a systematic series of 106 gastric cancer patients, 10 with a family history of the disease and 96 sporadic cases. No pathogenic mutations were observed in any of the 106 patients. The results indicate that germline mutations in E-cadherin will not account for more than 3% of gastric cancers.

Adenocarcinoma↗
PubMed1998

p53 mutation with frequent novel condons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours.

The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P<0.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16INK4, Ki-ras and beta-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not reflect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF beta type II receptor (TGF beta IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21Waf1 was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21Waf1. These data do not support, therefore, the simple model based on studies of BRCA-/- embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21Waf1 expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.

BRCA1 Protein↗
PubMed1998

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Adult↗
PubMed1998

Predicted anti-oestrogen resistance in BRCA-associated familial breast cancers.

There is controversy concerning the prognosis of breast cancers arising in women carrying loss of function mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. This study was carried out to assess the likely hormone dependence of this group of tumours in comparison with an age and grade matched group of control sporadic tumours. We used quantitative immunohistochemical analysis for the oestrogen receptor (ER), progesterone receptor (PgR), cyclin D1 and pS2 on sections of primary tumours and ductal carcinoma in situ (DCIS). Expression of PgR (P < 0.05) and cyclin D1 (P < 0.01) was low in the BRCA1- and BRCA2-associated cancers compared with sporadic cases. The low frequency of expression of ER (9/40), PgR (2/40) cyclin D1 (5/36) and pS2 (5/36) in the familial tumours indicates that the majority of such tumours will be oestrogen insensitive and unlikely to respond to hormonal manipulation even at the in situ stage in their evolution. The low level of PgR (2/40 cases) suggests that there may be some abnormality of transactivating function of the ER in these tumours.

Adult↗
PubMed1998

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Adult↗
PubMed1997

Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

Adult↗
PubMed1997

Human papillomavirus type 16 sequence variation in cervical cancers: a worldwide perspective.

We examined intratype human papillomavirus type 16 (HPV-16) sequence variation in tumor samples that were collected and analyzed in an international study of invasive cervical cancer. The collection included tumors from 22 countries in five continents. Using our recently developed E6 and L1 PCR-based hybridization systems to distinguish HPV-16 variant lineages, we analyzed material from tumors previously found to contain HPV-16 DNA. Of 408 specimens analyzed in the E6 hybridization assay, 376 (92.2%) belonged to previously reported HPV-16 variant lineages. The remaining 32 specimens (7.8%) harbored HPV-16 variants with novel hybridization patterns, novel nucleotide changes, or both. Nucleotide sequences (1,203 bp) were determined for the E6, the MY09/11 region of L1, and the long control region of each novel variant and representative specimens from each hybridization pattern observed. Based on E6 hybridization patterns, most of the variants from European and North American samples were phylogenetically classified as European prototype (E) while samples from Africa contained primarily African 1 (Af1) or African 2 (Af2) variants. The majority of Asian (As) variants were observed in Southeast Asia, and almost all Asian American (AA) variants were from Central and South America or Spain. A single North American 1 (NA1) variant was detected in a tumor from Argentina. Nucleotide changes previously shown to covary between the MY09/11 region of L1 and the E6 coding region were examined in a subset of 249 specimens. We observed 22 combined E6-L1 hybridization patterns, of which 11 (in 21 samples) were novel. No unanticipated nucleotide covariation was observed between the E class and the AA-Af1-Af2-NA1 classes, suggesting the absence or rarity of genomic recombination between HPV-16 lineages. This extensive description of HPV-16 variants forms a basis for further examining the relationship between intratype variation and basic functional differences in biological activities. HPV-16 variants may prove important for the determination of the risk of cervical neoplasia and for the design of HPV-16 vaccine strategies.

Capsid Proteins↗
PubMed1996

Cancer mortality in relatives of women with breast cancer: the OPCS Study. Office of Population Censuses and Surveys.

Mortality from cancer and other causes in male and female first-degree relatives of women with breast cancer diagnosed before age 60 has been examined in a large population-based cohort study, providing estimates of familial risks free from ascertainment or recall bias. Relatives of 3,295 patients with breast cancer diagnosed in the UK between 1954 and 1981 were identified through a register of households established in 1939. The 11,678 first-degree relatives thus identified were followed up through national records until the end of 1992. Over this period 5,421 deaths (including 1,527 cancer deaths) occurred in these relatives. Mortality from breast cancer was significantly raised in first-degree relatives (SMR 187, 248 deaths), and there was also significant excess mortality from cancers of the larynx (SMR 177, 17 deaths), endometrium (SMR 166, 29 deaths) and unspecified neoplasms (SMR 153, 70 deaths). The SMR for ovarian cancer was 130, based on 58 deaths (p = 0.06). There was no marked excess for other sites or for non-neoplastic causes of death, but there was a significant deficit in mortality from cervical cancer (SMR 63, 18 deaths). The SMR for breast cancer increased significantly with decreasing age of the relative. After allowing for age, sisters of cases had a slightly (though non-significantly) higher risk than mothers (ratio of SMRs 1.22). These results, together with penetrance estimates from linked families, suggest that approximately one woman in 800 carries BRCAI, the susceptibility gene on chromosome 17q, and that this gene causes about 1% of all breast cancers.

Adult↗
PubMed1996

Cancer mortality in relatives of women with ovarian cancer: the OPCS Study. Office of Population Censuses and Surveys.

Mortality from cancer and other causes in first-degree relatives of women with ovarian cancer diagnosed before age 60 has been examined in a large population-based cohort study in England and Wales. Relatives of 1,188 ovarian-cancer cases diagnosed between 1954 and 1981 were identified through a register of households established in 1939. Some 4,111 first-degree relatives living in the same household and having the same surname as the index case were followed up through national records until the end of 1992. Over this period, 1,950 deaths (including 574 cancer deaths) occurred in the relatives. Mortality rates within the cohort were compared with age-, sex- and period-adjusted mortality rates for England and Wales. Mortality from ovarian cancer in first-degree relatives was significantly raised (SMR 223, 95% CI 155-310) although the excess was smaller than that found in case-control studies. The SMR increased with decreasing age of the relative, though not with decreasing age of the index case. After allowing for age, sisters of cases had higher ovarian-cancer mortality than mothers (sister:mother SMR ratio 1.89, p = 0.06). The SMR was greater in individuals having 2 first-degree relatives with ovarian cancer (4 deaths versus 0.17 expected, SMR 242). Relatives of ovarian cancer cases also had significantly increased mortality from cancers of the stomach (SMR 146, 69 deaths) and rectum (SMR 150, 33 deaths), and increased mortality from colon cancer, breast cancer and pancreatic cancer which failed to reach statistical significance. Individuals having a relative with colorectal cancer and a relative with ovarian cancer showed a high mortality from both cancers (11 colorectal-cancer deaths versus 1.23 expected, 4 ovarian-cancer deaths versus 0.66 expected.

Adult↗