Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies.

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.

Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

CYP17 promoter polymorphism and breast cancer risk in males and females in relation to BRCA2 status.

A T-C polymorphism in the promoter region of the CYP17 gene has been associated with male and female breast cancer risk as well as early-onset familial breast cancer. The potential role of this polymorphism was investigated in relation to breast cancer risk in Icelandic male and female carriers and noncarriers of a BRCA2 mutation. The study population consisted of 39 male and 523 female breast cancer cases and 309 male and 395 female controls. Of the cases, 15 males and 55 females carried a BRCA2 mutation. We did not find a significant association between male breast cancer risk and CYP17 genotypes. Among male breast cancer cases, the frequency of the CC genotype was higher among carriers of the 999del5 mutation (33.3%) than noncarriers (16.7%), although this difference also did not reach a statistical significance. No association was observed with breast cancer risk among females irrespective of menopausal status, stage of the disease or BRCA2 status. Our findings do not indicate a role for the CYP17 T-C polymorphism in female breast cancer, but a role in male carriers of a BRCA2 mutation could not be excluded because of the small sample size.

[Changes in the prevalence of disability pension in Iceland 1976-1996.].

OBJECTIVE: To determine changes in the prevalence of disability pension in Iceland and to describe the distribution of those receiving disability pension according to gender, age and main diagnoses between the years 1976 and 1996. MATERIAL AND METHODS: The study includes all those receiving disability pension on the 1st of December in the years 1976 and 1996 as ascertained by the disability register at the State Social Security Institute of Iceland. There are two levels of disability pension, full disability pension (disability assessed as being more than 75%) and reduced disability pension (disability assessed as being 50% or 65%). Information on age and gender distribution of the Icelandic population was obtained. Age-standardized risk ratio between the years 1976 and 1996 was calculated for both pension levels combined and for full disability pension alone. RESULTS: There was no significant change in crude prevalence rate for both pension levels combined between the years 1976 and 1996, when the increase in the population was accounted for but without paying attention to changes in gender or age distribution. However, the standardized risk ratio showed a significantly decreased risk for both pension levels combined both for men and women in the year 1996 as compared with the year 1976, the age-standardized risk ratio being 0.95 and 0.93 respectively. It also showed a significant change between pension levels with an increased risk of full disability pension and a decreased risk of reduced disability pension. The increase in full disability pension was noted for both males and females and was largely independent of age. There was a significant increase in full disability pension in most disease categories. Disability due to diseases of the nervous system and sense organs and injury and poisoning increased amongst women only. A significant decrease in full disability pension due to infections and diseases of the digestive system occurred in both men and women. CONCLUSION: The prevalence of a disability pension amongst men and women in the year 1996 as compared to the year 1976 was significantly decreased when changes in population size and age distribution had been accounted for. This is particularly interesting because unemployment was increasing just prior to the year 1996. The prevalence of full disability pension had however significantly increased in 1996 compared with 1976. A plausible explanation for the observed change in disability pension levels is a pressure from the labour market, with increasing unemployment and competition. Also, the introduction of a disability card for those with full disability pension in 1980, which granted lower price for medication and the services of physicians, is likely to have increased the pressure for the higher level of disability pension (full disability pension). It seems unlikely that the increase in full disability pension and the decrease in reduced disability pension is due to a deterioration of health of the Icelandic population. Increased disability due to injury and poisoning amongst women is probably a result of their increased participation in the labour market. The decrease in disability due to infections is a result of a reduction in the number of cases of tuberculosis and poliomyelitis. The decrease in disability due to diseases of the digestive system is probably a result of improvement in the treatment of oesophageal reflux and peptic ulcer.

[Incidence of disability in Iceland before and after introduction of a new method of disability evaluation.].

OBJECTIVE: To assess changes in disability evaluation, since the introduction on September 1st 1999 of a new assessment method based on the British functional capacity evaluation, "All work test". Previously, the disability assessment was based on the applicant's medical, social and financial circumstances. MATERIAL AND METHODS: The study includes all those having their disability assessed for the first time at the State Social Security Institute of Iceland in 1997, 1998 and 2000. Information was obtained from the disability register on degree of disability, gender, age and primary diagnoses. RESULTS: After the introduction of the new assessment method, there has been a significant increase in the number of women who have disability more then 75% (p<0.0001). This increase occurs amongst women older than 30 years, having musculoskeletal disorders (mainly soft tissue disorders). There has also been a slight (statistically insignificant) increase in more than 75% disability amongst men (p=0.25). The number of people who have had their disability evaluated as 50-65% has decreased (p<0.0001). No significant change in the total number of new disability pensioners (having their disability assessed as being more than 75% or 50-65%) was observed. CONCLUSIONS: The new method of disability assessment has resulted in a significant rise in the number of women who have had their disability assessed as being more than 75%, but there has not been a rise in the total number of new disability pensioners, as the increased number of women with the higher degree of disability has been balanced by a significant fall in the number of new disability pensioners with the lower degree of disability.

[Educational level, occupation and income of those who became disability pensioners in Iceland in the year 1997.].

INTRODUCTION: All claims for disability benefits in Iceland are managed by the State Social Security Institute of Iceland. The decision to grant a claimant disability benefits was until September 1999 mainly based on medical certificates but social and economic factors were also taken into consideration. As information on social and economic conditions in medical certificates is limited it was decided to investigate these factors particularly. In this paper a comparison of educational level, employment, and income is made between new recipients of disability benefits and a random sample of the Icelandic nation. MATERIAL AND METHODS: All new recipients of disability benefits (full disability pension, partial disability pension and rehabilitation pension) in 1997 were contacted by phone and asked to answer a questionnaire. Their answers were compared with those obtained in a national survey carried out by the Institute of Social Sciences at the University of Iceland in 1996 and 1997 with a sample representing accurately the Icelandic population in terms of gender, age and place of residence. Information about average income of disability pensioners was obtained and compared to that of people in employment. RESULTS: Educational level of those receiving disability benefits was considerably lower than expected in comparison with the population and unskilled workers were overrepresented. Contrary to what might be expected a larger proportion of the recently disabled have been employed at some time than is the case for the national sample, even though 63.6% of the new disability pensioners were women. Considerable number of those receiving disability benefits were still in employment, particularly those with partial disability pension. Mean monthly income of Icelanders participating in the labour market was almost twice that received by those on disability benefits. CONCLUSIONS: Since lower educational level and more restricted employment opportunities characterize disability pensioners as compared to the nation, it seems likely that more varied occupational rehabilitation and educational opportunities could improve the situation of those who have had to leave the labour market because of ill health, lack of education and poor working conditions.

Population-based study of risk of breast cancer in carriers of BRCA2 mutation.

BACKGROUND: Estimates of an 80-90% risk of breast cancer for carriers of germline mutations in the BRCA1 and BRCA2 genes are based on studies of families at high risk of breast cancer. Risk estimates for a population are possible if the mutation status of a representative sample of that population can be assessed. In Iceland, one common founder BRCA2 mutation occurs in 0.6% of the population. Iceland has a population-based cancer registry and a large collection of pedigrees, and estimation of cancer risk in mutation carriers is therefore possible. METHODS: We studied 575 breast-cancer patients, 541 women and 34 men unselected for family history of breast cancer. Data on cancer in first-degree relatives were available from the cancer registry. Risk of cancer was estimated by comparing the history of cancer in first-degree relatives of carriers and non-carriers. FINDINGS: 56 (10.4%) of the 541 women and 13 (38%) of the 34 men carried the 999del5 mutation. The estimated risk of breast cancer at age 50 for all female carriers of the 999del5 mutation was 17.0% (95% CI 9.1-25.9) and 37.2% (22.4-53.9) at age 70. INTERPRETATION: The results of our population-based study show that the mean risk of breast cancer in carriers of mutation in BRCA2 is lower than previously suggested. Individual risk assessment will, however, have to take account of family history.

BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability.

The products of the BRCA breast cancer susceptibility genes have been implicated in cell cycle control and DNA repair. It has been suggested that mutations in the p53 gene are a necessary step in tumorigenesis in BRCA tumors. We tested samples from 402 breast cancer patients for germ-line BRCA2 and p53 mutations in tumors. p53 mutations are more frequent in BRCA2 mutation carriers than they are in controls. Tumors with mutations in either gene had multiple chromosomal abnormalities, as shown by cytogenetic analysis.

Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters.

The pattern of loss of heterozygosity (LOH) on chromosome 17 in human breast cancer is complicated and shows many different regions of loss. In an attempt to narrow down the relevant regions of LOH on chromosome 17, we have studied the deletion pattern and its association with clinical parameters in 1280 breast carcinoma-venous blood lymphocyte pairs. In total, 42 different chromosome 17 loci were investigated, and between 25 and 625 cases were analyzed at each locus. The frequency of LOH observed on the p arm was much higher than that observed on the q arm. The opposite effect was observed in 52 ovarian cancer cases investigated, with less LOH on 17p than on 17q. Patterns of loss consistent with interstitial and terminal deletions, as well as loss of either the p or q arm or monosomy 17 were observed. To determine whether loss at particular loci may be associated with biological features of breast tumors, clinical data including age of onset, family history of breast cancer, tumor histopathology, tumor size, estrogen receptor (ER) status, and occurrence of lymph node or distant metastases were collected for each case. Overall, large-sized, ER-negative, lymph node-positive ductal tumors showed the highest frequencies of LOH, with ER-negative and ductal tumors showing LOH for markers along the majority of the chromosome. Eight regions of chromosome 17 appear to be associated with human breast cancer, two on 17p and six on 17q. These regions were not necessarily in the areas exhibiting the highest frequencies of LOH but were defined by interstitial and terminal deletions in multiple independent cases. Seven of these regions showed statistically significant differences in LOH associated with clinical parameters. These data strongly suggest that loci on chromosome 17 may determine aspects of tumor presentation and disease behavior in human breast cancer and pinpoint candidate tumor suppressor gene loci.

[Disability in Iceland 1996: size and characteristics.].

OBJECTIVE: To determine the size and main medical and social characteristics of the group of individuals receiving disability benefits in Iceland and compare those with figures from the other Nordic countries. MATERIAL AND METHODS: The study includes all those receiving disability benefits on the 1st of December 1996 as ascertained by the disability register at the State Social Security Institute of Iceland. RESULTS: On the prevalence day 8714 individuals were receiving disability benefits. Of those there were 7315 individuals who had disability assessed as being more than 75% (4.2% of the total population between 16 and 66 years of age); women: 4286 (58.6%), men: 3029 (41.4%). Disability was assessed as being 50% or 65% for 1399 individuals (0.7% of the total population between 16 and 66 years of age); women: 914 (65.3%), men: 485 (34.7%). Of those receiving disability benefits there is thus a significant excess of women (p<0.0001). Individuals with >75% disability are in excess in the capital region as compared with other areas (p<0.001 for men, p=0.03 for women). When different age groups within the population are compared there is a steady increase with age of the ratio of individuals with >75% disability. Disability is most commonly associated with mental disorders or diseases of the musculoskeletal system. CONCLUSION: The percentage of the total population receiving disability benefits in Iceland, is similar to that in Denmark but considerably lower than in Finland, Norway and Sweden. When different age groups are compared it emerges that there are more individuals below 30 years of age receiving disability benefits in Iceland than in the other Nordic countries. In the older age groups this ratio is reversed and gets more marked with increasing age. The following main explanations for this difference are suggested: the level of allowance and organization of the social security system is different in Iceland compared with the other Nordic countries; the Icelandic unemployment level is lower and work participation higher, especially in the upper age groups in Iceland.

BRCA2 mutation in Icelandic prostate cancer patients.

Molecular genetic analysis of prostate cancer has gained considerable attention in recent years. The hope is to find genetic markers that can help to determine which patients are likely to develop a progressive or lethal disease and would therefore benefit from early treatment. The BRCA2 gene on chromosome 13 has been associated with familial male and female breast cancer. A founder mutation in this gene has been detected in the Icelandic population. This is a 5-bp deletion that leads to an early termination and truncated protein. Clustering of prostate cancers in some of the Icelandic BRCA2 families implies that mutation carriers are at increased risk of developing cancer of the prostate. The aim of the study was to investigate this mutation in Icelandic prostate cancer patients related to BRCA2 positive breast cancer probands and to estimate the prevalence of this mutation in unselected prostate cancer patients. To examine the potential role of this mutation in prostate cancer we analyzed prostate cancer cases from 16 BRCA2 families and all available samples from individuals diagnosed with prostate cancer in Iceland over a period of 1 year. The risk ratio of prostate cancer was 4.6 (1.9-8.8) in first-degree relatives and 2.5 (1.2-4.6) in second-degree relatives of the 16 BRCA2 positive breast cancer probands. Of 26 prostate cancer cases found in these families 12 were analyzed, and 8 of these (66.7%) had the BRCA2 mutation. All of these patients developed an advanced disease, and all have died of prostate cancer (median survival 22.5 months). Among unselected cases 3.1% (2/65) had the mutation and developed an advanced disease as well. This specific mutation in the BRCA2 gene is found in a subset of Icelandic prostate cancer cases and appears to be a marker for poor prognosis.

Anxiety disorders: a result of long-term chronic fatigue--the psychiatric characteristics of the sufferers of Iceland disease.

OBJECTIVE: In order to clarify the lifetime likelihood of developing psychiatric disorder following the Akureyri disease, we have investigated 55 well documented cases of the Akureyri disease. MATERIALS AND METHODS: All participants were interviewed and diagnosed as to psychiatric disorders according to DSM-III. RESULTS: Of the 55 subjects included in this analysis 53 were women. The mean age of the participants was 67.7 years. The most common problem was agoraphobia with panic attacks 12.7% (P < 0.0001); agoraphobia without panic attacks 21.8% (P < 0.0001); social phobia 14.5% (P < 0.001); simple phobia 18.1% (P < 0.05); schizophrenia 3.6% (P < 0.01); and alcohol dependence 5.4% (P < 0.05). CONCLUSION: Prolonged chronic fatigue most commonly results in anxiety disorders. Following the infection, the more serious psychiatric disorders do not seem to play a major role in the long run.

Study of a single BRCA2 mutation with high carrier frequency in a small population.

Germ-line changes in the cancer-predisposition gene BRCA2 are found in a small proportion of breast cancers. Mutations in the BRCA2 gene have been studied mainly in families with high risk of breast cancer in females, and male breast cancer also has been associated with BRCA2 mutations. The importance of germ-line BRCA2 mutations in individuals without a family history of breast cancer is unknown. The same BRCA2 mutation has been found in 16/21 Icelandic breast cancer families, indicating a founder effect. We determined the frequency of this mutation, 999del5, in 1,182 Icelanders, comprising 520 randomly selected individuals from the population and a series of 632 female breast cancer patients (61.4% of patients diagnosed during the study period) and all male breast cancer patients diagnosed during the past 40 years. We detected the 999del5 germ-line mutation in 0.6% of the population, in 7.7% of female breast cancer patients, and in 40% of males with breast cancer. The mutation was strongly associated with onset of female breast cancer at age <50 years, but its penetrance and expression are varied. A number of cancers other than breast cancer were found to be increased in relatives of mutation carriers, including those with prostate and pancreatic cancer. Furthermore, germ-line BRCA2 mutation can be present without a strong family history of breast cancer. Comparison of the age at onset for mother/daughter pairs with the 999del5 mutation and breast cancer indicates that age at onset is decreasing in the younger generation. Increase in breast cancer incidence and lower age at onset suggest a possible contributing environmental factor.

A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.

The BRCA2 gene on chromosome 13 has been shown to be associated with familial male and female breast cancer. Here we describe a study on BRCA2 in 21 Icelandic families, including 9 with male breast cancer. We have previously reported linkage to the BRCA2 region in an Icelandic male breast cancer family and subsequently found a strong indication of linkage to BRCA2 and the same BRCA2 haplotype in breast cancer cases from 15 additional families, indicating a common origin. We describe a five base-pair deletion in exon 9 of BRCA2 in an affected male from the male breast cancer family. The same mutation occurs in all the families with the shared BRCA2 haplotype indicating a founder effect. Among mutation carriers there are 12 males with breast cancer, which accounts for 40% of all males diagnosed with breast cancer in Iceland over the past 40 years. Three of them have no family history of breast cancer indicating that this mutation may have variable penetrance. The same BRCA2 mutation appears to be associated with different cancer phenotypes in this population including male and female breast cancer, prostate cancer, pancreas cancer and ovarian cancer.

The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.

Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.

Male breast cancer in Iceland.

All malignant tumours of the male breast diagnosed in Iceland during the 40-year period 1955-1994 were studied with regard to histological classification, tumour grading and flow cytometric analysis. Of 31 malignant tumours diagnosed, 29 were primary breast carcinomas. Male breast carcinoma constitutes 1% of all breast malignancies in Iceland and 0.25% of all malignant tumours in males. About 80% of the male breast carcinomas were diagnosed during the latter half of the study period. The mean age of the patients was 66.3 years and the left-to-right ratio was 1.9:1.0. Right-sided tumours appeared to be more aggressive. The mean tumour size was 2.6 cm. The vast majority of the carcinomas (79%) were of the infiltrating ductal type. Of these 21.7% were grade I, 43.5% were grade II and 34.8% grade III. Papillary carcinomas made up 17% of the total. These occurred in slightly older patients than the infiltrating ductal carcinomas and were diploid tumours. In this study 57% of the tumours were found to be aneuploid, but nearly 70% of the invasive ductal carcinomas NOS were aneuploid. In general, the aneuploid tumours were larger, of higher average histological grade and had a higher mean S-phase value. The overall mean S-phase fraction was 7.2% which is similar to that found in female breast tumours in Iceland. It is concluded that male-to-female ratio of breast carcinoma in Iceland is similar to that found in other Western countries. The age-standardised incidence has increased considerably in the last 20 years, in contrast to the rates reported from most other countries. Papillary tumours are unusually common in Icelandic males.

[Neuropsychiatric manifestations in an unselected group of patients with systemic lupus erythematosus in Iceland.].

INTRODUCTION: There has been substantial difference in the reported frequency of neuropsychiatric manifestations in systemic lupus erythematosus (SLE). This difference can at least partly be explained by methodological difference, especially in case identification. MATERIAL AND METHODS: A retrospective study in a group of 65 unselected SLE patients was performed. The study consisted of two parts: 1) a neuropsychiatric evaluation which included a review of the patient's charts and a neurological interview, 2) a structured psychiatric interview, i.e. the Diagnostic Interview Schedule. RESULTS: In part one 37 patients or 57% had positive findings, while in part two the number was 32 pa nottients or 49%. Overall, 46 patients or 71% had experienced one or more neuropsychiatric manifestations. The most prevalent manifestations in part one were headache and psychoses, and in part two simple phobia, agarophobia, social phobia and generalized anxiety. Approximately 25% of the patients were treated solely outside hospitals. CONCLUSION: The unselected nature of this study gives a picture probably more representative of the true neuropsychiatric involvement in systemic lupus erythematosus than previous studies of selected patient populations.

TP53 mutations and abnormal p53 protein staining in breast carcinomas related to prognosis.

Abnormalities in the TP53 tumour suppressor gene were evaluated in 106 unselected breast carcinomas and compared to clinical outcome of the disease. Tumours were screened for p53 abnormalities using immunohistochemical staining and polymerase chain reaction-constant denaturant gel electrophoresis (PCR-CDGE) analysis, followed by PCR and direct sequencing. Allelic loss at the TP53 locus was determined with polymorphic markers by comparing normal and tumour DNA. For approximately half of the patients, abnormal p53 protein expression in serum was determined by an ELISA assay. p53 abnormalities, detected as mutations and/or nuclear staining, were found in 37.6 (38/101) of cases. Nuclear staining for p53 protein could be identified in 33.7% of the tumours. Mutations in exons 5-8 were detected in 18.9% of the tumours, and an association was found between mutations and nuclear staining. Allelic loss in the TP53 region on 17p was more frequent in tumours showing changes in the TP53 gene (72.7%) compared to tumours with no mutation (45.8%). Serum levels of p53 antibodies showed no association with either TP53 mutations or nuclear staining. Women with TP53 mutations in their tumours had an elevated risk of dying during the study period (RR (relative risk) = 3.4, P = 0.014). The effects of p53 positive staining were similar (RR = 3.2, P = 0.013). Considering all abnormalities, mutation and/or staining, the relative risk of dying from breast cancer was 3.5 (P = 0.008).

TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains.

Acquired mutations in TP53 as well as immunohistochemically detectable protein expression have been implicated as prognostic factors for breast cancer. We have evaluated the relationship between mutations detected in 119 breast tumours and various clinicohistopathological indices, stratifying the mutations according to the functional domains as defined by the recent elucidation of the crystal structure of the protein. Patients with missense mutations located in regions encoding parts of the protein involved in zinc-binding had significantly decreased disease-free and overall survival relative to patients whose tumours had mutations in other domains. These results indicate that these biochemically defined domains also have biological relevance in terms of breast cancer disease course, and suggest that some mutations in TP53, more than others, can contribute to the development of clinically more aggressive and perhaps treatment resistant breast tumours. When confirmed, this will be of potential importance in predicting the clinical behaviour of breast cancer and its responsiveness to therapy.