Comparison between frozen section histology and touch cytology of the breast

Tissue biopsies of the breast with and without carcinomas were examined simultaneously by intraoperative histology and imprint cytology. In 95 per cent of the cases there was a good correlation between the histologic and cytologic diagnoses. The reliability of imprint cytology was tested in some complicated cases such as proliferating fibroadenomas, pseudoinvasive adenosis and carcinomas. In 20,2 per cent of the cases with carcinoma, the tumor cells showed peculiar intracytoplasmic inclusions, whereas such inclusions were found only in 0,43 per cent of the biopsies of mammas without carcinoma. Their morphological variations and the histochemical pattern are discussed. The results have demonstrated that simultaneous cytologic examination of unfixed mamma biopsies can be a good screening method and that the intracytoplasmic inclusions may be an especially helpful histopathologic feature in the diagnosis of breast cancer.     

Posttraumatic stress disorder after treatment for breast cancer: prevalence of diagnosis and use of the PTSD Checklist-Civilian Version (PCL-C) as a screening instrument

The presence of a posttraumatic stress disorder (PTSD) diagnosis in women (n = 82) diagnosed with Stage 0-IIIA breast cancer was assessed 6 to 72 months after cancer therapy. The PTSD Checklist-Civilian Version (PCL-C) and the PTSD module for the Structured Clinical Interview for DSM-IV, Nonpatient Version, PTSD module (SCID-NP-PTSD) were administered in a telephone interview. SCID-NP-PTSD results indicated prevalence rates of 6% and 4% for current and lifetime PTSD, respectively. Use of the recommended cutoff score of 50 on the PCL-C to determine diagnosis of current cancer-related PTSD resulted in a sensitivity of .60 and a specificity of .99 with 2 false-negative diagnoses. In conclusion, PTSD can be precipitated by diagnosis and treatment of breast cancer, and the PCL-C can be a cost-effective screening tool for this disorder.     

MR lesion detection in a breast cancer population

Implementation of MR imaging of the breast as an extension of the existing imaging modalities in the diagnosis of breast cancer was evaluated in a university cancer center, MR imaging of the breast was performed in 54 patients, in whom the MR results were compared with the triple test (the combination of clinical examination, mammographic evaluation, and cytology) and the final histological diagnosis. MR imaging of the breast depicted 30 of the 33 malignancies (sensitivity, 91%). In two of the malignancies, the carcinoma was clinically and mammographically occult. For the three patients with a false-negative MRI diagnosis, the conventional mammography showed suspicions clustered microcalcifications as a sign of in situ carcinoma. For seven patients, MR imaging of the breast incorrectly suggested the presence of a malignant lesion (specificity, 67%). To improve MR specificity, we perform MR-guided ultrasonographic fine-needle aspiration biopsy (FNAB). Although MR imaging of the breast is a highly sensitive examination, conventional x-ray mammography remains the most efficient imaging modality in the diagnosis of breast cancer. In our patient population, MR imaging of the breast had additional value for women with mammographically dense breast tissue and especially for patients with clinical evidence of breast carcinoma that could not be detected with conventional diagnostic methods.     

Cytologic diagnosis of signet-ring cell carcinoma of the breast

OBJECTIVE: To examine the cytologic features of signet-ring cell carcinoma (SRCC), defined as carcinoma dominated by signet-ring cells, of the breast and to discuss problems that occur in cytodiagnosis. STUDY DESIGN: Five cases of SRCC of the breast were examined cytopathologically. Signet-ring cells were subclassified into intracytoplasmic lumina (ICL) type and non-ICL type. ICL type had large ICL containing mucin. Non-ICL-type cells had wide, amorphous cytoplasm diffusely dispersed with mucin. RESULTS: In cases 1 and 2, fine needle aspiration biopsy (FNAB) revealed many signet-ring cells (non-ICL type), suggesting SRCC. Histologic diagnoses were ductal SRCC containing many signet-ring cells (non-ICL type). In cases 3 and 4, signet-ring cells (ICL type) were found sporadically among carcinoma cells without signet-ring features. Signet-ring cells were not regarded as the major component of the cells; thus, the cytologic diagnoses were lobular carcinoma, not otherwise specified. Pathologic diagnoses were lobular SRCC. Signet-ring cells were mostly ICL type. In case 5, most carcinoma cells on the smears showed signet-ring features (non-ICL type), suggesting SRCC. The histologic diagnosis was lobular SRCC, and signet-ring cells were mostly non-ICL type. CONCLUSION: Ductal SRCC yielded more cellular smears as compared with lobular SRCC; therefore, cytologic diagnosis was easier in the former.     

BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease

Breast cancer is a rare disease in men, affecting less than 0.1% of the male population. Two heritable gene defects have been associated with a predisposition to male breast cancer development, ie., germ-line mutations in the breast cancer susceptibility gene BRCA2 and the androgen receptor (AR) gene. In this study, the entire coding regions of BRCA2 and AR were screened for mutations in 34 consecutive male breast cancer patients. Five different truncating BRCA2 mutations were identified in 7 (21%) of the 34 cases, with all mutations being of germ-line origin. Three of the mutated cases carried the same mutation (4186delG), which has been found earlier in two Swedish families with multiple female breast cancer cases. Haplotype analysis supported a common ancestry of 4186delG. One mutation, 6503delTT, was found in a male carrying also a previously identified COOH-terminal polymorphic stop codon (Lys3326ter). No differences were seen between mutation carriers and noncarriers with respect to clinical stage and estrogen or progesterone receptor status. Mutation carriers tended to be younger at diagnosis. No germ-line AR mutations were found in the present material, but the number of AR polyglutamine repeats tended to be lower among mutation carriers. Most surprisingly, only one of the seven BRCA2 mutation carriers had a positive family history of breast cancer, suggesting a lower penetrance of some BRCA2 mutations or an influence of modifying factors for disease development in males and females. The present study implies that approximately one-fifth of all male breast cancer cases in the Swedish population are due to germ-line BRCA2 mutations.     

Detection of the first recurrence during intensive follow-up of breast cancer patients

BACKGROUND: Breast cancer patients are routinely followed after primary treatment. Many intensive diagnostic methods (tumor markers, chest X-ray, mammography, liver echography, bone scans) are performed periodically. However, it remains to be determined how often attempts should be made to detect the first recurrence of breast cancer by these methods. METHODS: To evaluate the effect of imaging diagnosis and tumor markers, we analyzed methods of detection of first recurrence sites during intensive follow-up of breast cancer patients. RESULTS: Of 550 female patients who had been surgically treated between July 1992 and December 1996, 65 recurrent cases had been diagnosed as of December 1997. Thirty cases (46%) had been found as a result of symptoms related to the site of recurrence and 14 cases (22%) were detected by physical examination. In the remaining 21 cases (32%), detection was by other methods: in eight cases by imaging diagnosis, in three cases based on abnormal tumor markers and in 10 cases by imaging diagnosis and abnormal tumor markers. Twenty-nine cases (45%) followed every 1-3 months had presented with symptoms at routine or interval appointments. There was a significant difference between first recurrence sites (loco-regional, bone and viscera) and the methods of detection (symptoms, physical examination and other diagnostic methods) (P < 0.0001). However, no statistical difference in overall survival after operation was observed between the 30 cases found as a result of symptoms and the 35 cases detected by physical examination or other diagnostic methods. CONCLUSIONS: Taken together with ASCO's surveillance guidelines (J Clin Oncol 1997;15:2149-56), intensive follow-up of breast cancer patients should be limited to high-risk breast cancer patients, especially those who enter randomized clinical trials. A careful history and physical examination are in practice indicated every 3-6 months for 3 years and then every 6 months for the following 2 years.     

Brain metastases of bronchial and breast carcinoma. Differences in metastatic behavior and prognosis

Evaluation of 135 cases with brain metastases from non-small-cell lung cancer (group 1) compared with 51 cases from small-cell lung cancer (group 2) and 56 cases from breast cancer (group 3) showed that the frequency of solitary metastases was significantly higher in group 1 and 3. However, in group 2 lesions without surrounding edema occurred more frequently. The rate of patients with extracerebral metastases was significantly higher in groups 2 and 3. The longest median interval between primary tumor and brain metastases was observed in breast cancer patients. The highest local remission rate was seen in small-cell lung cancer if patients who received whole-brain irradiation of 30 Gy alone were compared (63% vs 45% in group 1 and 52% in group 3). However, with regard to clinical course no significant differences were recorded. Survival of lung cancer cases was similar, whereas breast cancer cases survived significantly longer, both after radiotherapy alone and after surgery plus radiotherapy. This might be caused by differences in the natural course of the two diseases as well as adjuvant treatment modalities like hormone and chemotherapy. In conclusion, because long-term survivors were observed only in the breast cancer group, these patients probably have the highest chance of profiting from a locally aggressive treatment approach.     

Parietal motor syndrome: a clinical description in 32 patients in the acute phase of pure parietal strokes studied prospectively

Although survival rates are useful for monitoring progress in the early detection and treatment of cancer and are of particular interest to patients with new diagnoses, there are limited population-based estimates of long-term survival rates. We used data collected by the Surveillance, Epidemiology, and End Results Program for cases diagnosed during 1974-1991 and followed through 1992 to estimate relative survival at 5, 10, and 15 years after diagnosis of cancer of the breast, prostate, colon and rectum, and lung. Relative survival after diagnosis of breast and prostate cancer continued to decline up through 15 years after diagnosis, whereas survival after diagnosis of lung and colon or rectal cancer remained approximately constant after 5 and 10 years, respectively. Age-specific patterns of survival varied by site, stage, and demographics. Among patients with localized breast and prostate cancer, women who were younger than age 45 at breast cancer diagnosis and men who were 75 years and older at prostate cancer diagnosis had the poorest relative survival. Relative survival among lung cancer patients decreased with age at diagnosis, regardless of stage or demographics, and age-specific patterns of relative survival for patients with cancer of the colon and rectum differed according to race. Among white patients diagnosed with cancers of the colon and rectum, relative survival did not vary by age at diagnosis; among black patients older than 45 at diagnosis, relative survival decreased with age. This study provides population-based estimates of long-term survival and confirms black/white, male/female, and stage- and age-specific differences for the major cancers.     

Povidone iodine and skin disinfection before initiation of epidural anesthesia

OBJECTIVE: The clinical, mammographic and low grade cytologic features of mucinous carcinoma can make it difficult to diagnose by fine needle aspiration (FNA). Fine needle aspirates of mucinous carcinoma were reviewed with the mammographic findings to improve the diagnostic criteria and specificity for FNA. STUDY DESIGN: All aspirates were reviewed for cytologic criteria and cellularity, atypia and single epithelial cells (SEC). A nuclear grade was assigned to each aspirate. The mammographic findings were correlated with the FNA diagnoses. RESULTS: Forty-five patients with an aspirate and confirmed diagnosis of mucinous carcinoma were identified. The clinical impressions were: benign tissue (5), fibroadenoma (6) and cancer (32). The initial cytologic diagnoses were: adenocarcinoma (32), atypical/suspicious for cancer (11), insufficient (1) and negative (1). The cytologic findings showed smears with increased cellularity (35/45 cases) and minimal atypia. SEC with eccentrically located nuclei and eosinophilic cytoplasm were numerous. The assigned nuclear grade was as follows: grade 1, 16 cases; grade 2, 20 cases; and grade 3, 6 cases. Abundant mucin was present in Papanicolaou-stained slides in 23 cases; focal mucin was observed in 14 cases. The mammograms showed a smoothly outlined to lobulated mass with only slight irregularities identified. CONCLUSION: Mucinous carcinoma has a cytologic pattern that includes increased cellularity, with numerous single cells and abundant mucin. Although the mammographic findings may mimic a benign lesion, in the most patients a specific diagnosis of mucinous carcinoma can be made by FNA.     

Randomized trial of physical exercise alone or combined with bright light on mood and health-related quality of life

OBJECTIVE: To present our experience with liver fine needle aspiration (FNA) diagnosis based on Riu's stain. STUDY DESIGN: We reviewed a total of 322 liver fine needle aspirates from 286 patients seen in a seven-year period from April 1990 to April 1997 at Koo Foundation Sun Yat-Sen Cancer Center, Taipei. Surgical and/or clinical follow-up was available for confirmation in 292 aspirates. RESULTS: The cytologic diagnosis was categorized into four groups: benign in 81 cases, suspicious in 13, malignant in 225, and inadequate specimen in 3 cases. There were 16 false negative and no false positive diagnoses. Two suspicious aspirates were negative. Our results showed a sensitivity of 93.3% and a specificity of 100% for the detection of malignancy. If suspicious cases were considered positive, the specificity decreased to 95.1%, while the sensitivity increased to 93.6%. Among 87 hepatocellular carcinomas (HCCs) in our series, correct FNA diagnosis was made in 84 cases with an accuracy of 96.6%. Out of 135 cases of non-HCCs, 1 was incorrectly diagnosed. The accuracy of identifying a liver malignancy as non-HCC was 99.3%. CONCLUSION: Cytologic features of HCC are well demonstrated by Riu's stain, with high accuracy in identifying them. Liver FNAs using Riu's stain combined with cell block study and clinicopathologic correlation can achieve very high sensitivity and specificity in the detection of hepatic malignancies.     

Awakening propofol concentration with and without blood-effect site equilibration after short-term and long-term administration of propofol and fentanyl anesthesia

The stage at which breast cancer is diagnosed is an important determinant of prognosis. In contrast to the many investigations of the relationship between alcohol consumption and the risk of developing breast cancer, few have examined how alcohol consumption may affect the stage of this cancer at diagnosis. This article examines the relationship between alcohol intake and breast cancer stage and assesses consumption in relation to the volume of drinks consumed per week and the patterns of consumption 1 year prior to the breast cancer diagnosis. A total of 1191 women, aged 40 to 84 years, with newly diagnosed breast cancer were identified through the population-based Metropolitan Detroit Cancer Surveillance System, a participant of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Of these, 1011 (85%) were interviewed 2 to 4 months following diagnosis. The analyses for this article were limited to 920 cases with local and regional stage disease. The bivariate analysis showed that frequent drinkers were more likely than abstainers or infrequent drinkers to present with regional disease. Logistic regression showed that frequent drinkers were 1.45 times more likely than infrequent drinkers to be diagnosed with later stage breast cancer (95% CI: 1.01-2.10; p = 05). The association between alcohol consumption and disease stage may be due to the relationship between heavy consumption and other unhealthy behaviors. In addition, women who drink more frequently may have less awareness of and access to cancer screening services. Heavy exposure to alcohol may also contribute to accelerated tumor growth once breast cancer is present.     

Report of two cases presenting with myelodysplastic syndrome during treatment of recurrent breast cancer

Two women with recurrent breast cancer presenting with myelodysplastic syndrome (refractory anemia) during chemotherapy were reported. At diagnosis of myelodysplastic syndrome, white blood cell count, hemoglobin and platelet count were 3,300/mm3, 4600/mm3, 5.5 g/dl, 6.3 g/dl, 1.1 x 10(4)/mm3 and 6.8 x 10(4)/mm3, respectively, in case 1 and 2. Bone marrow taps showed hypercellular marrows with dysplastic changes of erythrocytes, granulocytes and megakaryocytes in both cases. Before the occurrence of the myelodysplastic syndrome, both patients received various cytotoxic agents (mitomycin C: 77 mg, 108 mg; cyclophosphamide: 34,400 mg, 40,000 mg; doxorubicin: 340 mg, 460 mg; methotrexate: 410 mg, 700 mg; and vincristine: 9.5 mg, 14 mg, in case 1 and 2, respectively). One patient died 2 months after the onset of the myelodysplastic syndrome, and the other died 3 months after due to progression of metastatic breast cancer. Risk-benefits analysis of chemotherapy, especially adjuvant chemotherapy, should be performed in cases of breast cancer.     

Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer

BACKGROUND: Options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic mastectomy. The data on the outcomes for surveillance and prophylactic mastectomy are incomplete. METHODS: We conducted a retrospective study of all women with a family history of breast cancer who underwent bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. The women were divided into two groups - high risk and moderate risk - on the basis of family history. A control study of the sisters of the high-risk probands and the Gail model were used to predict the number of breast cancers expected in these two groups in the absence of prophylactic mastectomy. RESULTS: We identified 639 women with a family history of breast cancer who had undergone bilateral prophylactic mastectomy: 214 at high risk and 425 at moderate risk. The median length of follow-up was 14 years. The median age at prophylactic mastectomy was 42 years. According to the Gall model, 37.4 breast cancers were expected in the moderate-risk group; 4 breast cancers occurred (reduction in risk, 89.5 percent; P<0.001). We compared the numbers of breast cancers among the 214 high-risk probands with the numbers among their 403 sisters who had not undergone prophylactic mastectomy. Of these sisters, 38.7 percent (156) had been given a diagnosis of breast cancer (115 cases were diagnosed before the respective proband's prophylactic mastectomy, 38 were diagnosed afterward, and the time of the diagnosis was unknown in 3 cases). By contrast, breast cancer was diagnosed in 1.4 percent (3 of 214) of the probands. Thus, prophylactic mastectomy was associated with a reduction in the incidence of breast cancer of at least 90 percent. CONCLUSIONS: In women with a high risk of breast cancer on the basis of family history, prophylactic mastectomy can significantly reduce the incidence of breast cancer.     

Hamartoma of the breast, an underrecognized breast lesion. A clinicopathologic and radiographic study of 25 cases

This study investigated the clinical, radiographic, and pathologic features of breast hamartoma. The patients ranged in age from 18 to 89 years, with a mean age of 45 years, and a median age of 43 years. Seventy-five percent of the patients were asymptomatic, other than reporting a breast lump. In two patients, the lesions recurred at 7 and 18 months after the initial resection. The clinical diagnoses were fibroadenoma in 10 cases, carcinoma in 5 cases, hamartoma in 4 cases, and phyllodes tumor and lipoma in 2 other cases. Mammograms were available in 12 cases, the majority of which showed a well-defined mass of homogeneous density. Grossly, these lesions were oval to round, well-circumscribed masses, ranging in size from 1 to 7 cm in maximum dimension (mean, 3.9 cm). The microscopic appearance of these tumors corresponded to their gross appearance. Lesions that were grossly firm, rubbery, and white consisted largely of dense fibroconnective tissue with variable amounts of glandular elements with little adipose tissue. Softer, pale, yellow lesions contained more adipose tissue. A consistent and important diagnostic feature was the presence of both lobules and ducts, in contrast to fibroadenoma in which lobules are often absent or rare. The current trend of mammographic breast screening has made us aware that mammary hamartomas are not uncommon. These lesions may go unrecognized by the pathologists because they show all the constituents of normal breast tissue and may be reported as "no pathological diagnosis" or "normal breast tissue," which are inappropriate diagnoses for a lesion that presents as a palpable and a well-circumscribed mass.     

Risk factors for familial and sporadic ovarian cancer among French Canadians: a case-control study

OBJECTIVE: The objective was to compare risk factors between familial and sporadic ovarian cancer by means of a case-control approach. STUDY DESIGN: We conducted a case-control study among French Canadian women in Montreal during 1995-1996. One hundred seventy women 20 to 84 years old with histologically confirmed diagnoses of primary ovarian carcinomas or borderline tumors were interviewed concerning their reproductive, family, and medical histories. During the same period 170 randomly selected population control subjects, frequency-matched to the case patients according to age and ethnic group, were also interviewed. Unconditional logistic regression methods were used for data analysis. RESULTS: The major factors influencing the risk of development of ovarian cancer were as follows: (1) family history of breast or ovarian cancer, (2) a late age at use of oral contraceptives (a protective effect), and (3) a late age at last childbirth (a protective effect for familial case patients only). CONCLUSION: These factors had equally great impacts in familial and sporadic cases, implying that the underlying mechanisms of carcinogenesis in sporadic and familial ovarian cancer may be similar and that hereditary ovarian cancer may be preventable.     

Validity of self-reported cancers in a prospective cohort study in comparison with data from state cancer registries

The accuracy of self-reported cancer diagnoses in a prospective study was compared with population-based cancer registry data in four states. The study cohort included 65,582 men and women aged 39-96 years who were participants in the Cancer Prevention Study II Nutrition Survey, begun by the American Cancer Society in 1992. Estimates of sensitivity (the proportion of study participants with a registry-documented cancer who self-reported the cancer) ranged from 0.79 for an exact match of cancer site and year of diagnosis (+/- 1 year) to 0.93 for a match of any reported cancer. The sensitivity of exact matches varied considerably by cancer site and was highest for breast, prostate, and lung cancers (0.91, 0.90, and 0.90, respectively) and lowest for rectal cancer and melanoma (0.16 and 0.53, respectively). Sensitivity also varied slightly by the age, education, and smoking status of study participants. Estimates of sensitivity were virtually identical for each of the four states. The positive predictive value (the proportion of self-reported cancers that were confirmed by the registries) was 0.75 overall and also varied by cancer site. Unlike sensitivity, however, this proportion varied considerably by state. All self-reports of cancer that were not confirmed by the registries were further investigated by repeat questionnaires and acquisition of medical records. Low positive predictive values were due to underascertainment of true cancer cases by the registries, inaccurate reporting on the part of study participants, and problems with the algorithm used by the state to link the study population to the registry data. In conclusion, the ability of members of this cohort to report a past diagnosis of cancer accurately is quite high, especially for cancers of the breast, prostate, lung, and colon, or for the occurrence of any cancer.     

Breast cancer diagnosis by lactate dehydrogenase isozymes in nipple discharge

BACKGROUND: The diagnosis of breast cancer based on nipple discharge, often the only clinical manifestation of early breast cancer, is currently unsatisfactory. Because M subunits of lactate dehydrogenase (LDH) have been noted to increase in cancer tissue, the author assessed the value of using LDH isozyme patterns in nipple discharge for the diagnosis of breast cancer. METHODS: LDH isozyme levels in (1) nipple discharge of patients diagnosed as having breast cancer, intraductal papilloma, mastopathy, drug-induced nipple discharge, mastitis, or benign nipple discharge; (2) control samples of normal nipple discharge (milk) 6 days, 1-5 months, and 6 months to 2 years postpartum; (3) the serum of patients presenting with nipple discharge; and (4) normal and cancerous breast tissue extracts were measured using a Ciba-Corning LDH isozyme system (Ciba Corning Diagnostic Corp., Tokyo, Japan). RESULTS: LDH isozyme levels in the nipple discharge of patients with benign breast diseases displayed various patterns. Levels in the nipple discharge of patients with breast cancer, including noninvasive carcinoma, tended to increase in ascending order from LDH1 to LDH5. This pattern was similar to that in breast cancer tissue and was unrelated to the pattern in serum. CONCLUSION: LDH isozyme assay of nipple discharge may be a useful technique for providing a supporting diagnosis of breast cancer.     

A population-based study of contralateral breast cancer following a first primary breast cancer (Washington, United States)

To evaluate predictors of contralateral breast cancer risk, we examined data from a nested case-control study of second primary cancers among a cohort of women in western Washington (United States) diagnosed with breast cancer during 1978 through 1990 and identified through a population-based cancer registry. Cases included all women in the cohort who subsequently developed contralateral breast cancer at least six months after the initial diagnosis, but prior to 1992 (n = 234). Controls were sampled randomly from the cohort, matched to cases on age, stage, and year of initial breast cancer diagnosis. Information on potential risk factors for second primary cancer was obtained through medical record abstractions and physician questionnaires. Women who were postmenopausal due to a bilateral oophorectomy (i.e., a surgical menopause) at initial breast cancer diagnosis had a reduction in contralateral breast cancer risk compared with premenopausal women (matched odds ratio [mOR] = 0.25, 95 percent confidence interval [CI] = 0.09-0.68), whereas no reduction in risk was noted among postmenopausal women who had had a natural menopause (mOR = 0.90, CI = 0.39-2.09). Among postmenopausal women, there was a suggestion of a lower risk associated with relatively high parity (2+). A family history of breast cancer was associated with an increased risk (mOR = 1.96, CI = 1.22-5.15) and varied little by menopausal status. Having an initial tumor with a lobular component (c.f. a ductal histology) was not related strongly to risk (mOR = 1.47, CI = 0.79-2.74). The results of the present and earlier studies argue that we have limited ability to predict the occurrence of a contralateral breast tumor. Better predictors will be required before diagnostic and preventive interventions can be targeted to subgroups of patients with unilateral breast cancer.     

BRCA1 mutations in southern England

If genetic testing for breast and ovarian cancer predisposition is to become available within a public health care system there needs to be a rational and cost-effective approach to mutation analysis. We have screened for BRCA1 mutations in 230 women with breast cancer, all from the Wessex region of southern England, in order to establish the parameters on which to base a cost-effective regional mutation analysis strategy. Truncating mutations were detected in 10/155 (6.5%) consecutive cases selected only for diagnosis under the age of 40 (nine of these ten women had a strong family history of breast or ovarian cancer), 3/61 (4.9%) bilateral-breast cancer cases (all three mutations occurring among women for whom the first cancer was diagnosed under 40 years) and 8/30 (26.6%) breast cancer cases presenting to the genetics clinic (for whom a strong family history of breast and/or ovarian cancer was present). Ten different mutations were detected in 17 families, but three of these accounted for 10/17 (59%) of the families. The cost of screening the population for mutations in the entire BRCA1 gene is unacceptably high. However, the cost of screening a carefully selected patient cohort is low, the risk of misinterpretation much less and the potential clinical benefits clearer.     

Characterization of IS1515, a functional insertion sequence in Streptococcus pneumoniae

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).