A comprehensive guide to MEGA-PRESS for GABA measurement.

The aim of this guideline is to provide a series of evidence-based recommendations that allow those new to using MEGA-PRESS to produce high-quality data for the measurement of GABA levels using edited magnetic resonance spectroscopy with the MEGA-PRESS sequence at 3T. GABA is the main inhibitory neurotransmitter of the central nervous system and has been increasingly studied due to its relevance in many clinical disorders of the central nervous system. MEGA-PRESS is the most widely used method for quantification of GABA at 3T, but is technically challenging and operates at a low signal-to-noise ratio. Therefore, the acquisition of high-quality MRS data relies on avoiding numerous pitfalls and observing important caveats. The guideline was developed by a working party that consisted of experts in MRS and experts in guideline development and implementation, together with key stakeholders. Strictly following a translational framework, we first identified evidence using a systematically conducted scoping literature review, then synthesized and graded the quality of evidence that formed recommendations. These recommendations were then sent to a panel of 21 world leaders in MRS for feedback and approval using a modified-Delphi process across two rounds. The final guideline consists of 23 recommendations across six domains essential for GABA MRS acquisition (Parameters, Practicalities, Data acquisition, Confounders, Quality/reporting, Post-processing). Overall, 78% of recommendations were formed from high-quality evidence, and 91% received agreement from over 80% of the expert panel. These 23 expert-reviewed recommendations and accompanying extended documentation form a readily useable guideline to allow those new to using MEGA-PRESS to design appropriate MEGA-PRESS study protocols and generate high-quality data.

Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus.

Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4). To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5). Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.

General practitioners' knowledge of whiplash guidelines improved with online education.

OBJECTIVE: The primary objective of this study was to evaluate the effect of an online education program used to implement the Australian (New South Wales) whiplash guidelines with general practitioners (GP). The secondary aim was to identify factors associated with learning. METHODS: An online educational and evaluation activity was developed to reflect the key messages for GP from the Australian whiplash guidelines. The educational activity was hosted on the Royal Australian College of General Practitioners' website (www.gplearning.com.au) for a period of 3 years. Participants were recruited through advertisement and media releases. Participants completed a baseline evaluation of their knowledge, participated in the interactive educational activity and completed a post-knowledge questionnaire. The primary outcome was change in professional knowledge, predictors of learning were computed using linear regression. RESULTS: Two hundred and fifteen GP participated. Knowledge significantly improved between baseline and post-knowledge questionnaire scores (P < 0.00001). A total of 57.2% of participants improved their knowledge by more than 20%, indicating a large effect. Low baseline knowledge predicted learning, accounting for 71% of the variance. CONCLUSIONS: Online education of GP significantly improved their knowledge in relation to guidelines for whiplash. Those with low baseline knowledge improved their knowledge the most, suggesting that implementation strategies should be targeted at this group.

Referral practices of recent graduate and experienced physiotherapists working in Australian primary care for people with musculoskeletal conditions.

BACKGROUND: People with musculoskeletal conditions often seek care from physiotherapists. Some, particularly those at risk of poor outcomes, may benefit from referral to physiotherapists with expertise in managing musculoskeletal conditions and/or multidisciplinary care. Understanding referral practices of physiotherapists, and how experience influences those practices, may assist in implementing optimal care pathways in primary care. AIMS: Explore (i) current referral practices of recent graduate and experienced physiotherapists who manage musculoskeletal conditions; (ii) opinions about referral to specialist physiotherapists for people at risk of poor outcomes. METHODS: This qualitative study consisted of 23 semi-structured interviews with recent graduate (n = 9) and experienced physiotherapists (n = 14) working in primary care. Perspectives of participants' current referral practices (to whom, when and why they are referred) and referral to specialist physiotherapists were sought. Interviews were recorded and transcribed verbatim prior to analysis. RESULTS: Referral practices for both groups were influenced by specific diagnoses, complexity of presentations, confidence, self-awareness, the clinical environment and system-related factors. Experienced physiotherapists were more confident and specific in their referrals and had established trusted networks compared with new graduates. Early referral to specialist physiotherapists was more likely when therapists were co-located. Barriers to early referral were lack of awareness, health system factors and impact on the patient (e.g., financial, time, continuity of care). CONCLUSION: Understanding factors influencing referral decisions may improve both intra- and interprofessional care for people with musculoskeletal conditions. Referral of people at risk of poor outcomes to specialist physiotherapists may be improved by greater intraprofessional awareness and clarity of roles.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Prostate cancer age-standardised incidence increase between 2006 and 2016 in Gauteng Province, South Africa: A laboratory data-based analysis.

BACKGROUND: Prostate cancer (PCa) is the leading male neoplasm in South Africa (SA) and is the second most frequently diagnosed cancer among men globally. Age-specific incidence rates (ASIRs) vary by up to 189-fold globally, with an ASIR of 68.0 per 100 000 in 2018 in SA. OBJECTIVES: To describe PCa among men undergoing prostate biopsy in Gauteng Province, SA. METHODS: We undertook a retrospective descriptive study using prostate biopsy data collected from the National Health Laboratory Service (NHLS) database between 2006 and 2016. We extracted the Systematized Nomenclature of Medicine (SNOMED) clinical terms morphology and topography codes to assign histological findings using the International Classification of Diseases for Oncology. PCa was defined as adenocarcinoma with a reported Gleason Score (GS). The new grade group (GG) based on the GS is defined as follows; (i) GG1 for a GS ≤6; (ii) GG2 for a GS of 3 + 4 = 7 ; (iii) GG3 for a GS of 4 + 3 = 7; (iv) GG4 for a GS of 8; and (v) GG5 for a GS ≥9. Higher-grade disease was defined as GG4 and GG5 (GS ≥8), in line with local guidelines. We reported associations of PCa with a GS ≥7 with age and race and used provincial and world standard population data to determine annual ASIRs. RESULTS: We identified 22 937 biopsies referred to the NHLS between 2006 and 2016. Of the 6 448 biopsies (39%) with a PCa finding for black Africans, 46% were diagnosed with high-risk PCa compared with 36 - 40% for other race groups (p<0.0001). Black Africans were more likely than whites to have GG4 or GG5 PCa (odds ratio 1.45; 95% confidence interval 1.27 - 1.67). The ASIR increased from 44.9 per 100 000 in 2006 to 57.3 per 100 000 in 2016. CONCLUSIONS: Black African men were significantly more likely to present with PCa with a GS ≥8 (GG4 and GG5) compared with the other racial groups in Gauteng. The ASIR increased dramatically during the study period, perhaps as a result of increased screening and awareness. There is a need for additional research to better understand why black African men present with higher-grade disease.

Collaborations in gynecologic oncology education and research in low- and middle- income countries: Current status, barriers and opportunities.

Eighty-five percent of the incidents and deaths from cervical cancer occur in low and middle income countries. In many of these countries, this is the most common cancer in women. The survivals of the women with gynecologic cancers are hampered by the paucity of prevention, screening, treatment facilities and gynecologic oncology providers. Increasing efforts dedicated to improving education and research in these countries have been provided by international organizations. We describe here the existing educational and research programs that are offered by major international organizations, the barriers and opportunities provided by these collaborations and hope to improve the outcomes of cervical cancer through these efforts.

Pharmacogenetic modulation of combined hormone replacement therapy by progesterone-metabolism genotypes in postmenopausal breast cancer risk.

Combined hormone replacement therapy (CHRT) containing estrogens and progestins is associated with breast cancer risk. The authors evaluated interactions between CHRT use and progestin metabolism genotypes at CYP3A4 and the progesterone receptor (PGR) and their effects on breast cancer risk using the population-based Women's Insights and Shared Experiences (WISE) Study (1999-2002) of postmenopausal Caucasian women (522 breast cancer cases, 708 controls). The authors observed an elevated risk of ductal tumors in women with 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.35, 95% confidence interval (CI): 1.13, 9.99; two-sided p(interaction) = 0.035). They also observed an elevated risk of progesterone receptor-positive tumors in women who had had 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.82, 95% CI: 1.26, 11.55; p = 0.028). Finally, they observed an increased risk of estrogen receptor-negative tumors in women without CHRT exposure and CYP3A4*1B alleles compared with those who had neither factor (odds ratio = 6.46, 95% CI: 2.02, 20.66; p = 0.024), although the biologic interpretation of this result requires further study. When stratified by recency of use, PGR effects were observed only in current CHRT users, while CYP3A4 effects were observed only in former CHRT users. Breast cancer risk in women who have used CHRT may be influenced by genetic factors involved in progestin metabolism.

Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4.

BACKGROUND: Pathways involved in androgen metabolism have been implicated in the etiology of prostate cancer. The goal of this study was to evaluate the effect of CYP3A4, a gene associated with the oxidative deactivation of testosterone, on the clinical presentation of prostate cancers. METHODS: A polymerase chain reaction-based approach was used to identify sequence variants of the human CYP3A4 gene. To ascertain whether allelic variants of the CYP3A4 gene were associated with tumor stage and grade and age of the patient at diagnosis, we determined CYP3A4 genotypes in 230 Caucasian men with incident prostate cancer. RESULTS: We identified a novel genetic variant (CYP3A4-V) that has an altered 5' regulatory element, containing an A to G mutation, upstream of the CYP3A4 gene. We then compared clinical characteristics of prostate cancers in men who did and did not carry this variant. The presence of the CYP3A4-V allele was associated with a higher tumor-lymph node-metastasis (TNM) stage and Gleason grade. The association between CYP3A4 genotype and tumor stage was most pronounced in men diagnosed at a relatively old age who reported no family history of prostate cancer. In this group, 46% of men with stage T3/T4 tumors carried CYP3A4-V, whereas only 5% of individuals with stage T1 tumors carried CYP3A4-V (adjusted odds ratio = 9.45; 95% confidence interval = 2.54-35.17; chi2(1) = 12.28; two-sided P<.001). CONCLUSIONS: We determined that a single base change in the 5' flanking region of the CYP3A4 gene was associated with higher clinical stage and grade in men with prostate tumors. Our results suggest that mutations in the CYP3A4 gene may influence prostate carcinogenesis.

Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers.

BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. METHODS: We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. RESULTS: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. CONCLUSIONS: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.

Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes.

BACKGROUND: Smoking has carcinogenic effects, and possibly antiestrogenic effects as well, but it has not been found to be a risk factor for breast cancer in women in the general population. However, hereditary breast cancer is primarily a disease of premenopausal women, and interactions between genes and hormonal and environmental risk factors may be particularly important in this subgroup. METHODS: We conducted a matched case-control study of breast cancer among women who have been identified to be carriers of a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women were assessed for genetic risk at one of several genetic counseling programs for cancer in North America. Information about lifetime smoking history was derived from a questionnaire routinely administered to women who were found to carry a mutation in either gene. Smoking histories of case subjects with breast cancer and age-matched healthy control subjects were compared. Odds ratios for developing breast cancer were determined for smokers versus nonsmokers by use of conditional logistic regression for matched sets after adjustment for other known risk factors. RESULTS: Subjects with BRCA1 or BRCA2 gene mutations and breast cancer were significantly more likely to have been nonsmokers than were subjects with mutations and without breast cancer (two-sided P = .007). In a multivariate analysis, subjects with BRCA1 or BRCA2 mutations who had smoked cigarettes for more than 4 pack-years (i.e., number of packs per day multiplied by the number of years of smoking) were found to have a lower breast cancer risk (odds ratio = 0.46, 95% confidence interval = 0.27-0.80; two-sided P = .006) than subjects with mutations who never smoked. CONCLUSIONS: This study raises the possibility that smoking reduces the risk of breast cancer in carriers of BRCA1 or BRCA2 gene mutations.

Association of SRD5A2 genotype and pathological characteristics of prostate tumors.

The enzyme product of SRD5A2, 5alpha-reductase type II, is responsible for converting testosterone to the more metabolically active dihydrotestosterone. Therefore, SRDSA2 may be involved in the development or growth of prostate tumors. To examine the effects of allelic variants in the gene SRDSA2 on the presentation of prostate tumors, we studied a sample, primarily Caucasian, of 265 men with incident prostate cancer who were treated by radical prostatectomy. We assessed the relationship of the A49T and V89L polymorphisms at SRD5A2 with clinical and pathological tumor characteristics of these patients. We found no association of V89L genotypes with any of the characteristics studied. The presence of the A49T variant was associated with a greater frequency of extracapsular disease [odds ratio (OR), 3.16; 95% confidence interval (CI), 1.03-9.68] and a higher pathological tumor-lymph node-metastasis (pTNM) stage (OR, 3.11; 95% CI, 1.01-9.65). In addition, the A49T variant was overrepresented in two poor prognostic groups, which have been correlated with reduced rates of biochemical disease-free survival. One group included men with at least two of the following poor prognostic variables: (a) stage T3 tumor; (b) PSA level >10; and/or (c) Gleason score, 7-10 (OR, 3.46; 95% CI, 1.04-11.49). The second group included men with positive margins and high Gleason score (OR, 6.28; 95% CI, 1.05-37.73). Our results suggest that the A49T mutation may influence the pathological characteristics of prostate cancers and, thus, may affect the prognosis of these patients.

Familial predisposition to neuroblastoma does not map to chromosome band 1p36.

Familial predisposition to neuroblastoma, a common embryonal cancer of childhood, segregates as an autosomal dominant trait with high penetrance. It is therefore likely that neuroblastoma susceptibility is due to germ line mutations in a tumor suppressor gene. Cytogenetic, functional, and molecular studies have implicated chromosome band 1p36 as the most likely region to contain a suppressor gene involved in sporadic neuroblastoma tumorigenesis. We now demonstrate that neuroblastoma predisposition does not map to any of eight polymorphic markers spanning 1p36 by linkage analysis in three families. In addition, there is no loss of heterozygosity at any of these markers in tumors from affected members of these kindreds. Furthermore, there is strong evidence against linkage to two Hirschsprung disease (a condition that can cosegregate with neuroblastoma) susceptibility genes, RET and EDNRB. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 tumor suppressor and the currently identified Hirschsprung disease susceptibility genes.

Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history.

Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance. We studied the effect of alleles at the AIB1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations. We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at AIB1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had AIB1 alleles no shorter than 28 or 29 or more AIB1 polyglutamine repeats (OR, 4.62; 95% CI, 2.02-10.56 and OR, 6.97; 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through AIB1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk.

Prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers.

The availability of genetic testing for inherited mutations in the BRCA1 and BRCA2 genes provides potentially valuable information to women at elevated risk of breast or ovarian cancer. Unfortunately, women who have inherited a mutation in BRCA1 or BRCA2 have relatively few clinical management options available to reduce their risk of developing breast or ovarian cancer. Because most options for ovarian cancer prevention are not highly efficacious, many high-risk women consider the option of bilateral prophylactic oophorectomy (BPO), in the hope that removal of healthy ovarian tissue will reduce their risk of developing invasive malignancy. It is clear that BPO cannot completely prevent the subsequent development of ovarian cancers because reports have been made of patients who have developed cancers of epithelial ovarian origin subsequent to surgery. However, a number of studies have suggested that BPO may reduce the risk of subsequent breast or ovarian cancers in women. In general, these studies have been conducted in women who represent a heterogeneous group with respect to breast/ovarian cancer risk. Only one study of BPO has been undertaken in women whose elevated cancer risk has been based on knowledge of inherited mutations. This study indicated that a 50% to 70% breast cancer risk reduction could be achieved in women with BRCA1 mutations who underwent BPO. However, substantial additional information is required to provide clinically useful information about cancer prevention to women who carry mutations in BRCA1 or BRCA2.

Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer.

PURPOSE: To review the published literature on the efficacy and adverse effects of prophylactic mastectomy (PM) and prophylactic oophorectomy (PO) in women with a hereditary predisposition to breast and ovarian cancer and to provide management recommendations for these women. METHODS: Using the terms "prophylactic," "preventive," "bilateral," "mastectomy," "oophorectomy," and "ovariectomy," a MEDLINE search of the English-language literature for articles related to PM and PO was performed. The bibliographies of these articles were reviewed to identify additional relevant references. RESULTS: There have been no prospective trials of PM or PO for the reduction of breast cancer or ovarian cancer incidence or mortality. Most of the available retrospective studies are composed of women who had surgery for a variety of indications and in whom genetic risk was not well characterized. However, some reports in women at increased risk of breast or ovarian cancer have shown that PM and PO can reduce cancer incidence. CONCLUSION: Interest in and use of PM and PO are high among physicians and high-risk women. PM and PO seem to be associated with considerable reduction in the risk of breast and ovarian cancer, albeit incomplete. The surgical morbidity of PM and PO is low, but the complications of premature menopause may be significant, and few studies address quality-of-life issues in women who have opted for PM and PO. Management recommendations for high-risk individuals are presented on the basis of the available evidence.

BAG-1: a novel biomarker predicting long-term survival in early-stage breast cancer.

PURPOSE: Among women with early-stage breast cancer treated with lumpectomy and radiation therapy, 30% to 40% will develop metastatic disease, which is often fatal. A need exists therefore for biomarkers that distinguish patients at high risk of relapse. We performed a retrospective correlative analysis of BAG-1 protein expression in breast tumors derived from a cohort of early-stage breast cancer patients. PATIENTS AND METHODS: Archival paraffin blocks from 122 women with stages I to II breast cancer treated with lumpectomy and radiation therapy (median follow-up, 12.1 years) were analyzed by immunohistochemical methods using monoclonal antibodies recognizing BAG-1 and other biomarkers, including Bcl-2, estrogen receptor, progesterone receptor, p53, and HER2/Neu. Immunostaining data were correlated with distant metastasis-free survival (DMFS) and overall survival (OS). RESULTS: Cytosolic immunostaining for BAG-1 was upregulated in 79 (65%) of 122 invasive breast cancers (P <.001) compared with normal breast. Elevated BAG-1 was significantly associated with longer DMFS and OS, overall (stages 1 and II) and in node-negative (stage I only) patients, on the basis of univariate and multivariate analyses (DMFS, P =.005; OS, P =.01, in multivariate analysis of all patients; DMFS, P =.005; OS, P =.001, in multivariate analysis of node-negative patients). All other biomarkers failed to reach statistical significance in multivariate analysis. Clinical stage was an independent predictor of OS (P =.04) and DMFS (P =.02). CONCLUSION: These findings provide preliminary evidence that BAG-1 represents a potential marker of improved survival in early-stage breast cancer patients, independent of the status of axillary lymph nodes.

Group sequential methods and sample size savings in biomarker-disease association studies.

Molecular epidemiological association studies use valuable biosamples and incur costs. Statistical methods for early genotyping termination may conserve biosamples and costs. Group sequential methods (GSM) allow early termination of studies on the basis of interim comparisons. Simulation studies evaluated the application of GSM using data from a case-control study of GST genotypes and prostate cancer. Group sequential boundaries (GSB) were defined in the EAST-2000 software and were evaluated for study termination when early evidence suggested that the null hypothesis of no association between genotype and disease was unlikely to be rejected. Early termination of GSTM1 genotyping, which demonstrated no association with prostate cancer, occurred in >90% of the simulated studies. On average, 36.4% of biosamples were saved from unnecessary genotyping. In contrast, for GSTT1, which demonstrated a positive association, inappropriate termination occurred in only 6.6%. GSM may provide significant cost and sample savings in molecular epidemiology studies.

BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers.

Ninety-eight women ascertained from high-risk breast/ovarian cancer clinics with breast cancer reporting at least one other primary cancer in themselves or in a relative with breast cancer were compared with 99 women with breast cancer who reported a family history of breast cancer only. All DNA was screened for coding region mutations in BRCA1 and BRCA2 using heteroduplex analysis, followed by direct sequencing. Our data indicate that 42.9% of families reporting breast and any second nonbreast type of primary cancer in the same individual had a BRCA1 or BRCA2 mutation, as compared with the 12.1% of families reporting breast cancer only (P < 0.001). Among the 66 women reporting breast cancer and a nonovarian second primary cancer, 15 (22.7%) had mutations in BRCA1 or BRCA2 (P = 0.04). Among the 32 families where ovarian cancer was the second primary cancer, 27 (84.4%) had a mutation in BRCA1 or BRCA2 (P < 0.001). BRCA1 and BRCA2 mutations were twice as common in the presence of a reported second nonovarian cancer. These data suggest that the presence of multiple primary cancer of any kind may predict for an increased likelihood of finding a BRCA1 or BRCA2 mutation and supports previous studies suggesting that BRCA1 and BRCA2 mutations may be associated with an increased susceptibility to cancers other than breast and ovarian cancer.