Background In families with a proven BRCA1/2 mutation, women not carrying the familial mutation should follow the cancer screening recommendations applying to women in the general population. In the present study, we evaluated the cancer screening practices of unaffected noncarriers from families with a proven BRCA mutation, and we assessed the role of family history in their screening practices. Methods Self-report data were provided retrospectively by 220 unaffected female noncarriers for periods of up to 10 years (mean: 4.3 years) since disclosure of their BRCA1/2 genetic test result. A ratio for the annual frequency of breast and ovarian cancer screening exams (mammography, breast ultrasonography, breast magnetic resonance imaging, transvaginal or pelvic ultrasound, cancer antigen 125 testing) was calculated as number of screening exams divided by the number of years in the individual observation period. Results The annual average for mammography exams was 0.15, 0.4, 0.56, and 0.71 in women 30-39, 40-49, 50-59, and 60-69 years of age respectively. The uptake of other breast and ovarian cancer screening exams was very low. Mammography and breast ultrasonography and magnetic resonance imaging were generally more frequent among participants with at least 1 first-degree relative affected by breast cancer. Conclusions In most noncarriers, screening practices are consistent with the guidelines concerning women in the general population. When noncarriers adopt screening behaviours that are different from those that would be expected for average-risk women, those behaviours are influenced by their familial cancer history. Impact Decision tools might help female noncarriers to be involved in their follow-up in accordance with their genetic status and their family history, while taking into account the benefits and disadvantages of cancer screening.

In recent years, risk stratification has sparked interest as an innovative approach to disease screening and prevention. The approach effectively personalizes individual risk, opening the way to screening and prevention interventions that are adapted to subpopulations. The international PERSPECTIVE project, which is developing risk stratification for breast cancer, aims to support the integration of its screening approach into clinical practice through comprehensive tool-building. Policies and guidelines for risk stratification—unlike those for population screening programs, which are currently well regulated—are still under development. Indeed, the development of guidelines for risk stratification reflects the translational aspects of PERSPECTIVE. Here, we describe the risk stratification process that was devised in the context of PERSPECTIVE, and we then explain the consensus-based method used to develop recommendations for breast cancer screening and prevention in a risk-stratification approach. Lastly, we discuss how the recommendations might affect current screening policies.

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case–control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2–78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8–217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.

BackgroundMMRpro, prediction of mutations in MLH1 and MLH2 (PREMM1,2) and MMRpredict are models which were developed to predict the probability that an individual carries a Lynch syndrome-causing mutation. Each model utilizes data from personal and family histories of cancer. To date, no studies have compared these models in a cancer genetics clinic. The purpose of this study was to determine each model's ability to predict the probability of carrying a Lynch syndrome-causing mutation in individuals with a family history of colorectal cancer and to determine their clinical applicability.MethodsWe obtained family pedigrees from 81 individuals who presented for Lynch syndrome testing due to a personal and/or family history of cancer. Data from each pedigree were entered into the models and analyzed using SPSS.ResultsWe found that MMRpredict, PREMM1,2 and MMRpro showed similar performances with areas under the receiver-operating characteristic curve of 0.731, 0.765 and 0.732, respectively. MMRpro showed the least dispersion of mutation probability estimates with a P value of 0.205, compared with 0.034 for PREMM1,2 and 0.001 for MMRpredict.ConclusionWe found all three carried out well in a cancer genetics setting, with PREMM1,2 giving slightly better estimates. There were some significant discrepancies between the models in cases where the proband had endometrial cancer.

Many BRCA1-related tumors have a distinct histological characteristics which together have been called "basal-like." Typically such tumors are ER-, HER2- and express cytokeratin 5/6, cytokeratin 8/18, EGFR and vimentin. These characteristics can be used to predict which breast cancers are most likely to be associated with germline BRCA1 mutations which has important implications for breast pathologists. Moreover, BRCA1-related breast cancers generally have a poorer prognosis which may paradoxically be more pronounced in node negative cancers. This may relate in part to a different pattern of metastatic spread with in increased frequency of brain and lung metastases in BRCA1 carriers. Conversely, BRCA1-related tumors may respond better to neoadjuvant chemotherapy and their characteristic molecular signature may provide opportunities to develop specific molecular targeted therapies akin to traztuzumab in HER2+ cancers. Finally, many of the phenotypic features of BRCA1-related tumors might also be found in putative breast stem cells and therefore characterization of the BRCA1 breast cancer phenotype will improve our understanding of sporadic breast carcinogenesis.

BACKGROUND Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. PATIENTS AND METHODS We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(Kip1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. RESULTS The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27(Kip1) protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27(Kip1) protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002). CONCLUSIONS In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.

Hereditary non‐polyposis colorectal cancer (HNPCC) is an inherited cancer syndrome caused by a defect in the mismatch repair pathway. The majority of HNPCC mutations have been detected in MLH1 and MSH2. Most reported mutations are substitutions, small insertions and deletions, but standard methods of mutation analysis do not detect large rearrangements. It is now established that large deletions, insertions and rearrangements account for a significant proportion of MLH1 and MSH2 mutations. We report an unusual rearrangement resulting in the deletion of exons 6, 7 and 8 of MLH1, with the retention of part of intron 6 and insertions of two nucleotides each flanking the retained sequence. The 349‐bp‐retained sequence is made up of two closely spaced Alu sequences. The mutation was initially detected by protein truncation test and cDNA sequencing. Multiplex ligation‐dependent probe amplification confirmed the deletion of three exons. PCR and sequencing were used to characterize the breakpoint. Despite the high density of Alu elements in MLH1, there is no homology at the deletion breakpoints or insertion junctions in this case to suggest that homologous recombination has occurred. We propose a mechanism involving non‐homologous end joining to explain the occurrence of this complex deletion.

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27(Kip1), or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27(Kip1), p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27(Kip1) levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

he functions of the breast cancer susceptibility genes BRCA1 and BRCA2 are not fully elucidated, but appear to include the regulation of X chromosome activity.Xist is a non-coding RNA that accumulates on the inactive X chromosome and is required for X chromosome inactivation during the silencing step. 1 The RING domain of BRCA1 and Xist interact in mammalian cells and it has been suggested that BRCA1 contributes to the initiation of X chromosome inactivation. 2Women with ovarian cancer possessing germ- line mutations in BRCA1 have been found to frequently demonstrate non-random X chromosome inactivation. 3In the light of these findings, a recent report by de la Hoya et al is of interest. 4In this study of 68 Spanish breast/ovarian pedigrees they reported that 67% of the children of women who carried a BRCA1 mutation were female.By contrast, only 54% of the offspring of BRCA2 carriers and 52% of the offspring of non-carriers were female.This highly skewed sex ratio in the offspring of BRCA1 carriers from Spain prompted us to ask whether this is true in other populations as well.To address this question, we examined the sex ratios of the offspring of a total of 1040 women (229 BRCA1 carriers, 104 BRCA2 carriers, and 707 non-carriers) from five different studies which were conducted in Montreal, Toronto, and Oslo between 1993 and 2003.In four studies the carriers were identified through hospital-based and population-based ascertainment and were not selected for family history, [5][6][7][8] whereas one of the studies (the single study from McGill University, Montreal, Quebec, Table 1) was composed of Ashkenazi Jewish women ascertained via a high risk clinic.Three of the studies were also restricted to Ashkenazi Jews.In these studies the participants were tested for the three Ashkenazi Jewish founder germline mutations in BRCA1 and BRCA2.In the fourth study of ovarian cancer patients in Ontario, BRCA1 was screened in its entirety using PTT and DGGE and BRCA2 was screened in part using PTT. 5 The fifth study, restricted to women with ovarian cancer diagnosed in southern Norway, was conducted in Oslo, and the results presented here are restricted to mutation analysis of known Norwegian founder BRCA1 mutations as previously reported for this series of cases, 8 and the results of an extended mutation search in patients with a positive family history of breast and ovarian cancer.We counted all the female and male births reported by the proband in each pedigree.We did not find any evidence for sex ratio distortion in the overall sample (Table 1).Among 229 BRCA1 carriers, there was no statistically significant excess of female births (221 males vs 234 females, p = 0.54).The p value was derived from the binomial distribution, using an exact method, comparing the observed proportion with the expected proportion of 0.50.The proportion of female offspring was quite similar for children of BRCA1 carriers (51.4%), of BRCA2 carriers (50.2%), and of non-carriers (51.6%).This is in contrast to the striking results of the previous report (65 males vs 133 females offspring among confirmed BRCA1 carriers, p(0.001). 4Three subgroup results were of borderline . . . . . . .

Glomeruloid microvascular proliferation (GMP) in breast cancer independently adversely affected survival (relative risk 1.9, 95% CI: 1.2–3.0), particularly among women who received adjuvant chemotherapy (10-year survival 27 vs 69%, P=0.0003), and was significantly associated with p53 overexpression and BRCA1 germline mutations. The presence of GMP may influence treatment decisions.

BACKGROUND. Overexpression of p53 has been associated with poor survival following breast carcinoma. BRCAI interacts biochemically with p53 and may also contribute to poor outcome when constitutionally mutated. The joint effect of both abnormalities has not been studied. The primary objective of this study was to assess the impact of germline BRCA1 mutations and p53 overexpression on survival after 10 years of follow-up.METHODS. A historical cohort of Ashkenazi Jewish women 65 years or younger with invasive breast carcinoma was tested for BRCA1 founder mutations. p53 overexpression was assessed by immunohistochemistry. Clinicopathologic information was obtained by chart review.RESULTS. in total, 278 women were analyzed. On univariate analysis, p53 overexpression (n = 63) was prognostic for worse overall survival (relative risk [RR] 2.6, P = 0.001) whereas BRCA1 germline mutations (n = 30) were of borderline significance (RR 1.9, P = 0.052). In the lymph node-negative subpopulation, BRCAI mutation status conferred a higher mortality on univariate (RR 5.6, P < 0.001) and multivariate (RR 3.5, P = 0.03) analyses. There was a trend in favor of a worse prognosis for women who carried a germline BRCA1 mutation and whose tumor overexpressed p53. When compared with noncarriers, BRCAI mutation carriers had a worse overall survival if they did not receive adjuvant chemotherapy (RR 3.3, P= 0.01) or adjuvant hormonal therapy (RR 2.3, P = 0.02).CONCLUSIONS. Germline BRCA1 mutations and p53 overexpresion carry a negative prognosis that is not additive to known prognostic factors. Given the experimental sensitivity of BRCA1-mutated cells to chemotherapy, the worse survival among BRCA1 mutation-carrying lymph node-negative breast carcinoma patients may be partly explained by the significantly lower proportion of lymph node-negative patients who received adjuvant chemotherapy (P < 0.001). Cancer 2003;97: 527-36. (C) 2003 American Cancer Society.

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.02.130 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12228218 Nonovarian Pelvic Cancers in BRCA1/2 Mutation Carriers and the BRCAPRO Statistical Model Carol CreminxCarol CreminSearch for articles by this author , Nora WongxNora WongSearch for articles by this author , Karen BuzagloxKaren BuzagloSearch for articles by this author , Ann-Josée ParadisxAnn-Josée ParadisSearch for articles by this author , William FoulkesxWilliam FoulkesSearch for articles by this author D.A. BerryxD.A. BerrySearch for articles by this author , G. ParmigianixG. ParmigianiSearch for articles by this author , W. RubinsteinxW. RubinsteinSearch for articles by this author , P. WatsonxP. WatsonSearch for articles by this author Show More Sir M.B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, CanadaUniversity of Texas M.D. Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.2002.02.130 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15092002In Reply:Cremin et al make an important point. BRCAPRO does not incorporate whether each family member has been diagnosed with fallopian tube or peritoneal cancer. The same is true for other cancers that may have different penetrance in mutation carriers than in noncarriers. BRCAPRO could be modified to incorporate family history information about these two cancers, but such a modification requires quantitative information about penetrance. This quantification does not exist. Until it becomes available and BRCAPRO can be modified, some users incorporate fallopian tube and peritoneal cancers as though they were ovarian cancers. This is at best an approximation, but it probably gives a more accurate assessment of risk than does ignoring them.

Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common autosomal dominant inherited diseases. Mutations in the human mismatch repair (MMR) proteins MLH1, MSH2, MSH6, PMS1, and PMS2 have been found to co-segregate with HNPCC. The MLH1 and MSH2 proteins have been demonstrated to interact with PMS1, PMS2, and MSH6 proteins. A previous study reported that missense mutations in specific regions of MLH1 can lead to defects in protein-protein interactions with PMS2. Here we report that three missense alterations previously identified as single nucleotide polymorphisms (SNPs) in PMS2 (P511K, T597S, and M622I) cause defective protein-protein interactions with MLH1, even though the alterations are not in the previously reported interaction domain. These results suggest that an additional domain in PMS2 affects MLH1-PMS2 interaction. This study also demonstrates that SNPs can result in gene alterations that indeed have a functional effect on protein phenotype. Thus, these three SNPs may ultimately represent variants with an increased risk factor for tumorgenesis in HNPCC. This study is one of the first to use a functional assay to appraise the role of SNPs and suggests that traditional definitions of polymorphisms and mutations are in need of reconsideration. Hum Mutat 19:108-113, 2002. (C) 2002 Wiley-Liss, Inc.

There has been much discussion regarding the penetrance of breast cancer in BRCA1 / 2 mutation carriers (hereafter “carriers”). Both genetic and epigenetic factors could be influencing the reported penetrance estimates. We wanted to establish whether the penetrance of BRCA1 / 2 mutations is changing over time. To limit the genetic variability, we studied a cohort of 292 Ashkenazi Jewish (AJ) women diagnosed with first primary invasive breast cancer between 1 January 1980 and 1 November 1995 at a single Montreal Hospital, without regard to family history. All women were diagnosed at less than 65 years of age. Pathology blocks were identified from all women and the three AJ founder mutations in BRCA1 / 2 (185delAG, 5382insC ( BRCA1 ) and 6174delT ( BRCA2 )) were identified in archival samples using PCR based techniques described previously.1 We identified 41 (14%, 95% CI 10.2-18.6) BRCA1/2 carriers (31 in BRCA1 and 10 in BRCA2 ). The difference in mutation frequency between BRCA1 and BRCA2 carriers (10.6% v 3.4%) is statistically significant (Z=3.40, p=0.0007). Given that the population allele frequencies of AJ founder mutations in BRCA1 and BRCA2 are approximately equal (∼1%), this would suggest that BRCA1 has a higher penetrance than BRCA2 by age 65. This observation supports previous data from Canada.2 We then divided the data into quartiles by year of diagnosis and determined whether the proportion of mutation carriers was changing over time. The number of founder BRCA1 / 2 mutations per quartile of year of diagnosis increased from eight (11.0%) to 15 (20.5%) over the 15 year period of the study, and the χ2 p value for the trend in mean scores was 0.047 (table 1). This suggests that the penetrance of BRCA1 / 2 mutations to the age of 65 years is increasing. This is important, as previous studies of …