paywalled: Evolutionary Pathways in BRCAl-Associated Breast Tumors

Evolutionary Pathways in BRCAl-Associated Breast Tumors

Abstract

BRCAl-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.

SIGNIFICANCE: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors.  

Cancer Discov; 2(6); 1–9. ©2012 AACR.

open access: A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome - study of 19 BRCA carriers

A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome 

 ".....ShaRIT strives to ease the “burden of the messenger” and decrease the possibility of mis-communicating and misinterpreting
important medical information to their relatives."

BRCA 1/2 Decision Tool - Stanford Medicine Cancer Institute

 Blogger's Note: variables can be changed eg. age/prophylactic surgery/s (type), easy to use, tip: hold your cursor over the chart to show %'s (outcomes)

BRCA Decision Tool

open access: BRCA1 is an essential regulator of heart function and survival following myocardial infarction (in research, references doxorubicin)

Blogger's Note: technical paper, in research (eg. mice, tissue samples)

                          ~~~~~~~~~~~~~~~~~

BRCA1 is an essential regulator of heart function and survival following myocardial infarction

"BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure."

Marker of DNA Damage Could Predict Response to Platinum Chemotherapy

Marker of DNA Damage Could Predict Response to Platinum Chemotherapy:

• Assay could direct treatment options for triple-negative breast cancer.
• Accumulations of telomere AI predicted sensitivity to therapy.

PHILADELPHIA — Scientists have uncovered a marker of DNA damage that could predict who will respond to platinum-based chemotherapy drugs like cisplatin or carboplatin.
These drugs are widely used for ovarian cancer, but as with most cancer drugs, it can be difficult to predict who will respond to therapy.
A team of researchers from the Dana-Farber Cancer Institute found that this marker, telomeric allelic imbalance or tAI, could predict sensitivity to therapy in patients with triple-negative breast cancer.
The results are published in Cancer Discovery, a journal of the American Association for Cancer Research.
“We currently do not have any targeted therapies for patients with triple-negative breast cancer, so if these laboratory findings are confirmed and an assay is created to predict sensitivity to drugs that target defective DNA repair, it would be a major step forward,” said lead pathologist Andrea Richardson, M.D., Ph.D., assistant professor of medicine at Dana-Farber Cancer Institute.
Scientists have long known that DNA repair status is a predictor of sensitivity to therapy and thus prognosis. However, measurements of DNA repair status have been slow to arrive.
Richardson and colleagues looked for genomic signatures in cell lines and tumors and correlated them to platinum sensitivity.
In patients with triple-negative breast cancer, they found that a high level of subchromosomal regions with allelic imbalance extended to the telomere predicted response to cisplatin treatment. The same was true for serous ovarian cancer.
Importantly for patients with triple-negative breast cancer, researchers found an inverse relationship between the level of tAI and BRCA1 expression.

abstract: Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival.

Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival

Cancer Genet. 2012 Jan;205(1-2):34-41


Abstract
Previous studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared with that of sporadic EOC, but few studies have evaluated differences between BRCA genotypes.

We compared characteristics and outcome by genotype in BRCA-associated EOC. Patients with BRCA-associated EOC who were diagnosed between January 30,1981, and December 30, 2008, were retrospectively identified through institutional review board-approved registry studies. We examined clinical characteristics, including event-free survival (EFS) and overall survival (OS), for BRCA1 versus BRCA2 patients. We identified 197 cases (148 BRCA1 cases; 49 BRCA2 cases); the median follow-up period was 63 months. BRCA2 patients were older (55.4 vs. 51.1 y) and had fewer poorly differentiated tumors (67% vs. 82%). No difference in EFS was observed. OS at 5 years was 75% in BRCA2 patients versus 61% in BRCA1 patients; this was not statistically significant. A non-significant trend toward improved OS was observed in BRCA2 patients with advanced-stage disease (hazard ratio = 0.59; 95% confidence interval 0.32-1.08).

Age and grade differed significantly between BRCA1 and BRCA2 carriers in our study population. Whereas no overall differences in EFS or OS were observed, there was a trend toward improved OS in BRCA2 carriers with advanced-stage disease.

This may reflect important differences between BRCA genotypes and should be validated in larger studies.

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases. (300T>G mutation)

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.:
Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.
Fam Cancer. 2012 Mar 1;


Abstract
It is estimated that about 5-10% of ovarian and 2-5% of all breast cancer patients are carriers of a germline BRCA1 or BRCA2 gene mutation. Most families with detected BRCA1 or BRCA2 gene mutation are qualified for molecular testing on the basis of family history of breast or ovarian cancers. The purpose of our study was to establish the frequency of positive family history of cancer in a series of Polish consecutive breast and ovarian cancer patients in two groups, with and without the BRCA1 gene mutations. We analysed the prevalence of four of the most common BRCA1 mutations: 5382insC (c.5266dupC), 300T>G (p.181T>G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5). The patient group consisted of 1,845 consecutive female breast and 363 ovarian cancer cases. 19 out of 37 (51%) of BRCA1-positive ovarian cancer patients and 21 out of 55 (39%) BRCA1-positive breast cancer had negative family history of breast and/or ovarian cancer among first- and second-degree relatives.

In ovarian cancer patients, negative family history was more frequent in those with 300T>G BRCA1 gene mutation than in 5382insC carriers. This finding indicates the necessity of searching for 300T>G mutation in families with a single diagnosis of ovarian cancer in family. The high frequency of mutations detected in breast cancer patients lacking obvious family history shows that breast cancer patients should be qualified for genetic testing on the basis of wide clinical and pathological criteria.

abstract: Age-Specific Incidence Rates for Breast Cancer in Carriers of BRCA1 Mutations from Norway (compared to Poland/North America)

Clin Genet. 2012 Feb 9. doi: 10.1111/j.1399-0004.2012.01855.x. [Epub ahead of print]

"Incidence rates of breast cancer among women with a BRCA1 mutation vary according to their reproductive histories and country of residence. To measure cancer incidence, it is best to follow cohort of healthy women prospectively. We followed a cohort of 675 women with a BRCA1 mutation who had not had breast or ovarian cancer prior to inclusion and who had a normal clinical examination and mammography at first visit. After a mean of 7.1 years, 98 incident cases of breast cancer were recorded in the cohort. Annual cancer incidence rates were calculated, and based on these, a penetrance curve was constructed. The average annual cancer risk for the Norwegian women from age 25 to 70 was 2.0%. Founder mutations had lower incidence rate (1.7%) than less frequent mutations (2.5%) (p=0.03). The peak incidence (3.1% annual risk) was observed in women from age 50 to 59. The age-specific annual incidence rates and penetrance estimate were compared with published figures for women from North America and from Poland. The risk of breast cancer to age 70 was estimated to be 61% for women from Norway, compared to 55% for women from Poland and 69% for women from North America. (of those BRCA1)"

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers - abstract

Abstract

"Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers."
"Four SNPs, rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31) and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases."
" The identification of multiple loci modifying ovarian cancer risk may be useful for counselling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer."

Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes

"Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations."

European Journal of Human Genetics - Abstract of article: On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

"The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual.............Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice."

abstract: A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas

"Approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a founder mutation in the BRCA1 gene - this is the highest reported mutation prevalence for any country studied to date."

Preventive Surgeries Linked To Lower Risk Of Breast And Ovarian Cancer - BRCA mutations/international study

news article:



free full text/paper:
http://jama.ama-assn.org/cgi/content/full/304/9/967

"Women who have in herited mutations inthe BRCA1 or BRCA2(BRCA1/2) genes have substantially elevated risks of breast cancer and ovarian cancer, with a lifetime risk of breast cancer of 56% to 84%.^1-3 The estimated ovarian cancer risks range from 36% to 63% for BRCA1 mutation carriers and 10% to 27% for BRCA2 mutation carriers.^3-6 Women who are mutation carriers have cancer risk–management options that include risk-reducing salpingo-oophorectomy, risk-reducing mastectomy, annual cancer screening, and chemoprevention. Due to the lack of effective screening for ovarian cancer, salpingo-oophorectomy is strongly recommended once childbearing is complete."

U of Toronto researcher discovers key protein involved in DNA repair Discovery gives insight into the way cells protect their own genetic material

Note: in research

"In a groundbreaking study, U of T researchers including Professors Daniel Durocher, Anne‐Claude Gingras and Frank Sicheri have uncovered a protein called OTUB1 that blocks DNA damage in the cell—a discovery that may lead to the development of strategies to improve some cancer therapies.
Lead author Durocher, a senior investigator at Mount Sinai Hospital’s Samuel Lunenfeld Research Institute and the Thomas Kierans Research Chair in Mechanisms of Cancer Development, as well as colleagues at U of T, Mount Sinai Hospital and the Keio University in Japan, have revealed pivotal new information on how cells regulate their genetic material. In addition, the discovery improves understanding of familial breast and ovarian cancer, as the research shows that OTUB1 inhibits the action of BRCA1, a DNA repair protein often mutated in these cancers...."cont'd

Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations

Abstract
Mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. Patients with mutations in both genes are rarely reported and often involve Ashkenazi founder mutations. ......Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family double heterozygote for BRCA1 and BRCA2 mutations.

clinical trial: Attitudes About Childbearing And Fertility With Inherited Breast And Ovarian Cancer Syndromes (HBOC) - Full Text View - ClinicalTrials.gov

Purpose

Objectives:

- To evaluate the attitudes and opinions of women undergoing genetic counseling for hereditary breast and ovarian cancer syndrome, both before and after testing, in regards to pregnancy and fertility

Cancer drug olaparib (PARP inhibitor) shows early promise | Philadelphia Inquirer (BRCA 1/2)

Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit From Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer

ABSTRACT

Purpose
The prevalence of BRCA1/2 mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA1/2 changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.

Conclusion
BRCA1/2 somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.

Testing for CHEK2 in the cancer genetics clinic: ready for prime time?

Abstract

Narod SA.
Testing for CHEK2 in the cancer genetics clinic: ready for prime time?

The 1100delC mutation of the CHEK2 gene was found to be a cause of breast cancer in 2002. The lifetime risk of breast cancer among women with a mutation and with a family history of breast cancer is approximately 25%. These women are good candidates for screening with MRI and for chemoprevention with tamoxifen. It is reasonable to test for this single mutation when women undergo testing for BRCA1 and BRCA2.

BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer — Ann Oncol

Background:
Neoadjuvant chemotherapy has shown a modest benefit in muscle-invasive bladder cancer patients; however, the subset of patients most likely to benefit has not been identified. BRCA1 plays a central role in DNA repair pathways and low BRCA1 expression has been associated with sensitivity to cisplatin and longer survival in lung and ovarian cancer patients.

Conclusions:
Our data suggest that BRCA1 expression may predict the efficacy of cisplatin-based neoadjuvant chemotherapy and may help to customize therapy in bladder cancer patients.