Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin.

Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin

Breast Cancer Res Treat. 2012 Mar 21;

Abstract

Large genomic rearrangements (LGRs) at the BRCA2 locus explain a non-negligible proportion of hereditary breast and ovarian cancer (HBOC) syndromes. The multiplex ligation and probe amplification (MLPA) assay has permitted in recent years to identify several families carrying LGRs at this locus, but very few such alterations have been fully characterized at the molecular level. Yet, molecular characterization is essential to identify recurrent alterations, to analyze the genetic mechanisms underlying such alterations, or to investigate potential genotype/phenotype relationships. We have used MLPA

abstract: Peritoneal washing cytology in patients with BRCA1 or BRCA2 mutations undergoing risk-reducing salpingo-oophorectomies: A 10-year experience and reappraisal of its clinical utility

Peritoneal washing cytology in patients with BRCA1 or BRCA2 mutations undergoing risk-reducing salpingo-oophorectomies: A 10-year experience and reappraisal of its clinical utility



Peritoneal washing cytology in patients with BRCA1 or BRCA2 mutations undergoing risk-reducing salpingo-oophorectomies: A 10-year experience and reappraisal of its clinical utility.

Abstract

OBJECTIVE:

To evaluate the utility of peritoneal washing cytology (PWC) for detecting occult primary peritoneal carcinoma in patients with BRCA1 or BRCA2 mutations, we reviewed PWCs obtained during risk-reducing salpingo-oophorectomy (RRSO) from 117 patients at our institution and correlated the results with surgical pathology findings.........

JCO abstract: Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers (185delAG, 5382insC, 6174delT)

Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers

Purpose 

Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. 

Methods 

Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. 

Results 

Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers. No significant difference was seen in cancer risk reduction after RRSO among subgroups. 

Conclusion 

Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.

Myriad, Prometheus Continue to Defend Diagnostic Patents while Others Urge More Licensing (BRCA patients)

MBCC: PARP Inhibitors for Breast Cancer—Which Subpopulation to Target? - Cancer Network (BRCA, triple-negative breast...)

MBCC: PARP Inhibitors for Breast Cancer—Which Subpopulation to Target? - Cancer Network

"Speaking at the 29th Annual Miami Breast Cancer Conference, Jorge S. Reis-Filho, PhD, MD, professor of medical pathology at the Institute of Cancer Research in London, England, described the rationale of applying poly (ADP-ribose) polymerase inhibitors (PARP) to breast cancer patients.

Tumors that have a loss of function in DNA-repair genes such as BRCA1 and BRCA2, and homologous recombination, as Dr. Joyce O'Shaughnessy described during her session on emerging triple-negative breast cancer therapies, may be particularly sensitive to PARP inhibitors.

Reis-Filho highlighted that sequencing tumors may not be enough to characterize whether tumors have intact DNA-repair pathways—tumors also have epigenetic changes that regulate homologous recombination......"

abstract: Shared Genetic Basis for Breast Cancer and Breast Density

Shared Genetic Basis for Breast Cancer and Breast Density:

" Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants."

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer.

Recurrent germline mutations in BRCA... [Breast Cancer Res Treat. 2012] - PubMed - NCBI

Recurrent germline mutations in BRCA... [Breast Cancer Res Treat. 2012] - PubMed - NCBI
 Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel.

Abstract

The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations, respectively.

open access: Nature Reviews: Key Advances in Medicine - Ovarian Cancer/Markman page 15-16

Key Advances in Medicine (book)


Nature Reviews Clinical Oncology  (page 15)S11 ovarian cancer | Mutations and non-inferiority analyses show a way forward Maurie Markman      (page 15-16)






Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of alternative primary and second-line management strategies.

"Although there were a number of very interesting
preliminary reports of therapeutic
advances in ovarian cancer in 2011 (for
example, bevacizumab in the first-line and
second-line management of the malignancy,
and olaparib  (Blogger's Note: links to Olaparib (parp inhibitor) - Cancer Research UK)  as maintenance therapy for
high-grade serous cancers), as of the writing
of this commentary these studies have not
appeared in the peer-reviewed oncology literature......."

Key advances
■■ There are currently no evidence-based
data supporting the clinical utility of any
ovarian cancer screening strategy in
non‑high-risk populations1
■■ Provocative data suggest there may be a
clinically meaningful difference between
the presence of a BRCA1 or a BRCA2
mutation in influencing outcome in ovarian
cancer6
■■ Under specific circumstances (for example,
neuropathy) it might be reasonable to
substitute pegylated liposomal doxorubicin
for paclitaxel in the front-line chemotherapy
management of ovarian cancer7

Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200

                                   ~~~~~~~~~~~~~
"The articles included in Nature Reviews Key Advances in
Medicine were originally published in the February 2012
issues of the eight clinical Nature Reviews journals. The journals’
editors commissioned international experts to write a short
essay highlighting up to five key papers that made the biggest
contribution to their field in 2011."

open access - pdf: Risk-Reducing Bilateral Salpingo-Oophorectomy and Sexual Health: A Qualitative Study

Abstract
Objective: To examine the impact of risk-reducing bilateral salpingo-oophorectomy (RRBSO) on sexual function in BRCA gene
mutation carriers, compared with the effect on women undergoing
BSO (bilateral salpingo-oophorectomy) for benign indications from
a qualitative perspective.

Methods: 
Our study included 25 women who had undergone either
a RRBSO because of BRCA carrier status or a BSO for a benign
gynaecologic indication. Women were invited to participate if they
were at least six months post-BSO. They took part in an individual,
private interview during which they were asked open-ended
questions about their sexual health in the context of undergoing
BSO......

Long-term outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance (risk reducing surgery - breasts/bilateral salpino-oophorectomies)

Abstract

BACKGROUND:

For BRCA1/BRCA2 gene testing to benefit public health, mutation carriers must initiate appropriate risk management strategies. There has been little research examining the long-term use and prospective predictors of the full range of risk management behaviors among women who have undergone BRCA1/2 testing. We evaluated long-term uptake and predictors of risk-reducing mastectomy (RRM), risk-reducing bilateral salpingo-oophorectomy (RRBSO), chemoprevention, and cancer screening among women at a mean of 5.3 years after testing.

METHODS:

The study participants comprised 465 women who underwent BRCA1/2 testing. Prior to genetic counseling, we measured family/personal cancer history, sociodemographics, perceived risk, cancer-specific distress, and general distress. We contacted patients at a mean of 5.3 years after testing to measure use of RRM, RRBSO, chemoprevention, and breast and ovarian cancer screening.

RESULTS:

Among participants with intact breasts and/or ovaries at the time of testing, BRCA1/2 carriers were significantly more likely to obtain RRM (37%) and RRBSO (65%) compared with women who received uninformative (RRM, 6.8%; RRBSO, 13.3%) or negative (RRM, 0%; RRBSO, 1.9%) results. Among carriers, precounseling anxiety was associated with subsequent uptake of RRM. RRO was predicted by age. Carriers were also more likely have used breast cancer chemoprevention and have undergone magnetic resonance imaging screening.

CONCLUSION:

This prospective evaluation of the uptake and predictors of long-term management outcomes provides a clearer picture of decision making in this population. At a mean of 5.3 years after testing, more than 80% of carriers had obtained RRM, RRBSO, or both, suggesting that BRCA1/2 testing is likely to have a favorable effect on breast and ovarian cancer outcomes.

Earlier age of onset of BRCA mutation-related cancers (breast and ovarian cancers)... [Cancer. 2012] - PubMed - NCBI

Earlier age of onset of BRCA mutation-related cancers in subsequent generations.

Abstract

BACKGROUND:

Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages. In this study, the authors assessed age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations.

METHODS:

Of the 132 BRCA-positive women with breast cancer who participated in a high-risk protocol at The University of Texas MD Anderson Cancer Center (Gen 2), 106 women could be paired with a family member in the previous generation (Gen 1) who was diagnosed with a BRCA-related cancer (either breast cancer or ovarian cancer). Age at diagnosis, location of the mutation, and year of birth were recorded. A previously published parametric anticipation model was applied in these genetically predisposed families.

RESULTS:

The median age of cancer diagnosis was 42 years (range, 28-55 years) in Gen 2 and 48 years (range, 30-72 years) in Gen 1.
In the parametric model, the estimated change in the expected age at onset for the entire cohort was 7.9 years. Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer-identified and ovarian cancer-identified families.

CONCLUSIONS:

Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations. The authors concluded that patients who are younger at the onset of BRCA-related cancers should continue to be tracked to offer appropriate screening modalities at appropriate ages.

Clinical Oncology News - Study Details Risks for Contralateral Cancer in BRCA1/2

"For years, researchers have known that the risk that a woman will develop CBC is higher than an average woman’s risk for developing a first cancer and that this risk is even greater if the woman carries the BRCA1/2 mutation."


Table. 10-year Risk for Contralateral Breast Cancer: Key Stats



"Dr. Van Poznak said the information in the study would help doctors counsel patients. “The analysis performed in this large database of European women under the age of 50 suggests that risks for contralateral breast cancer within 10 years may be estimated based on age and BRCA1/2 status,” she said.

Ms. van den Broek said that if the results are confirmed in other studies, age criteria and receptor status of the first breast cancers might be included in guidelines for prophylactic measures and screening in the follow-up of BRCA1/2 mutations carriers."

not yet recruiting: phase 11/BRCA - Veliparib in Treating Patients With Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer - Full Text View - ClinicalTrials.gov

Condition:
brca1 Mutation Carrier
brca2 Mutation Carrier
Fallopian Tube Cancer
Ovarian Cancer
Primary Peritoneal Cavity Cancer

Criteria

DISEASE CHARACTERISTICS:

• Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma AND carry a germline mutation in BRCA1 or BRCA2 (confirmation required via Myriad test report); histologic documentation of the original primary tumor is required via the pathology report........

Veliparib in Treating Patients With Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This study is not yet open for participant recruitment.

Verified February 2012 by National Cancer Institute (NCI)

First Received on February 22, 2012. No Changes Posted

Sponsor:	Gynecologic Oncology Group
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT01540565

open access: Correspondence Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: More Trouble With Phenocopies

Correspondence:  Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: More Trouble With Phenocopies

• D. Gareth Evans and
• Anthony Howell

JCO published online on February 27, 2012; DOI:10.1200/JCO.2011.40.8021.

• [PDF]

abstract: Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Blogger's Note: large study size/international collaboration

Abstract

BACKGROUND:

Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

METHODS:

Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.

RESULTS:

......We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1  and BRCA2 mutation carriers. (#'s removed for ease of reading - see abstract)

CONCLUSIONS:

19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.Impact:
These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.

recruiting: Validation of a Mouse Model of Pancreatic Carcinogenesis - Full Text View - ClinicalTrials.gov (note: brca1/brca2/Ashkenazi Jew)) pancreatic cancer tissue)

First Received on April 12, 2010. Last Updated on February 14, 2012 History of Changes

Purpose

The primary aim of this study is to determine if mutations of BRCA1 and BRCA2 result in different precancerous pathways to pancreatic ductal adenocarcinoma (PDAC), as suggested in our validated mouse model.

Genomic DNA will be isolated on normal tissue obtained from patients who underwent pancreatic resection for PDAC, intraductal papillary mucinous neoplasm (IPMN) or mucinous cystic neoplasm (MCN).

Tissue will be examined for the three most common founder mutations in Ashkenazi Jews. In the cases in which BRCA1 or BRCA2 mutations are found, heterozygote normal and abnormal tissue will be examined to look for mutations in the other BRCA1 or BRCA2 allele. The interaction between other cancer causing genes with BRCA1/2 will also be evaluated by comparing the sequences of the other genes in pre-cancerous lesions.

We hypothesize that BRCA1- and BRCA2-mediated pancreatic ductal adenocarcinoma progresses through the PanIN route, as seen in both BRCA1 and BRCA2 murine (mouse/mice)models of pancreatic cancer. We further hypothesize that BRCA1 mutations may enable an additional pre- neoplastic pathway through MCN, and that IPMN may embody yet another pre- neoplastic pathway.

Study Population

All subjects have a tissue-confirmed diagnosis of pancreatic adenocarcinoma, MCN or IPMN and underwent surgical resection for pancreatic adenocarcinoma, MCN or IPMN at Columbia-Presbyterian Medical Center.

Criteria

Inclusion Criteria:

• Tissue-confirmed diagnosis of pancreatic adenocarcinoma, MCN, or IPMN.
• Underwent surgical resection for pancreatic adenocarcinoma, MCN, or IPMN.

Seminars in Oncology: Variants of Uncertain Significance in Breast Cancer–Related Genes: Real-World Implications for a Clinical Conundrum. Part One: Clinical Genetics Recommendations

Article Outline (August 2011)

• Positive BRCA1 or BRCA2
• Negative BRCA1 and BRCA2
• Variant of Uncertain Clinical Significance
• Case No. 1: BRCA1 VUS
  • Clinical Discussion Points
• Case No. 2: BRCA2 VUS
• Case No. 3: BRCA2 VUS Favoring Polymorphism
• Clinical Discussion Points (Cases No. 2 and 3)
• Clinical Geneticists' Opinions
• Cancer Geneticists' Opinions
• Clinical Geneticists' Opinions
• Discussion
• References

abstract: Cochrane review: Cancer genetic risk assessment for individuals at risk of familial breast cancer.

Cochrane Database Syst Rev. 2012 Feb 15;2:CD003721.

Abstract

BACKGROUND:

The recognition of an inherited component to breast cancer has led to an increase in demand for information, reassurance, and genetic testing, which has resulted in the creation of genetic clinics for familial cancer. The first step for patients referred to a cancer genetic clinic is a risk assessment.

OBJECTIVES:

To evaluate the impact of cancer genetic risk-assessment services on patients at risk of familial breast cancer.

SELECTION CRITERIA:
We considered trials looking at interventions for cancer genetic risk-assessment services for familial breast cancer for inclusion. Trials assessed outcomes such as understanding of risk, satisfaction and psychological well-being. We excluded studies if they concerned cancers other than breast cancer or if participants were not at risk of inherited breast cancer. We also excluded trials concerning the provision of general cancer genetic information or education as this review was concerned with the delivery of genetic risk assessment. Participants could be individuals of any age or gender, with or without a known BRCA mutation, but without a previous history of breast cancer or any other serious illness.

MAIN RESULTS:
In this review update, we included five new trials, bringing the total number of included studies to eight. The included trials (pertaining to 10 papers), provided data on 1973 participants and assessed the impact of cancer genetic risk assessment on outcomes including perceived risk of inherited cancer, and psychological distress. This review suggests that cancer genetic risk-assessment services help to reduce distress, improve the accuracy of the perceived risk of breast cancer, and increase knowledge about breast cancer and genetics. The health professional delivering the risk assessment does not appear to have a significant impact on these outcomes.

AUTHORS' CONCLUSIONS:

This review found favourable outcomes for patients after risk assessment for familial breast cancer. However, there were too few papers to make any significant conclusions about how best to deliver cancer genetic risk-assessment services. Further research is needed assessing the best means of delivering cancer risk assessment, by different health professionals, in different ways and in alternative locations.

Is Myriad’s Patent On Breast Cancer Genes Valid? | CT Health I-Team (some things you may not know)

re: NICE guidelines - Hundreds more breast cancer patients should be tested for BRCA1 gene