OVARIAN CANCER and US: BRCA

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Showing posts with label BRCA. Show all posts
Showing posts with label BRCA. Show all posts

Saturday, May 26, 2012

Squamous Cell Carcinoma of the Oral Cavity in Nonsmoking Women: A New and Unusual Complication of Chemotherapy for Recurrent Ovarian Cancer? PLD (pegylated liposomal doxorubicin)





Squamous Cell Carcinoma of the Oral Cavity in Non smokingWomen: A New and Unusual Complication of Chemotherapy for Recurrent Ovarian Cancer?

Abstract
Purpose.
To describe occurrences of oral squamous cell carcinoma (SCC) in patients who had received long-term pegylated liposomal doxorubicin (PLD) for ovarian cancer.

Patients and Methods.
In our cohort of patients on maintenance PLD for ovarian and related mullerian epithelial malignancies, we encountered two patients with invasive SCC of the oral cavity (one of them multifocal) and one with high-grade squamous dysplasia. Review of patients at our institution receiving PLD for recurrent ovarian cancer identified three additional patients. The duration of treatment, cumulative PLD dose, human papillomavirus (HPV) positivity, BRCA status, stage at diagnosis, outcome, and other characteristics are reviewed.

Results.
All five cases were nonsmokers with no known risk factors for HPV and four were negative for p16 expression. Four of the patients had known BRCA mutations whereas one tested negative. Cumulative doses of PLD were >1,600 mg/m(2) given over 30-132 months. Three had SCCs staged as T1N0 oral tongue, alveolar ridge (gingival), and multifocal oral mucosa; one had a T2N0 oral tongue; and one had dysplasia. After excision, two were given radiation but recurred shortly thereafter; the others remain well and have had no further exposure to cytotoxic drugs, including PLD.

Conclusion. 
Awareness of this possible long-term complication during PLD treatment should enhance the likelihood of early detection of oral lesions in these patients. Decisions to continue maintenance PLD after complete response of the original cancer should perhaps consider the benefits of delaying ovarian cancer recurrence versus the possible risk for a secondary cancer. 

The finding of oral SCC in patients on long-term PLD
maintenance should alert oncologists to have a high index of
suspicion with any oral complaints that arise, and suggests a
possible need for regular oral examinations in this treatment
population. How long to continue maintenance with PLD after
a CR has been achieved is an unanswered question. The possible
risks to patients receiving maintenance PLD beyond CR
must be weighed against the presumed benefits of delaying
ovarian cancer recurrence on an individual basis.

Thursday, May 17, 2012

paywalled: Long-term results of screening with magnetic resonance imaging in women with BRCA mutations : British Journal of Cancer



Long-term results of screening with magnetic resonance imaging in women with BRCA mutations : British Journal of Cancer

Background: 

The addition of breast magnetic resonance imaging (MRI) to screening mammography for women with BRCA mutations significantly increases sensitivity, but there is little data on clinical outcomes. We report screening performance, cancer stage, distant recurrence rate, and breast cancer-specific mortality in our screening study.

Methods:

From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2 mutation, of whom 380 had no previous cancer history, were enrolled in a prospective screening trial that included annual MRI and mammography.

Results:

In 1847 screening rounds, 57 cancers were identified (53 screen-detected, 1 interval, and 3 incidental at prophylactic mastectomy), of which 37 (65%) were invasive. Sensitivity of MRI vs mammography was 86% vs 19% over the entire study period (P<0.0001), but was 74% vs 35% from 1997 to 2002 (P=0.02) and 94% vs 9% from 2003 to 2009 (P<0.0001), respectively. The relative sensitivities of MRI and mammography did not differ by mutation, age, or invasive vs non-invasive disease. Of the incident cancers, 97% were Stage 0 or 1. Of 28 previously unaffected women diagnosed with invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%). Three patients died of other causes. None of the 24 survivors has had a distant recurrence at a median follow-up of 8.4 years since diagnosis.

Conclusion:

Magnetic resonance imaging surveillance of women with BRCA1/2 mutations will detect the majority of breast cancers at a very early stage. The absence of distant recurrences of incident cancers to date is encouraging. However, longer follow-up is needed to confirm the safety of breast surveillance.

Wednesday, May 09, 2012

paywalled: Diathermy-Induced Injury May Affect Detection of Occult Tubal Lesions at Risk-Reducing Salpingo-Oophorectomy




Diathermy: In the natural sciences, the term diathermy means "electrically induced heat" and is commonly used for muscle relaxation. It is also a method of heating tissue electromagnetically or ultrasonically for therapeutic purposes in medicine.





Diathermy-Induced Injury May Affect Detection of Occult Tuba... : International Journal of Gynecological Cancer

Background: Electrosurgery-induced tubal thermal injury obscures cellular detail and hampers histomorphological assessment for occult pathology.

Objective
The objectives of this study were to report on diathermy-related thermal injuries to the fallopian tube observed at RRSO and explore its potential impact on the detection of occult tubal epithelial lesions.

Design
This study was composed of high-risk women from breast and/or ovarian cancer families attending a tertiary high-risk familial gynecologic cancer clinic. This was a retrospective case-control analysis of high-risk women who underwent RRSO. Cases were all women detected to have occult lesions (tubal atypia/carcinoma in situ/cancer) between January 2005 and December 2010. Control subjects were all women with normal tubal/ovarian histology between August 2006 and December 2007.

Conclusions: This report highlights the potential impact of electrosurgical thermal injury on detection of occult tubal pathology following RRSO. It is important for surgeons to avoid thermal injury to the distal end of the tube.

paywalled - Outcomes of Primary Surgical Cytoreduction in Patients with BRCA-associated High-grade Serous Ovarian Carcinoma



 Outcomes of Primary Surgical Cytoreduction in Patients with BRCA-associated High-grade Serous Ovarian Carcinoma


Objective

BRCA-associated and sporadic ovarian cancers have different pathologic and clinical features. Our goal was to determine if BRCA mutation status is an independent predictor of residual tumor volume following primary surgical cytoreduction.

Highlights

► Differences in the biology of BRCA-associated and sporadic ovarian cancers do not result in differences in primary surgical outcomes.
► The improved survival of BRCA-associated ovarian cancers is not confounded by differences in primary surgical outcome.

Sunday, May 06, 2012

Epigenetic modification and cancer: mark or stamp? (BRCA/fallopian tube....)



Epigenetic modification and cancer: mark or stamp?

Abstract

Hypotheses are built upon data, but data require hypotheses before they can be understood. The development of the ‘two-hit’ hypothesis of carcinogenesis was a key event in cancer genetics because it provided a testable model of how tumours develop. In this commentary on ‘Promoter hypermethylation patterns in Fallopian tube epithelium of BRCA1 and BRCA2 germline mutation carriers’ by Bijron et al. published in the February 2012 issue of Endocrine-Related Cancer, the need for new grammar and some new hypotheses in epigenetics is discussed. Meanwhile, data suggesting an important role of epigenetic modification in the cause, progression and treatment of cancer continues to accumulate............

Introduction

In hereditary tumours, the first hit occurs in the germ line, whereas in non-hereditary tumours, the first hit occurs in the cell from which the tumour arises. The second hits are always somatic, and can inactivate the second allele in various different ways. The development of the ‘two-hit’ hypothesis of carcinogenesis was a key event in cancer genetics because it provided a testable model of how tumours develop (Knudson 1971, 1978). Although there have been extensions and revisions to the basic model (Tomlinson et al. 2001), the essential elements of the basic hypothesis remain intact, 40 years on. In the original ‘test case’ of RB-1 mutations in retinoblastoma, these events were physical alterations in the structure of the chromosome or gene (Cavenee et al. 1983), and the perception was such that physical changes put a ‘stamp’ on the tumour that could be detected by examination of genomic DNA.............
continue to read full paper

Wednesday, April 25, 2012

paywalled: Targeting the DNA damage response in oncology: past, presen... : Current Opinion in Oncology



Targeting the DNA damage response in oncology: past, presen... : Current Opinion in Oncology

Current Opinion in Oncology:
May 2012 - Volume 24 - Issue 3 - p 316–324
doi: 10.1097/CCO.0b013e32835280c6
INNOVATIVE EARLY CLINICAL TRIALS METHODOLOGY AND NEW THERAPEUTICS IN CANCER: Edited by Ahmad Awada

Targeting the DNA damage response in oncology: past, present and future perspectives

Abstract

Purpose of review: 
The success of poly(ADP-ribose) polymerase inhibition in BRCA1 or BRCA2 deficient tumors as an anticancer strategy provided proof-of-concept for a synthetic lethality approach in oncology. There is therefore now active interest in expanding this approach to include other agents targeting the DNA damage response (DDR). We review lessons learnt from the development of inhibitors against DNA damage response mechanisms and envision the future of DNA repair inhibition in oncology.

Wednesday, April 18, 2012

abstract: [Clinical aspects of familial ovarian cancer - current status and issues in Japan] (focus on brca)



Blogger's Note: the [ ] indicates translated version


[Clinical aspects of familial ovarian cancer - current status and issues in Japan]

Abstract
Familial ovarian cancer occurs as part of two genetically distinct syndromes: hereditary breast and ovarian cancer(HBOC) and hereditary nonpolyposis colorectal cancer(HNPCC) (Lynch Syndrome) .

HBOC caused by inherited mutations of BRCA1/2 and HNPCC caused by mismatch-repair genes are considered responsible for about 65 to 75% and 10 to 15% of familial ovarian cancers, respectively. Germline mutations of BRCA1 are considered responsible for about 50% of ovarian cancer families and 80% of breast-ovarian cancer families. BRCA2 mutations are less common than BRCA1 mutations in ovarian cancer families. A high proportion of serous adenocarcinomas at an advanced stage has been reported with BRCA-related ovarian cancers in several studies. It is controversial whether BRCA-related ovarian cancer patients carry a better prognosis despite the aggressive tumor-pathological characteristics of their disease, compared to sporadic cases. However, a good therapeutic response may be attributable to platinum-based chemotherapy. Recently in Japan, gene testing of BRCA1/2 has been available as a routine clinical test for diagnosing ovarian cancer families. Because the mutation spectrum of BRCA1/2 in Japanese was different from that of non-Ashkenazi individuals, the clinical application of BRCA1/2 gene testing for Japanese has been advocated. Approximately 1-5% of ovarian cancer pa-tients in Japan are thought to have a family history of breast and/or ovarian cancer. The prevalence of deleterious mutations of BRCA1/2 in Japanese was reportedly significantly higher than that of non-Ashkenazi individuals despite the low frequency of familial cases in Japan. Although the age at diagnosis of ovarian cancers with BRCA1/2 mutation in the United States was earlier than those of the sporadic cases, there were no differences among Japanese. These results suggest that clinical and genetic aspects of BRCA-related ovarian cancer of the Japanese are different from those of Caucasians.

A serious issue in this field is how the results will lead to a basis for the clinical application of a cancer prevention strategy targeting BRCA mutation carriers in Japanese.


Monday, April 16, 2012

open access: Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations (technical)



Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations - UKPMC Article - UK PubMed Central

Abstract
Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.
Key words: homologous recombination, PARP inhibitor, BRCA1, BRCA2, PTEN, PALB2, EMSY, double strand break repair

Saturday, April 14, 2012

open access: Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome



ScienceDirect.com - Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome

 "....While endometrial cancer diagnosed under the age of 50 is not included in the Revised Bethesda Guideline, evidence suggests that these individuals should be evaluated for Lynch syndrome (Resnick et al., 2009). The patient presented was diagnosed with endometrial cancer at the age of 41 and genetic testing revealed triple heterozygosity for BRCA2, MLH1 and MSH6 mutations."

 Introduction

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant cancer susceptibility syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and less frequently MSH6 and PMS2. MMR mutation carriers are predisposed primarily to colorectal cancer and endometrial cancer, with an increased frequency of stomach, ovary, pancreas, upper urinary tract, brain, small bowel, and skin consistently reported. This hereditary syndrome accounts for approximately 2–3% of colorectal cancers and 1–4% of endometrial cancers in the United States (Lynch and de la Chapelle, 2003). Depending on the MMR gene involved, women with Lynch syndrome can have up to an 80% lifetime risk of developing colorectal cancer, and a 20–60% risk of endometrial cancer.

Germline mutations in BRCA1 or BRCA2 (BRCA1/2) cause hereditary breast ovarian cancer syndrome. Female carriers of BRCA1/2 mutations have excessive risks for both breast and ovarian cancer, with lifetime breast cancer estimates ranging from 45% to 84%, and lifetime ovarian cancer estimates ranging from 11% to 62%, depending upon the population studied. BRCA1/2 kindreds are also noted to have an increased frequency of prostate cancer, and in BRCA2 kindreds, increased frequencies of pancreatic cancer and melanoma are observed. The frequency of BRCA1 or BRCA2 mutations in the general population is estimated to be 1 in 300 to 1 in 800, respectively (King et al., 2003).

While there are kindreds with more than one cancer susceptibility syndrome and/or mutation reported in the literature ( [Thiffault et al., 2004] and [Smith et al., 2008]), they are not often encountered in routine clinical settings........


Highlights

► Endometrial cancer with BRCA2 mutation and double heterozygosity for Lynch syndrome.
► Loss of MLH1 and PMS2 by immunohistochemical stain.
► MSH1 and MSH6 gene mutations by genomic sequencing.

Thursday, April 12, 2012

abstract: Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases.



Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases.:

J Med Genet. 2012 Apr 6;

Abstract

Background
Alterations in telomere maintenance mechanisms leading to short telomeres underlie different genetic disorders of ageing and cancer predisposition syndromes. It is known that short telomeres and subsequent genomic instability contribute to malignant transformation, and it is therefore likely that people with shorter telomeres are at higher risk for different types of cancer. Recently, the authors demonstrated that the genes BRCA1 and BRCA2 are modifiers of telomere length (TL) in familial breast cancer. The present study analysed TL in peripheral blood leucocytes of hereditary and sporadic ovarian cancer cases, as well as in female controls, to evaluate whether TL contributes to ovarian cancer risk.

Methods
TL was measured by quantitative PCR in 178 sporadic and 168 hereditary ovarian cases (46 BRCA1, 12 BRCA2, and 110 BRCAX) and compared to TL in 267 controls.

Results
Both sporadic and hereditary cases showed significantly shorter age adjusted TLs than controls. Unconditional logistic regression analysis revealed an association between TL and ovarian cancer risk with a significant interaction with age (p<0.001). Risk was higher in younger women and progressively decreased with age, with the highest OR observed in women under 30 years of age.

Conclusion
These findings indicate that TL could be a risk factor for early onset ovarian cancer.


Tuesday, April 10, 2012

abstract: Medium-sized deletion in the BRCA1 gene: Limitations of Sanger sequencing and MLPA analyses.



Medium-sized deletion in the BRCA1 gene: Limitations of Sanger sequencing and MLPA analyses

Sanger sequencing and MLPA analyses.
Genet Mol Biol. 2012

Abstract
We describe a family with a history of breast and ovarian cancer in which MLPA analysis of the BRCA1 gene pointed to a deletion including a part of exon 11. Further characterization confirmed a loss of 374 bp in a region completely covered by conventional sequencing which had not revealed the deletion. Because this alteration was only detected serendipitously with an MLPA probe, we calculated the probabilities of detecting medium-sized deletions in large exons by methods including initial PCR amplification. This showed that a considerable fraction of medium-sized deletions are undetectable by currently used standard methods of mutation analyses. We conclude that long, widely overlapping amplicons should be used to minimize the risk of missing medium-sized deletions. Alternatively, large exons could be completely covered by narrow-spaced MLPA probes.



abstract: BRCA genetic testing of individuals from families with low prevalence of cancer: experiences of carriers and implications for population screening : small study 14 Ashkenazi Jewish women



BRCA genetic testing of individuals from families with low prevalence of cancer: experiences of carriers and implications for population screening : Genetics in Medicine : Nature Publishing Group

Purpose:

BRCA genes are associated with hereditary breast and ovarian cancers. Guidelines worldwide currently recommend BRCA genetic testing in asymptomatic individuals only if they belong to “high-risk” families. However, population screening for BRCA1/2 may be the logical next step in populations with a high prevalence of founder mutations, such as Ashkenazi Jews. This study aimed to explore (i) the impact of a positive BRCA genetic test result on individuals who have neither a personal history nor a familial history of cancer and (ii) their attitudes toward the concept of population screening.

Methods:

Semistructured in-depth interviews were carried out with 14 Ashkenazi Jewish women who were asymptomatic BRCA carriers and who belonged to families with low prevalence of cancer.

Results:

Three main findings emerged: (i) having no family history of cancer was a source of optimism but also confusion; (ii) engaging in intensified medical surveillance and undergoing preventive procedures was perceived as health-promoting but also tended to induce a sense of physical and psychological vulnerability; and (iii) there was overall support for BRCA population screening, with some reservations.

Conclusion:

Women belonging to low-cancer-prevalence families within a “high-risk” ethnic community view BRCA genetic testing positively despite the difficulties entailed, because it allows prevention or early detection of cancer. However, implementing a BRCA population screening program should be carried out with proper pre- and post-testing preparation and support for the individuals undergoing testing.

Thursday, April 05, 2012

abstract: Eligibility criteria in private and public coverage policies for BRCA genetic testing and genetic counseling.



Eligibility criteria in private and public coverage policies for BRCA genetic testing and genetic counseling

Genet Med. 2011 Dec;13(12):1045-50. doi: 10.1097/GIM.0b013e31822a8113.

Abstract

PURPOSE:

Coverage policies for genetic services for hereditary cancers are of interest because the services influence cancer risk reduction for both persons with cancer and their family members. We compared coverage policies for BRCA genetic testing and genetic counseling among selected payers in the United States to illuminate eligibility criteria variation that may explain differential access by insurance type. We compared these policies with policies for breast cancer screening with magnetic resonance imaging to consider whether payers apply a unique policy approach to genetic services.

METHODS:

We conducted a case study of large private and public payers selected on number of covered lives. We examined coverage policies for BRCA genetic testing, genetic counseling, and screening with magnetic resonance imaging and the eligibility criteria for each. We compared eligibility criteria against National Comprehensive Cancer Network guidelines.

RESULTS:

Eligibility criteria for BRCA testing were related to personal history and family history of cancer. Although private payers covered BRCA testing for persons with and without cancer, the local Medicare carrier in our study only covered testing for persons with cancer. In contrast, Arizona's Medicaid program did not cover BRCA testing. Few payers had detailed eligibility criteria for genetic counseling. Private payers have more detailed coverage policies for both genetic services and screening with magnetic resonance imaging in comparison with public payers.

CONCLUSION:

Despite clinical guidelines establishing standards for BRCA testing, we found differences in coverage policies particularly between private and public payers. Future research and policy discussions can consider how differences in private and public payer policies influence access to genetic technologies and health outcomes.

Friday, March 30, 2012

science daily: New breast cancer susceptibility gene (brca)



New breast cancer susceptibility gene

"....XRCC2 may also provide a new target for chemotherapy. "A type of drug called a PARP inhibitor appears to kill tumor cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. It's reasonably likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with PARP inhibitors," said Tavtigian......."

Cancer Connect: Decoding Annie Parker - 2012 film (breast, ovarian, BRCA...)



Decoding Annie Parker:

A cancer survivor’s personal mission to educate others about genetic testing brings her story to the big screen.

The film is produced by Dorado Media and Capital and Media House Capital and initially will be presented at international film festivals before it is broadly distributed. For more information visit www.doradomedia.com.


When Anne Parker was diagnosed with first breast and, later, ovarian cancer, she knew in her heart that, as she says, “there was something more than ‘bad luck’ involved” in her diagnoses. Having lost both her mother and her sister to the disease, she had grown up in the shadow of cancer, convinced that her family shared a deadly link. As she confronted her own diagnoses, her search for answers about the role the disease played in her family became, in her words, “all-consuming and obsessive.”
In 1998 Anne underwent genetic testing and discovered that she carries the BRCA1 genetic mutation. Armed with what she considered invaluable information about the role of genetics in predicting cancer risk, she felt compelled to share her story and educate other families about the value of genetic testing. “I wanted to write about the advantages of being tested for the BRCA1 and BRCA2 mutations with the hope it would inspire women who have a family history of breast cancer to be tested,” Anne says.
Propelled by the memory of her mother and sister, Anne began to write about her experiences, embarking on a project that, she hoped, would culminate in a book that could serve as a resource for families struggling with the decision about whether to undergo genetic testing. But in November 2008, a twist of fate sent Anne’s story on a different path when she was introduced to Steven Bernstein, who was looking for a new project. That initial meeting set the wheels in motion for Anne’s story to move beyond the page to the big screen: a film adaptation of her story, titled Decoding Annie Parker, will be released in late 2012.
Michael Moss, MD (who co-wrote the screenplay for the movie with Steven Bernstein and Adam Bernstein), was drawn to Anne’s story. Their script melded her personal journey with the scientific story of geneticist Mary-Claire King’s work to discover the BRCA1 and 2 genetic mutations. The result, Dr. Moss says, is a film that follows both Anne’s story, as she loses her mother and sister and confronts her own diagnosis, and also that of Dr. King, who is working to prove a genetic link to high rates of breast cancer incidence among some family members. Throughout, Dr. Moss says, the strength and the perseverance of both women shine through as they “seek to prove something that runs counter to prevailing opinion: King faces a lack of support from the medical establishment in obtaining adequate funding for her research, while Anne’s own search for answers is dismissed as pointless obsession.”
“It has been surreal,” Anne says, of the process of watching her story transformed into a screenplay and brought to life on-screen. Exposing her and her family’s story in such a public way wasn’t an easy decision, but the opportunity to inform so many people about issues related to genetic testing was too powerful to ignore. Her surviving family members, who have all been faced with the decision about whether to undergo genetic testing, stood behind her. “My family understands firsthand the emotional impact of loss,” Anne says, “and that the more people know about the genetic mutation, and about where to turn for information, the less anxious and fearful they will be.”
Steven Bernstein, who in addition to serving as one of the film’s producers is making his directorial debut with Decoding Annie Parker, says that Anne’s experience presented a unique opportunity to share a powerful story that will be relevant for a wide audience. “The film is about a great many things—as much about what sustains us as about what makes us ill,” he says, noting that it provides valuable insight into early-detection topics.
Executive producer Johnathan Brownlee agrees that the film provides an opportunity to educate the audience and says that the script is unique in another sense too: “The story has two female lead characters, which is a rarity in film today.”
For Anne, seeing her story reach so many is a “powerful privilege.” She hopes that the movie will both entertain and provoke discussions that will lead to early detection and cancer prevention. “It is my wish to arm people in a high-risk family with information that could help them either dodge the cancer bullet or at least have it diagnosed in early stages before it spreads.”

Decoding Annie Parker
Scheduled for release in late 2012, Decoding Annie Parker features an ensemble cast that includes Helen Hunt as Mary-Claire King; Samantha Morton as Annie Parker; Aaron Paul as Annie’s first husband, Paul; Alice Eve as Annie’s friend, Louise; Marley Shelton as Annie’s sister, Joan; Rashida Jones as Annie’s friend, Kim; Corey Stoll as a doctor and friend, Sean; Bradley Whitford as Annie’s second husband, Marshall; and Bob Gunton as a physician, Dr. Benton.
The film is produced by Dorado Media and Capital and Media House Capital and initially will be presented at international film festivals before it is broadly distributed. For more information visit www.doradomedia.com.

Sunday, March 25, 2012

open access - Revie: Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine (references to Lynch Syndrome/Familial Melanoma)



Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine

pdf file

Genetic variants associated with breast cancer risk for BRCA1 mutations carriers

Genetic variants associated with breast cancer risk for BRCA2 mutations carriers

Patterns of association and tumour characteristics

Genetic modifiers of ovarian cancer risk

Environmental, hormonal and reproductive modifiers of risk

Common alleles and cancer risks for mutation carriers

Future challenges     "Over the past 5 years, there has been substantial progress in our understanding of genetic factors that modify breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. This was made possible to a great extent because of the availability of large numbers of mutation carriers from the CIMBA consortium and GWAS data. However, the five loci described in this review that are associated with breast cancer risk for BRCA1 mutation carriers are estimated to explain only approximately 3% of the genetic variability in breast cancer risk for BRCA1 mutation carriers. Similarly, the 11 SNPs associated with breast cancer risk for BRCA2 mutation carriers are estimated to account for approximately 6% of the genetic variability in breast cancer risk for BRCA2 mutation carriers. Therefore, the majority of the genetic variability in breast cancer risk for mutation carriers still remains unexplained. Several more breast and ovarian cancer susceptibility alleles have been identified through GWAS in the general population, but have not yet been investigated in mutation carriers [61, 63, 72, 75]. Given the observed association patterns in mutation carriers with previously identified loci, it is expected that at least a subset of these will also be associated with breast or ovarian cancer risk for mutation carriers. Additional genetic modifiers of risk may also be identified through not only the ongoing GWAS in BRCA1 and BRCA2 mutation carriers but also other GWAS from the general population or by GWAS focusing on specific cancer subtypes such as oestrogen-receptor-negative or triple-negative breast cancers, or serous ovarian cancer. However, it is likely that several of the alleles identified through population-based GWAS may be associated with modest relative risks in the range of 1.05–1.10. Despite sample sizes of approximately 15 000 BRCA1 and 10 000 BRCA2 mutation carriers, CIMBA would still be underpowered to detect modifying polymorphisms conferring such modest relative risks. Given the rarity of BRCA1 and BRCA2 mutations, increasing sample sizes is currently only possible through increased collaboration between studies and through continued recruitment of mutation carriers........

Conclusions

As more cost-effective mutation screening techniques become available, the number of identified BRCA1 and BRCA2 mutation carriers in the population is likely to increase. Therefore, it will be important that all mutation carriers are provided with accurate information on their risk of developing breast and ovarian cancer, so that informed decisions on clinical management are made. Our understanding of factors influencing cancer risk variability in mutation carriers has increased over the last few years and is likely to improve further in the near future. Therefore, we are getting closer to the goal of being able to provide more individualized clinical management. Understanding how cancer risks are modified in BRCA1 and BRCA2 mutation carriers will also provide further insights for studying the biological mechanisms of cancer development in mutation carriers. These may lead to the development of novel therapies and more accurate prediction of breast and ovarian cancer progression in mutation carriers.
Studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has provided useful insights in study design, analytical methodology and applications, which could be used for studying modifiers of disease in carriers of other high-risk mutations such as the mismatch repair genes MSH2, MLH1, MSH6, PMS2 in colorectal cancer (Lynch Syndrome) and CDKN2A in melanoma but also other noncancer-related diseases.

 

 

 

 

 

 




open access: Apr 2012 -Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) - Journal of Internal Medicine (BRCA, Lynch, high/low penetrance mutations....)



Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC) -  Journal of Internal Medicine

open access pdf file


 "In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the ovarian cancer association consortium (OCAC) in these discoveries. The OCAC was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome-wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility, most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high-throughput next-generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work....

Saturday, March 24, 2012

Bulletin du Cancer - What management for the asymptomatic men carriers of BRCA1 or 2 mutation? Results of a survey in the French oncogenetic centers



Bulletin du Cancer

Summary : The aim of this survey of practice was to define, in the absence of guideline, the management in France of asymptomatic men bearing a mutation of BRCA1 or 2 genes. A questionnaire was addressed to 90 oncogenetics centers. We obtained the answers of 34 practitioners working in 58 centers. Among the responders, 85.3% offered a systematic genetic test in all cases to determine the risk of transmission to the children and to offer a personal follow-up in 79.4 % of cases. This screening was directed towards prostate cancer, breast cancer and pancreatic cancer in respectively 94.1, 67.6 and 47.1% of cases. The screening of prostate cancer was mainly proposed to men bearing a BRCA2 mutation and from the age of 40 years. It was based on clinical examination and testing of prostate specific antigen. The screening of breast cancer was mainly proposed to men bearing a BRCA2 mutation and based on clinical examination and self-palpation without stating a started age. The screening of pancreatic cancer was mainly proposed to men with familial history of pancreatic cancer and from the age of 40 years. It was based on tomography and MRI. For the majority of answerers, the general practitioner was the best to perform all these screenings. These experts’ opinions can help to establish guidelines for the global management of asymptomatic men carriers of BRCA1 or 2 mutations.

Thursday, March 22, 2012

Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.



Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.:

Study
Breast Cancer Res Treat. 2012 Mar 21;

Abstract

In spite the close association of the triple-negative breast cancer immunophenotype with hereditary breast cancers and the BRCA1 pathway, there is a lack of population studies that determine the frequency of BRCA1 mutations among triple-negative breast cancer patients. To address this, we have screened a large sample of 403 women diagnosed with triple-negative invasive breast cancer, independently of their age or family history, for germline BRCA1 mutations.

Median age at diagnosis was 50 years (range 20-83). The overall prevalence of triple-negative cases among the initial patient group with invasive breast cancer was 8 %. BRCA1 was screened by direct DNA sequencing in all patients, including all exons where a mutation was previously found in the Greek population (exons 5, 11, 12, 16, 20, 21, 22, 23, 24-77 % of the BRCA1 coding region), including diagnostic PCRs to detect the three Greek founder large genomic rearrangements. Sixty-five deleterious BRCA1 mutations were identified among the 403 triple-negative breast cancer patients (16 %).

Median age of onset for mutation carriers was 39 years. (?? Blogger's Note: screening guidelines...)  Among a total of 106 women with early-onset triple-negative breast cancer (<40 years), 38 (36 %) had a BRCA1 mutation, while 27 % of women with triple-negative breast cancer diagnosed before 50 years (56/208) had a BRCA1 mutation. A mutation was found in 48 % (50/105) of the triple-negative breast cancer patients with family history of breast or ovarian cancer.

It is noteworthy, however, that of the 65 carriers, 15 (23 %) had no reported family history of related cancers. All but one of the carriers had grade III tumors (98 %). These results indicate that women with early-onset triple-negative breast cancer, and ideally all triple-negative breast cancer patients, are candidates for BRCA1 genetic testing even in the absence of a family history of breast or ovarian cancer.