PLoS ONE: The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer (study of pts with both ovarian and breast cancers)

Blogger's Note: the other cancers (KRAS mutations) referred to beyond ovarian and breast cancers include references to lung and melanoma cancers; KRAS mutations have been established in colorectal cancers, however, there are no references on this particular subject within this research article regarding Lynch Syndrome -
an ongoing area of specific research (re: KRAS/Lynch Syndrome/blog posting of May 16, 2012 Jnl ASCP)
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PLoS ONE: The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer


Table 1. The KRAS-variant is significantly associated with uninformative breast and ovarian cancer patients.
doi:10.1371/journal.pone.0037891.t001

Purpose

A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.

Conclusions

These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative.

Introduction 

Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited cancer-susceptibility syndrome marked by an increased risk of developing both ovarian cancer and breast cancer [1]. Families generally considered as having HBOC syndrome are those with multiple family members that have one of these cancers, especially at young ages, or an individual with a cancer in both organs, a “double primary” patient. While this is a relatively rare presentation, a substantial number of women develop both breast and ovarian primaries over their lifetime. While BRCA1 and BRCA2 are strongly associated with HBOC syndrome [2], a large number of HBOC families and women with double primary cancer do not have detectable genetic mutations (herein referred to as “uninformative” patients).
The chances of identifying a mutation causative for HBOC increase when testing individuals diagnosed with double breast/ovarian primaries [3]–[5]. However, a recent report suggests that the rates of BRCA mutations are not higher in a patient with a double primary without a family history than that for isolated first degree relative pairs with single primaries (14% versus 17% with mutations, respectively) [4]. This supports the importance of family history even in patients with double primary cancers. Although BRCA mutations were found in 49% of double primary patients in this recent analysis, it should be noted that this indicates that over half of double primary patients do not have a known genetic cause for their disease. This is consistent with other reports of these patients [3], [5].............The goal of this study was to determine the association of the KRAS-variant with women with double primary breast and ovarian cancer, to further validate the association of this variant with HBOC families. Findings here support the importance of the KRAS-variant in uninformative HBOC families as well as in predicting the risk of multiple primary cancers in women.......

Association of the KRAS-variant with Multiple Cancers in All Patients

Because the KRAS-variant has been found to be associated with an increased risk for other cancers besides breast and ovarian cancer [11], [15] we tested the hypothesis that the KRAS-variant would predict for an increased risk of developing additional cancers in this double primary cohort, regardless of BRCA mutation status. For 183 of the patients in our study where this information was available, 79.2% (n = 145) had reported just the two cancers (breast and ovarian), 12.0% (n = 22) had two separate primary breast cancers and also ovarian cancer, and 8.7% (n = 16) had cancer in an additional organ outside of the breast and ovary (triple primary).

paywalled: Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer.

Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer.

Breast Cancer Res Treat. 2012 Apr 18;

Abstract
The genetic component of breast cancer predisposition remains largely unexplained. Candidate gene case-control resequencing has identified predisposition genes characterised by rare, protein truncating mutations that confer moderate risks of disease. In theory, exome sequencing should yield additional genes of this class. Here, we explore the feasibility and design considerations of this approach. We performed exome sequencing in 50 individuals with familial breast cancer, applying frequency and protein function filters to identify variants most likely to be pathogenic. We identified 867,378 variants that passed the call quality filters of which 1,296 variants passed the frequency and protein truncation filters. The median number of validated, rare, protein truncating variants was 10 in individuals with, and without, mutations in known genes. The functional candidacy of mutated genes was similar in both groups. Without prior knowledge, the known genes would not have been recognisable as breast cancer predisposition genes. Everyone carries multiple rare mutations that are plausibly related to disease. Exome sequencing in common conditions will therefore require intelligent sample and variant prioritisation strategies in large case-control studies to deliver robust genetic evidence of disease association.

abstract: Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions.

Blogger's Note: while this article is specific to BRCA 1/2 it also would apply to other genetic syndromes eg. Lynch Syndrome, Peutz-Jeghers 
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Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions.:


Genet Med. 2011 Dec;13(12):998-1005

Abstract
PURPOSE:
Approximately 5-10% of patients who undergo genetic testing of BRCA1 and BRCA2 receive a variant of unknown significance (VUS) result. The ambiguous nature of a VUS may increase difficulty in patient understanding and decision making regarding risk reduction and surveillance options, including cancer risk-reducing surgeries. VUS reclassification to benign or deleterious may occur in time; however, clinical decisions may need to be made expeditiously, and some patients may pursue irreversible treatments before VUS reclassification.

METHODS:
We reviewed the surgical decisions of 107 women postdisclosure of a BRCA VUS result counseled at our institute between 1998 and 2009.

CONCLUSION:
Among women receiving a BRCA VUS result at our center, 11 of 107 (10.3%) pursued cancer risk-reducing mastectomy and 22 of 107 (20.6%) pursued cancer risk-reducing bilateral salpingo-oophorectomy. Reclassification of VUS occurred up to 9 years after testing, and 5 of 22 (22.7%) women followed up for 8 or more years continue to have a VUS result. We discuss considerations for providers of genetic services to discuss with patients who receive a VUS result.

abstract: Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

 Blogger's Note: see recent post for a null finding XRCC/Lynch Syndrome

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.:

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

Am J Hum Genet. 2012 Mar 28;


Abstract

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p<0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

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.

 

 

 

 

 

 

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.:

Abstract
Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. .........................We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

The predicted truncation from a (ovarian) cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex

Abstract

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. MMR recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previously for LS-related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS...."(technical)

Cancers | Free Full-Text | The Clinical Significance of Unknown Sequence Variants in BRCA Genes

Luteinized Adult Granulosa Cell Tumor-A Series of 9 Cases: Revisiting a Rare Variant of Adult Granulosa Cell Tumor

abstract: Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: Probability of synergistic effects - Intl Jnl of Cancer

"These variants were identified through denaturing high performance liquid chromatography and subsequent DNA sequencing. In one Lynch family, the index case with early-onset colon cancer was a carrier of a polymorphism in the MSH2 gene and two variants in the MSH3 gene. These variants were associated with the disease in the family, thus suggesting the involvement of MSH3 in colon tumour progression. We hypothesise a model in which variants of the MSH3 gene behave as low-risk alleles that contribute to the risk of colon cancer in Lynch families, mostly with other low-risk alleles of MMR genes."

LOVD - An Open Source DNA variation database system (eg. genetic testing/unknown clinicial variant/s)

LOVD stands for Leiden Open (source) Variation Database.
LOVD's purpose : To provide a flexible, freely available tool for Gene-centered collection and display of DNA variations.

Mutalyzer

LOVD features integration with the Mutalyzer sequence variant nomenclature checker, allowing for direct nomenclature checking of sequence variants during the submission process.

If you are looking for a specific gene database, please check the list of gene variant databases at the HGVS site, in our list of LSDBs, or in the list of registered LOVD installations.

Genetic variants associated with breast-cancer risk : The Lancet Oncology (Steven A Narod)

Note: register (free) to view

Medical News: BRCA1 Breast Cancer Risk Linked to Other Mutations (more detailed report - Medpage)

NIH expands network focused on how genes affect drug responses, September 7, News Release - National Institutes of Health (NIH)

"...Spearheaded by the NIH's National Institute of General Medical Sciences (NIGMS) and launched in 2000, the PGRN has already identified gene variants linked to responses to medicines for different cancers, heart disease, asthma, nicotine addiction and other conditions...."cont'd

Genetic Risk Score Associated With Breast Cancer Risk; Predictive of Type of Disease

>“In this large study including 10,306 women with breast cancer and 10,393 without the disease, we confirm that some of the more important common genetic variants for breast cancer have different effects on different tumor types.”

Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts

BACKGROUND:
Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2.

CONCLUSIONS:
These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.

Clinical relevance of rare germline sequence variants in cancer genes

Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models.

Abstract

Multifactorial models developed for BRCA1/2 variant classification have proved very useful for delineating BRCA1/2 variants associated with very high risk of cancer, or with little clinical significance. Recent linkage of this quantitative assessment of risk to clinical management guidelines has provided a basis to standardize variant reporting, variant classification and management of families with such variants, and can theoretically be applied to any disease gene. As proof of principle, the multifactorial approach already shows great promise for application to the evaluation of mismatch repair gene variants identified in families with suspected Lynch syndrome. However there is need to be cautious of the noted limitations and caveats of the current model, some of which may be exacerbated by differences in ascertainment and biological pathways to disease for different cancer syndromes.

Chemotherapy use and risk of bone marrow suppression in a large population-based cohort of older women with breast and ovarian cancer.

Med Oncol. 2010 Apr 2

Nurgalieva Z, Liu CC, Du XL.

Division of Epidemiology and Disease Control, University of Texas School of Public Health, 1200 Herman Pressler Drive, RAS-E631, Houston, TX, USA.

We studied 65,521 women with breast cancer and 7,420 women with ovarian cancer aged >/= 65 identified from the 16 areas of the Surveillance, Epidemiology and End Results program linked with Medicare data during 1991-2002. Bone marrow toxicity associated with chemotherapy was defined using diagnosis codes from Medicare inpatient, outpatient and physician claims. The time to event Cox regression was utilized to estimate the risk of bone marrow toxicity. Use of anthracyclines, taxanes or platinums was associated with increased risks of short- (3 months) anemia and neutropenia in patients with breast cancer. Alkylating agents or antimetabolites were additional significant predictors of anemia in women with ovarian cancer. Patients who received chemotherapy (irrespective of regimens) were twice (breast cancer) or three times (ovarian cancer) as likely to develop thrombocytopenia compared to those not receiving chemotherapy. Among women with breast cancer, patients receiving cyclophosphamide, methotrexate and fluorouracil regimens (hazard ratio = 19.0, 95% CI = 11.2-32.5), platinum/taxane therapy (21.9, 11.9-40.4) or the cyclophosphamide, adriamycin and fluorouracil regimen (32.5, 19.6-53.9) were strongly associated with risk of aplastic anemia. There was a dose-response relationship between the use of taxane or platinum and the risk of bone marrow suppression, whereas the increased risk of bone marrow toxicity was consistently higher in those with use of alkylating agents or anthracycline-based regimens irrespective of the increasing number of cycles received. In conclusion, there was an association between chemotherapy use and clinical manifestations of bone marrow toxicities in a population-based setting.

NEJM -- Performance of Common Genetic Variants in Breast-Cancer Risk Models

Note: full text is pay-per-view
Conclusions The inclusion of newly discovered genetic factors modestly improved the performance of risk models for breast cancer. The level of predicted breast-cancer risk among most women changed little after the addition of currently available genetic information.

news article: Another Reason Not to Get Your Genes Scanned (gene variants)

"Scientists have discovered numerous gene variants that slightly boost the risk of breast cancer, heart disease, and other common illnesses in recent years. It’s pioneering science. But is the deluge of genetic data useful for doctors and patients?..."