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

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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.

 

 

 

 

 

 

Ovarian malignant melanoma: a clinicopathologic study of 5 cases (abstract)

Characteristics and survival associated with ovarian cancer diagnosed as first cancer and ovarian cancer diagnosed subsequent to a previous cancer

Abstract

Objective:
To examine the risk of subsequent primary ovarian cancer among women diagnosed previously with cancer (subsequent cohort) and to compare demographic and tumor characteristics affecting overall survival of these women and women diagnosed with first primary ovarian cancer (index cohort).


Methods: 
We identified the two cohorts of women using the 1973-2005 Surveillance, Epidemiology and End Results (SEER) result data. We calculated relative risk of subsequent primary ovarian cancer and estimated 5-year risks of dying (hazard-ratios) after diagnosis of the first or subsequent primary ovarian cancer in the two cohorts, respectively using Cox modeling.


Results:
Women diagnosed with index cancers of the corpus uteri, colon, cervix, and melanoma at age younger than 50 had increased risk of ovarian cancer within 5 years after diagnosis (p<0.05); young breast cancer survivors had continued risk beyond 20 years. In 5-year follow-up survival analysis, the factors associated with a better survival (p<0.05) were similar in both cohorts and included more recent diagnosis; localized or regional disease; age <50 years at diagnosis; and being white versus black. A lower risk of dying from mucinous, endometrioid, or non-epithelial tumors than from serous was seen after 15 months (p<0.01), or after 32 months from diagnosis of the index and subsequent cohorts, respectively. (clear cell??)


Conclusions:
Age, stage, and histology affect ovarian cancer survival. The increased risk of ovarian cancer over time, especially among breast and colon cancer survivors who are less than 50 years of age, suggests common etiologies and necessitates careful surveillance by health care providers and increased survivors awareness through educational efforts.

Targeted therapies for rare gynaecological cancers : The Lancet Oncology

The Lancet Oncology, Early Online Publication, 1 April 2010

Targeted therapies for rare gynaecological cancers

Summary

Some gynaecological cancers are uncommon, such as sex cord-stromal tumours, malignant germ-cell tumours, vulvar carcinoma, melanoma of the female genital tract, clear-cell carcinoma of the ovary and endometrium, neuroendocrine tumours of the cervix, and gestational trophoblastic neoplasia.

All these cancers have different clinicopathological characteristics, suggesting different molecular biological pathogeneses. Despite aggressive treatment, some cancers recur or respond poorly to therapy. Comprehensive knowledge of the molecular biology of each cancer might help with development of novel treatments that maximise efficacy and minimise toxic effects. Targeted therapy is a new treatment strategy that has been investigated in various tumours in clinical and laboratory settings.

Since these cancers are rare and large clinical trials are difficult to do, molecular biological techniques might allow rapid proof-of-principle experiments in few patients. Novel targeted agents either alone or in combination with other treatments offer promising therapeutic options.