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.

 

 

 

 

 

 

As I see it: Ten reasons to be happy about hormone replacement therapy: a guide for patients - Menopause International

"Discussion of side-effects should not be avoided, particularly the 1% extra lifetime risk of breast cancer. This should be balanced against the fewer heart attacks, fewer deaths and less osteoporotic fractures in those who start HRT below the age of 60."

Technique to Preserve Fertility in Young Women May Be Unsafe for Patients With Leukemia (AML/CML)-- press release

Note: study of 18 patients (AML/CML)

WASHINGTON, Aug. 13 /PRNewswire-USNewswire/ --

Although the use of ovarian tissue cryopreservation and transplantation has lead to 13 live births in women with lymphoma or solid tumors, this method of fertility preservation may be unsafe for patients with leukemia, according to a recent study published online in article: Blood, the journal of the American Society of Hematology "Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe". The method involves removing and freezing ovarian tissue before the patient undergoes aggressive chemotherapy and radiotherapy, and then reimplanting the tissue once the cancer has been brought under control. One major concern with leukemia patients is the risk that their frozen-thawed ovarian tissue might harbor malignant cells that could induce a recurrence of the disease after reimplantation.

"Our study provides clear evidence that cancer cells in women with acute and chronic leukemias can contaminate the ovaries," said Marie-Madeleine Dolmans, MD, professor at the Universite Catholique de Louvain in Brussels and lead author of the study. "If this tissue is reimplanted in these women when they're ready to have children, there's a good possibility that the cancer will come back." ...cont'd

"Moreover, chemotherapy before ovarian cryopreservation does not exclude malignant contamination. Finally, reimplantation of cryopreserved ovarian tissue from ALL and CML patients puts them at risk of disease recurrence."

PMH breast cancer researchers link ovarian hormone to breast stem cells growth

Note: easier to read Medscape article from previous blog post

"Cancer researchers at Princess Margaret Hospital (PMH) have discovered that the ovarian hormone progesterone plays a pivotal role in altering breast stem cells, a finding that has important implications for breast cancer risk.......The findings, published online today in Nature (10.1038/nature09091; http://dx.doi.org/), are significant because reproductive history is among the strongest risk factors for breast cancer, says principal investigator Rama Khokha, a molecular biologist at Ontario Cancer Institute and the Campbell Family Cancer Research Institute, PMH. Other major known risk factors are age, genetics and breast density."

Understanding Statistics Used to Estimate Risk and Recommend Screening | Cancer.Net

Cochrane Menstrual Disorders and Subfertility Group: Clomiphene citrate for unexplained subfertility in women

Plain English Summary: "Clomiphene citrate for unexplained subfertility in women Clomiphene citrate is a fertility drug that can increase the number of eggs released for possible fertilisation. It is used by women who do not ovulate regularly and by some who do but still have not become pregnant. Clomiphene citrate does not appear to increase the chance of pregnancy in women who ovulate regularly but have failed to conceive after more than a year of unprotected intercourse and so are considered to be subfertile. An associated risk of treatment with clomiphene citrate is a 10% chance of multiple pregnancy. The results of this review of trials should be used with caution due to the heterogeneity between some of the studies."

updated 2010 - MSH2 (one of the Lynch Syndrome genes)

"People with mutations in the MSH2 gene have an increased risk of developing several other types of cancer (colorectal), including cancers of the endometrium (lining of the uterus), ovary, stomach, small intestine, liver, gallbladder duct, upper urinary tract, brain, and skin.
Some mutations in the MSH2 gene increase the likelihood of several uncommon skin tumors occurring in addition to colorectal cancer, a combination called Muir-Torre syndrome. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in skin glands (sebaceous glands) that produce an oily substance called sebum. Multiple, rapidly growing skin tumors called keratoacanthomas may also occur, usually on sun-exposed areas.