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Guidelines on Risk Assessment for Hereditary GynCa November 4, 2007

Posted by ramunas in BRCA, breast cancer, cancer genetics, colorectal cancer, genetic testing, hereditary cancer, HNPCC, ovarian cancer.

Recently guidelines on risk assessment for inherited gynecologic cancer (Hereditary Breast/Ovarian Cancer (HBOC) and the Lynch/Hereditary Non-Polyposis Colorectal (HNPCC)) predispositions were published by The Society of Gynecologic Oncologists (SGO).

Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained (ref).

Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes (ref).

Up to 10% of breast cancer and 10-15% of ovarian cancer cases are related to BRCA 1/2 genes mutations (“faulty genes”), so called HBOC syndrome.

Mutations in BRCA1 genes confers a 39% to 46% chance of a woman developing ovarian cancer and a 65% to 85% risk of a woman developing breast cancer by age 70 years. The BRCA2 gene is associated with an ovarian cancer risk for 10% to 27% and a breast cancer risk for 45% to 85% by age 70 years (ref., subscription needed).

For comparison, overall life time breast cancer risk in the western population is 10-12%, and ovarian 1,5-2%.

The SGO guidelines recommend genetic risk assessment for women with a 20% to 25% likelihood of having BRCA1 or BRCA2 mutations. For patients whose probability of predisposition is greater than 5% to 10%, the guidelines suggest that genetic risk assessment “may be helpful.”(ref.)

It is a new thing (“20-25%”) for me, because to my knowledge, a guidelines in USA set by the American Society of Clinical Oncology (ASCO) suggested a 10% likelihood of finding BRCA1/2 mutations to undertake genetic testing. A stringent 20% likelihood threshold of having BCRA mutations is already applied in UK.

Lynch/HNPCC syndrome is caused by germline mutations in genes that oversee DNA mismatch repair. The family predisposition conferred by mutations in genes MLH1, MSH2, or MSH6 includes not only colorectal cancer and cancers of the endometrium but also cancers of the ovary, stomach, small intestine, and other organs. Women with one of these mutations have a 42% to 60% likelihood of developing endometrial cancer and a 9% to 12% chance of developing ovarian cancer by the age of 70 years. Their lifetime risk for colorectal cancer is 40% to 60 (via).

The SGO statement divides the Lynch/HNPCC guidelines into those for patients with a 20% to 25% chance of having the inherited predisposition and those with a greater than 5% to 10% chance. The guidelines reflect both personal and family profiles, with the “revised Amsterdam criteria” included for the higher-risk group.

“revised Amsterdam criteria” for HNPCC are as follows (ref.):

  • Patients have at least 3 relatives with a Lynch/HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis) in 1 lineage,
  • One affected individual should be a first-degree relative of the other 2,
  • At least 2 successive generations should be affected, and
  • At least 1 HNPCC-associated cancer should be diagnosed before age 50 years.

Performing the genetic testing and finding out that a patient does or does not have a genetic mutation can allow us to reduce risks for other related cancers, and can have tremendous impact for the patient’s family members if a mutation is found.

When assessments identify women at high risk for these cancers, they could receive magnetic resonance imaging breast screening, colorectal screening with colonoscopy, and preventive surgery, but the medical community must become aware of the importance of these strategies in improving individual outcomes. (ref.)

SMAD7 | Colorectal Cancer October 31, 2007

Posted by ramunas in cancer genetics, colorectal cancer, genetic testing, research.

A message is simple: variants (SNP’s) in SMAD7 gene (which is involved in TGF-beta and Wnt signaling; shown in red on the left side) influence colorectal cancer (CRC) risk.

Particulary association between rs4939827 and CRC was highly statistically significant. This study was performed by UK researchers and just published in Nature Genetics.

Just another SNP for future personalized genomic screen and risk assessment.

(image source)

A BRAF Story | Colorectal, Thyroid CA and Melanoma September 6, 2007

Posted by ramunas in cancer genetics, colon cancer, colorectal cancer, genetic testing, hereditary cancer, HNPCC, sporadic cancer.

For the first time I’ve read about BRAF oncogene in a poster presented during one of the European Society of Human Genetics conference, probably in Amsterdam, Holland. It appeared that a single amino acid substitution (p.V600E), a hotspot point mutation, is an useful marker to exclude HNPCC (hereditary non-polyposis colorectal cancer). Interestinlgy, this somatic mutation of BRAF gene, which belongs to the RAF family of protein kinases from the RAS/RAF/MAPK pathway, is more than 90% present in sporadic colorectal cancers with methylated hMLH1 gene. Therefore, if you have access to a tumor DNA after simple PCR test you can exclude or suspect hereditary form of this cancer. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer (via).

Obviously, the confirmation should be done by testing for germline mutations mismatch repair (MMR) genes (mostly MLH1, MSH2, MSH6). Also, immunohistochemistry may point you which protein is missing. The Bethesda guidelines , original (1997) and revised (2003), are designed to select cases for analysis of microsatelite instability (MSI) features of tumor, but testing for BRAF mutation can yield additional and faster information.

Conventional strategy for genetic testing of affected individuals from families with suspected hereditary non-polyposis colorectal cancer (source):


Screening of mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC, one article states.

That is a story about colorectal cancer, but it was interesting for me to find out, that the same mutation of BRAF oncogene can be present in thyroid cancer. That may be useful in predicting the level of aggression of thyroid cancer and help guide treatment options and follow-up care, says the new research paper published in the September issue of the “Annals of Surgery”.

Researchers concluded, that BRAF V600E mutation is primarily present in conventional papillary thyroid cancer. It is associated with an aggressive tumor phenotype and higher risk of recurrent and persistent disease in patients with conventional papillary thyroid cancer. Testing for this mutation may be useful for selecting initial therapy and for follow-up monitoring.

Study author, Kebebew E, explained that identification of the mutation in patients with thyroid cancer could be very useful in a variety of ways. For example, patients with the mutation may be candidates for a more aggressive approach to surgery, such as removing the central lymph node along with the diseased thyroid, to avoid the possibility of metastasis following surgery. BRAF V600E testing could also be useful for deciding between low- or high-dose radioiodine ablation therapy.

Other BRAF mutations are found in melanoma and BRAF possitive tumors may be more sensitive to a new class of drugs – protein MEK inhibitors (such as PD0325901, developed by Pfizer Research and Development).