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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).



1. Irene Fitch - June 14, 2008

Daughter in law , 44 yrs. old had one-half thyroid removed, right side after having two malanomas removed last year. Had other skin cancer lesions also removed. Her grandmother and mother have a history of hypothyroid problems and take medication, Teen daughter has also been diagnosed with hypothyroidism. Can you comment on spread of the disease, prognosis, future treatment or other information that may be helpful in the future.

Her surgery was done at Rober Packer Hospital, Sayer, Pa.

2. Janice Feldman - March 20, 2010

I am 10 years out from a level 4 melanoma on my abdomen with no apparent metastasis but multiple mass’s and nodules have been found on my thyroid. bilaterally. I have not yet seen a surgeon but suspect he/she will biopsy then remove my thyroid. I do have symptoms that I have been explaining to myself as coming from allergies and aging. I am a 59 yo female.
I read some articles around melanoma and thyroid cancer but would like to know how likely and if in the thyroid how curable is it.

3. Nowshari - March 22, 2010

A friend of mine, age 50 yrs working is suffering from
Malignant Melanoma(amelaniotic): Here is the complete histroy:

*History of nail bed infection of LEFT THUMB since july 2007,underwent
removal of nailbed thrice with skin grafting of nail bed in third
surgery assuming as nail bed infectionin. Diagnosed
as Malignant melanoma inJune 2008

*09.07.2008 PET Scan whole body revealed Hypermetabolism low grade
left thumb.Rest whole body normal
*11.07.2008–Disarticulation of terminal phalynx done.H/Path.
report:M.Melanoma of Skin Clark Level-V(Breslow,s tumour thickness is
0.5cm.Tumour invades underlying bone&shows spindel cell morphollogy)
Onchologist advised no role of Interferone/Chem0

*12.08.2008 Left axillary Lymph node appeared ,gradully increased in
size FNAC revealed Metastasis
*28.08 2008 PET Scan whole body revvealed mod.hypermetabolism in
axillary node.Rest of body normal

*29.08 2008–LT Axillary & Epical lymph node clearance done. out of 15
axillary 3 epical nodes only one axillary L.N. showed metastasis with
no perinodal extension

*01,10.2008–High dose Interferone -alpha-2-B started@30 MIU IV daily
5 days in a week for 4 weeks which completed on 28.010.2008 without
significant complication & adv. to continue 5 MIU 3 times/week

*12.01.2009 PET whole body Normal
*24.02.2009.One L.Node appeared in same axilla

*30.01.2009 PET whole body showed Lung metastasis.Onchologist advised
Chemo.(Carboplatin-660mg, Pacilataxil-330mg& Avastin800mg regime) of 6
cycles 1 each after 3 week,s interwal. which started on 05.04.2009
.After completion of 3 cycles PET whole body done on 01.07.2009.which
revealed increased in number & size of pul.nodules.But axillary node
size decreased.without liver or other viseral metastasis.

Dated:- 01/092009 started high dose interliekin-2(IL-2) ,recevid half of thecourse that is

six injection out of 14 injections in first stage of first cycle and 8 injections out of 14 injections in scond stage of first cycle as i could not tollerate whole therapy.

PET SCAN of whole body done on 28/10/2009. which revealed significant increase in number,size,and intensities of the bilateral pulmonary nodules.Small focus of increase tracer uptake seen in right lobe of liver (max suv 4.8).

Dr. advise to stop IL-2 as it did not show any responce and advise to take temozolamide 400mg daily for 5 days / 28 days cycle and advice to contact with clinical drug trail with plexxikon inc.for PLX4032(RG7204).

Can you comment on spread of the disease, prognosis, future treatment or other information that may be helpful in the future.

4. maryrsstewart - March 3, 2012

These disease is also alarming. I have read other article on how to detect if you’ve melanoma. Nobody can diagnose him- or herself. If you see a spot that looks as though it is new or changing, show it to a doctor. When it comes to spots on the skin, it is always better to be safe than sorry. These is so true by not taking granted what’s happening new to other body.

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