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NOTCH1 mutational status - high risk of transformation and poor outcome

NOTCH1 mutational status - high risk of transformation and poor outcome

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

From the Spanish research Abstract

'NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL).

To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two.

Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission.

Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability.

In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome.

This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.'


Also see...

Trisomy 12 and NOTCH1


New NOTCH1 tests are beginning to become available at a few major CLL research facilities in the U.S. How they will be accepted clinically remains to be seen.

9 Replies

In Australia, the only place that I know of where NOTCH1 testing can be done is at the Peter MacCallum Cancer Centre, Melbourne and that is only as part of a research project by Dr Constantine Tam, where they are also testing IgVH, FISH, P53, SF3B1 and BIRC3 in a study to show that the technology works and to determine which of these predict for progression.


I am a bit confused as to the difference between NOTCH1 and FISH testing? Also I thought that TRI 12 was an OK mutation to have but it appears not from these results.


This is a different genetic test than FISH. There will be a number of these new test in the future, looking at sub clonal genes, like SF3B1, BIRC3 etc. They are probably 2 to 3 years out from clinical use, if there is a reason to test for them, CLINICALLY.


I'm not a medical expert, but have been dealing with CLL Trisomy 12 since 2008. In FISH testing a few specific gene locations are selected and tagged with a fluorescent marker- these identify the deletions like 17P, etc. but the targets are limited. I had NOTCH1, and 6 other "new" suspects tested as part of a research trial, and I believe the testing is new and not commonly done. My doc explained that the NOTCH1 differentiates between Tri 12 patients that are higher risk for quick progression vs a slower group. It also is one of 3 markers that together forecast a high risk of Richters transformation- independent of the CLL progression.



Medscape has a good article on NOTCH1 and its interelationship with some cases of trisomy 12 and MYC.

There is ~50% risk at 15 years post diagnosis of developing Richter syndrome in this Trisomy 12 subgroup. Not all Richters follows this senerio either, but it is likely the most common...


Thanks for that information, it's very clearly put. I have asked about Tri 12 before at my onc clinic check ups but not had a straight answer, usually due to lack of time.


They wouldn't know if you are Tri12 unless you have had a FISH panel done...


My husband had the test done at Dana Farber in Boston and it showed a "slight" positive for the Notch 1 mutation. Since the test is so new, the doc said the test may have a false positive. Anyone else have any information? I couldn't find much online.

Thanks in advance.


Hi kreale,

I can't help with specifics on NOTCH1, but here's some general background on the challenges associated with determining if a test is positive or negative for a given mutation.

In addition to the difficulty of getting consistent testing results from different laboratories that could result in a false positive, there's the issue of what the cut off percentage is for a test to be considered positive or negative for a given mutation. From what you've been told, your husband is close to that cut-off percentage and just slightly into 'positive' territory.

This cut off figure can perhaps be better explained by an analogy. It's like looking at security camera picture of a crowd at an international airport and classifying the crowd as asian, caucasian, etc, if more than 20% of the crowd belongs to one particular ethic group.

Also that cutoff percentage point can vary between different centres with an agreed cutoff point gradually becoming defined, following experience gained from following the progression of a range of patients.

Finally, with CLL, it seems that it's total picture of genetic mutations that's important and how they interact, though some carry more weight in influencing outcomes than others.

Have you read these blogs by Dr Sharman that touch on NOTCH1?

Another post on this site providing more information on NOTCH1:

As Cllcanada said above a year ago "Note: New NOTCH1 tests are beginning to become available at a few major CLL research facilities in the U.S. How they will be accepted clinically remains to be seen."



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