Path report - kras and tp53

[crazylife]

Can someone help me decode this thing. Any insight would be appreciated.

Positive for the following somatic alternations in rather clinically validated panel:

1.kras exon 3 p.q61r
2.tp53 exon 5 p.q167

Positive for the following somatic alternations in the investigational panel:

3. Amer1
4. Apc
5. Apc
6. Pten
7. Rel

[StDrogo]

With the current state of genomics, there's not much to interpret. KRAS (which controls cell proliferation) mutations generally have an unfavorable prognosis (which is obvious on the face of it since the cell has lost the ability to switch off multiplication, which is really bad for a eukaryotic organism), particularly in more advanced stages. TP53 is a tumor suppressor that regulates over/irregular proliferation and is putatively part of the cascade of genomic mutations that leads to the development of a carcinoma. Amer1 is a transcription activator—not really sure how it's involved in carcinogenesis, but it's commonly implicated. The APC gene regulates APC protein, which is, in essence, a tumor suppressor; this mutation is present in the vast majority of colon cancers. Likewise PGEN, which is commonly also implicated in the carcinogenic cascade. I am really unclear about the role of the REL gene in cancer, but I'm now very interested.

In summary, the only currently clinically relevant mutation you have at the moment is KRAS.

[NHMike]

The KRAS Q61R mutation arises from a single nucleotide change (c.182A>G) and results in an amino acid substitution of the glutamine (Q) at position 61 by an arginine (R).

http://targetedcancercare.massgeneral.o ... -(c-182A-G).aspx

The issue with KRAS is that it's inside the cell so it's very hard to target it with immunotherapy. There is a little progress in this at NCI but they're only doing trials for specific mutations in one trial (G12D and G12V). They may be doing others as well but I think that they only take stage 4 patients.

[sdino]

Here is my take on a article I read on TP53: So... Healthy P53’s fight cancerous DNA. But when they get sick or mutated they stop fighting the bad cells. So there is efforts to boost the healthy P53’s to fight harder but years of testing, nothing has made it to the Market. Researchers are trying to restore the P53’s back to their normal state to carry-on the fight. They are finding drugs that bind to and prop up copies of mutated p53, restoring its shape and ability to carry out its job. One such drug has already passed an early stage safety trial in humans, and a more advanced clinical trial is now underway in Europe. The payoff could be big, however. Not only could the strategy treat many kinds of cancer, but just a handful of drugs might be enough, particularly when coupled with chemotherapy drugs that induce the tumor cell damage to which p53 responds. P53 mutations tend to be clustered in the core of the protein, where it binds to DNA.

Another protein, MDM2, latches onto P53 molecules and destroys them, keeping their numbers in check. But this control mechanism can fail in multiple ways. For starters, when p53 itself is mutated, MDM2 cannot attack it. As a result, the malfunctioning protein builds up in cells unchecked and keeps the remaining healthy p53 from doing its job. Without the genome’s guardian on patrol, precancerous cells survive and reproduce. This gives them the opportunity to build up the additional mutations they need to become fully malignant.

At this point, it’s slightly unclear which if any P53 stabilization strategy will pan out. They are trying like hell... with some promising results.

SIDE NOTES
- ovarian cancer, almost always has p53 mutations.
- Healthy P53’s = Good to fight Cancer
- Mutated P53’s = Not good, they are essentially working on restoring them back to healthy P53’s. Hope I explained this OK ?

[Achilles Torn]

Heres my 2 cents,

Tp53 is very common in advanced colon cancer while KRAS mutations occur in up to 50%. Studies are mixed on the subject- but the general consensus is that KRAS mutation does not mean a worse prognosis for Stage 4 patients (I would guess this is likley because others will have driver mutations that are as detrimental or worse). KRAS mutation usually indicates that the two standard EGFR inhibitors for CRC, Cetuximab (Erbitux) and Panitumumab (Vectibix), are not effective; however some papers show this may be limited to certain KRAS mutations such as codon 12, and that other KRAS variants may benefit from those therapies.

Follow research and clinical trials in all your listed mutations across cancer types as you never know when the next breakthrough may occur.

Hope that helps
AT