NRAS Q61R - what does that mean?

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Mercy110
Posts: 118
Joined: Wed Aug 16, 2017 12:13 am

NRAS Q61R - what does that mean?

Postby Mercy110 » Thu Nov 23, 2017 5:54 am

Lots of useful information I have encounter in the forum.
I know that my mum carries NRAS mutant since Aug as she became a stage4 patient after the surgery and a few rounds of xeloda.
Then I have come to notice that Q61R does mean something other than EGFR antibodies are not sensitive for her so she has only Avastin left.
So far her response is ok, but I would like to know is this Q61R thing similar to the KRAS G12V that makes prognosis more difficult than the others?
Guess this is not a common form of mutation. Thanks for any sharing and information in advance.
My Mum (age 56), NRAS-mutate Q61R (from HK)
2017-05: Surgery with stoma. T4N1M0. Stage3C. Xeloda Only. Increasing CEA. CT: Multiple lung nodules. Stage4.
2017-09: 85% FOLFOX + Avastin, stable CT
2018-03 to 05: Folfox Allergy, Folfiri (with Avastin since Oct)
2019: CEA:178, started Irinotecan+Zaltrip+TS-1, 25 times radio with xeloda
2020: CEA up, Stivarga for 6 months
2021: CEA up, 7L O2 and 24-hour morphine, on pc care
At peace 2021.4.14

NHMike
Posts: 2555
Joined: Fri Jul 21, 2017 3:43 am

Re: NRAS Q61R - what does that mean?

Postby NHMike » Thu Nov 23, 2017 10:05 am

NRAS is a gene that provides the code for making NRAS, a GTPase that converts GTP to GDP. This protein is part of the MAP kinase signaling cascade that relays chemical signals from the outside of the cell to the cell's nucleus, and is primarily involved in controlling cell division. When NRAS is attached (bound) to GDP, it is in its “off” position and can't send signals to the nucleus. But when a GTP molecule arrives and binds to NRAS, NRAS is activated and sends its signal, and then it converts the GTP into GDP and returns to the "off" position. HRAS and KRAS are other GTPases that are similar to NRAS.

When mutated, however, NRAS can act as an oncogene, causing normal cells to become cancerous. The mutations can shift the NRAS protein into the "on" position all the time. These NRAS mutations are said to be somatic, because instead of coming from a parent and being present in every cell (hereditary), they are acquired during the course of a person's life and are found only in cells that become cancerous.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of NRAS mutations in melanoma (~30%), acute myeloid leukemia (~15%) and thyroid carcinoma (5-10%).

Source: Genetics Home Reference

The NRAS 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).

The large randomized MRC COIN trial reported that the presence of an NRAS mutation was associated with worse prognosis in advanced colorectal patients.

The role of NRAS mutations for selecting anti-cancer targeted agents is unknown at this time. Unlike its closely-related family member KRAS, the frequency of NRAS mutation is low in colorectal cancer (4%) and this has precluded its determination as a biomarker of drug resistance to the anti-EGFR agent cetuximab or panitumumab. However, a single multi-center retrospective study has reported that the presence of an NRAS mutation was associated with significantly lower response to treatment with cetuximab plus chemotherapy in patients with chemotherapy-refractory, metastatic colorectal cancer.

Based on clinical evidence obtained in melanoma, downstream pathway MEK inhibitors may be a feasible treatment strategy for the treatment of NRAS-mutant tumors, citing an approximate 20% response rate to single-agent MEK162 treatment in patients with malignant melanoma. While it remains unclear whether NRAS mutations will predict response to current MEK inhibitors in colorectal cancer, a combination therapy approach that additionally targets the PI3K/AKT/mTOR pathway may confer a more robust treatment effect.

PubMed ID's
20619739, 20141835, 16273091, 19805051, 21641636, 23414587


https://targetedcancercare.massgeneral. ... -(c-182A-G).aspx
6/17: ER rectal bleeding; Colonoscopy
7/17: 3B rectal. T3N1bM0. 5.2 4.5 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
7/17-9/17: Xeloda radiation
7/5: CEA 2.7; 8/16: 1.9; 11/30: 0.6; 12/20 1.4; 1/10 1.8; 1/31 2.2; 2/28 2.6; 4/10 2.8; 5/1 2.8; 5/29 3.2; 7/13 4.5; 8/9 2.8, 2/12 1.2
MSS, KRAS G12D
10/17: 2.7 2.2 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/17: LAR, Temp Ileostomy, Path Complete Response
CapeOx (8) 12/17-6/18
7/18: Reversal, Port Removal
2/19: Clean CT

NHMike
Posts: 2555
Joined: Fri Jul 21, 2017 3:43 am

Re: NRAS Q61R - what does that mean?

Postby NHMike » Thu Nov 23, 2017 10:10 am

Frequency of NRAS mutations in colorectal cancer: 1–6% of colorectal cancers (COSMIC; De Roock et al. 2010; Irahara et al. 2009; Janku et al. 2007; Vaughn et al. 2011)​​

Frequency of Q61R among NRAS-mutated colorectal cancers: 16.8% (COSMIC)

https://www.mycancergenome.org/content/ ... r/nras/77/
6/17: ER rectal bleeding; Colonoscopy
7/17: 3B rectal. T3N1bM0. 5.2 4.5 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
7/17-9/17: Xeloda radiation
7/5: CEA 2.7; 8/16: 1.9; 11/30: 0.6; 12/20 1.4; 1/10 1.8; 1/31 2.2; 2/28 2.6; 4/10 2.8; 5/1 2.8; 5/29 3.2; 7/13 4.5; 8/9 2.8, 2/12 1.2
MSS, KRAS G12D
10/17: 2.7 2.2 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/17: LAR, Temp Ileostomy, Path Complete Response
CapeOx (8) 12/17-6/18
7/18: Reversal, Port Removal
2/19: Clean CT

NHMike
Posts: 2555
Joined: Fri Jul 21, 2017 3:43 am

Re: NRAS Q61R - what does that mean?

Postby NHMike » Thu Nov 23, 2017 10:16 am

I'm sorry for the difficulties that your mother is going through and hope that those two posts provide a bit more information about NRAS, and her particular mutation. From what I understand, the whole NRAS Gene mutation set tends to worse prognosis. NRAS isn't common so it seems that we're still a bit in the dark ages about how it responds to the usual treatment drugs. I have run into a few papers on therapy results for NRAS (and others) which I will have to look at later.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999563/
https://www.ncbi.nlm.nih.gov/pubmed/24758538
6/17: ER rectal bleeding; Colonoscopy
7/17: 3B rectal. T3N1bM0. 5.2 4.5 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
7/17-9/17: Xeloda radiation
7/5: CEA 2.7; 8/16: 1.9; 11/30: 0.6; 12/20 1.4; 1/10 1.8; 1/31 2.2; 2/28 2.6; 4/10 2.8; 5/1 2.8; 5/29 3.2; 7/13 4.5; 8/9 2.8, 2/12 1.2
MSS, KRAS G12D
10/17: 2.7 2.2 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/17: LAR, Temp Ileostomy, Path Complete Response
CapeOx (8) 12/17-6/18
7/18: Reversal, Port Removal
2/19: Clean CT


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