Difference between revisions of "KRAS mutation"

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[[Image:Colonic mucinous adenocarcinoma - low mag.jpg|thumb|right|[[Micrograph]] showing mucinous carcinoma, a histology associated with KRAS mutations.]] 
'''KRAS mutation''' is a re-occuring theme in [[molecular pathology]].  KRAS is an [[oncogene]].<ref name=omim190070>{{OMIM|190070}}</ref>
'''KRAS mutation''' is a re-occuring theme in [[molecular pathology]].  KRAS is an [[oncogene]].<ref name=omim190070>{{OMIM|190070}}</ref>


==General==
==General==
Kirsten RAS (KRAS) is a member of the Ras gene familiy, which encodes small G proteins with intrinsic GTPase activity.
Seen in:
Seen in:
*[[Invasive ductal carcinoma of the pancreas]].
*[[Invasive ductal carcinoma of the pancreas]].
*[[Colorectal carcinoma]].<ref name=pmid19792050>{{Cite journal  | last1 = Monzon | first1 = FA. | last2 = Ogino | first2 = S. | last3 = Hammond | first3 = ME. | last4 = Halling | first4 = KC. | last5 = Bloom | first5 = KJ. | last6 = Nikiforova | first6 = MN. | title = The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. | journal = Arch Pathol Lab Med | volume = 133 | issue = 10 | pages = 1600-6 | month = Oct | year = 2009 | doi = 10.1043/1543-2165-133.10.1600 | PMID = 19792050 }}</ref>
*[[Colorectal carcinoma]] (40%).<ref name=pmid19792050>{{Cite journal  | last1 = Monzon | first1 = FA. | last2 = Ogino | first2 = S. | last3 = Hammond | first3 = ME. | last4 = Halling | first4 = KC. | last5 = Bloom | first5 = KJ. | last6 = Nikiforova | first6 = MN. | title = The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. | journal = Arch Pathol Lab Med | volume = 133 | issue = 10 | pages = 1600-6 | month = Oct | year = 2009 | doi = 10.1043/1543-2165-133.10.1600 | PMID = 19792050 }}</ref><ref>{{Cite journal  | last1 = Imamura | first1 = Y. | last2 = Lochhead | first2 = P. | last3 = Yamauchi | first3 = M. | last4 = Kuchiba | first4 = A. | last5 = Qian | first5 = ZR. | last6 = Liao | first6 = X. | last7 = Nishihara | first7 = R. | last8 = Jung | first8 = S. | last9 = Wu | first9 = K. | title = Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review. | journal = Mol Cancer | volume = 13 | issue =  | pages = 135 | month = May | year = 2014 | doi = 10.1186/1476-4598-13-135 | PMID = 24885062 }}</ref>
*lung adenocarcinomas (approx 30%)<ref>{{Cite journal  | last1 = Korpanty | first1 = GJ. | last2 = Graham | first2 = DM. | last3 = Vincent | first3 = MD. | last4 = Leighl | first4 = NB. | title = Biomarkers That Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1, and KRAS. | journal = Front Oncol | volume = 4 | issue =  | pages = 204 | month =  | year = 2014 | doi = 10.3389/fonc.2014.00204 | PMID = 25157335 }}</ref>
*Squamous NSCLC (~5%).
*[[Mucinous ovarian tumours]].<ref name=pmid9118042>{{Cite journal  | last1 = Cuatrecasas | first1 = M. | last2 = Villanueva | first2 = A. | last3 = Matias-Guiu | first3 = X. | last4 = Prat | first4 = J. | title = K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. | journal = Cancer | volume = 79 | issue = 8 | pages = 1581-6 | month = Apr | year = 1997 | doi =  | PMID = 9118042 }}</ref>


Not seen in the context of:
Not seen in the context of:
*ALK rearrangements in [[non-small cell lung cancer]].<ref name=pmid23729361>{{Cite journal  | last1 = Gainor | first1 = JF. | last2 = Varghese | first2 = AM. | last3 = Ou | first3 = SH. | last4 = Kabraji | first4 = S. | last5 = Awad | first5 = MM. | last6 = Katayama | first6 = R. | last7 = Pawlak | first7 = A. | last8 = Mino-Kenudson | first8 = M. | last9 = Yeap | first9 = BY. | title = ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. | journal = Clin Cancer Res | volume = 19 | issue = 15 | pages = 4273-81 | month = Aug | year = 2013 | doi = 10.1158/1078-0432.CCR-13-0318 | PMID = 23729361 }}</ref>
*ALK rearrangements in [[non-small cell lung cancer]].<ref name=pmid23729361>{{Cite journal  | last1 = Gainor | first1 = JF. | last2 = Varghese | first2 = AM. | last3 = Ou | first3 = SH. | last4 = Kabraji | first4 = S. | last5 = Awad | first5 = MM. | last6 = Katayama | first6 = R. | last7 = Pawlak | first7 = A. | last8 = Mino-Kenudson | first8 = M. | last9 = Yeap | first9 = BY. | title = ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. | journal = Clin Cancer Res | volume = 19 | issue = 15 | pages = 4273-81 | month = Aug | year = 2013 | doi = 10.1158/1078-0432.CCR-13-0318 | PMID = 23729361 }}</ref>
*Almost mutually exclusive to [[BRAF V600E mutation|BRAF (V600E)]] in [[colon cancer]].<ref name=pmid24925349/>


===Implication===
===Implication===
====Colorectal cancer====
In the context of colorectal carcinoma:<ref name=pmid20956938>{{cite journal |author=Dunn EF, Iida M, Myers RA, ''et al.'' |title=Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab |journal=Oncogene |volume= |issue= |pages= |year=2010 |month=October |pmid=20956938 |doi=10.1038/onc.2010.430 |url=}}</ref><ref name=pmid19001320>{{cite journal |author=Di Nicolantonio F, Martini M, Molinari F, ''et al.'' |title=Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer |journal=J. Clin. Oncol. |volume=26 |issue=35 |pages=5705–12 |year=2008 |month=December |pmid=19001320 |doi=10.1200/JCO.2008.18.0786 |url=}}</ref>
In the context of colorectal carcinoma:<ref name=pmid20956938>{{cite journal |author=Dunn EF, Iida M, Myers RA, ''et al.'' |title=Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab |journal=Oncogene |volume= |issue= |pages= |year=2010 |month=October |pmid=20956938 |doi=10.1038/onc.2010.430 |url=}}</ref><ref name=pmid19001320>{{cite journal |author=Di Nicolantonio F, Martini M, Molinari F, ''et al.'' |title=Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer |journal=J. Clin. Oncol. |volume=26 |issue=35 |pages=5705–12 |year=2008 |month=December |pmid=19001320 |doi=10.1200/JCO.2008.18.0786 |url=}}</ref>
*Patient must have ''wild type'' KRAS to get drugs; KRAS mutation predicts resistance to [[cetuximab]] (Erbitux) and [[panitumumab]] (Vectibix).
*Patient must have ''wild type'' KRAS to get drugs; KRAS mutation predicts resistance to [[cetuximab]] (Erbitux) and [[panitumumab]] (Vectibix).
* The vast majority of activating mutations are found in codon 12/13, 61 and 146.<ref>{{Cite journal  | last1 = Imamura | first1 = Y. | last2 = Lochhead | first2 = P. | last3 = Yamauchi | first3 = M. | last4 = Kuchiba | first4 = A. | last5 = Qian | first5 = ZR. | last6 = Liao | first6 = X. | last7 = Nishihara | first7 = R. | last8 = Jung | first8 = S. | last9 = Wu | first9 = K. | title = Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review. | journal = Mol Cancer | volume = 13 | issue =  | pages = 135 | month = May | year = 2014 | doi = 10.1186/1476-4598-13-135 | PMID = 24885062 }}</ref>
* KRAS mutations are usually stable between primary and metastatic tumors. <ref>{{Cite journal  | last1 = Petaccia de Macedo | first1 = M. | last2 = Melo | first2 = FM. | last3 = Ribeiro | first3 = HSC. | last4 = Marques | first4 = MC. | last5 = Kagohara | first5 = LT. | last6 = Begnami | first6 = MD. | last7 = Neto | first7 = JC. | last8 = Ribeiro | first8 = JS. | last9 = Soares | first9 = FA. | title = KRAS mutation status is highly homogeneous between areas of the primary tumor and the corresponding metastasis of colorectal adenocarcinomas: one less problem in patient care. | journal = Am J Cancer Res | volume = 7 | issue = 9 | pages = 1978-1989 | month =  | year = 2017 | doi =  | PMID = 28979819 }}</ref>
* KRAS mutation predict poor response to FOLFOX treatment.<ref name=pmid25870609>{{Cite journal  | last1 = Zocche | first1 = DM. | last2 = Ramirez | first2 = C. | last3 = Fontao | first3 = FM. | last4 = Costa | first4 = LD. | last5 = Redal | first5 = MA. | title = Global impact of KRAS mutation patterns in FOLFOX treated metastatic colorectal cancer. | journal = Front Genet | volume = 6 | issue =  | pages = 116 | month =  | year = 2015 | doi = 10.3389/fgene.2015.00116 | PMID = 25870609 }}</ref>
====Lung cancer====
In the context of lung cancer:<ref>{{Cite journal  | last1 = Riely | first1 = GJ. | last2 = Kris | first2 = MG. | last3 = Rosenbaum | first3 = D. | last4 = Marks | first4 = J. | last5 = Li | first5 = A. | last6 = Chitale | first6 = DA. | last7 = Nafa | first7 = K. | last8 = Riedel | first8 = ER. | last9 = Hsu | first9 = M. | title = Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. | journal = Clin Cancer Res | volume = 14 | issue = 18 | pages = 5731-4 | month = Sep | year = 2008 | doi = 10.1158/1078-0432.CCR-08-0646 | PMID = 18794081 }}</ref>
* Mutations are rare in never-smokers.
* KRAS G12C is the most common G > T transversion mutation in smokers.<ref>{{Cite journal  | last1 = Dogan | first1 = S. | last2 = Shen | first2 = R. | last3 = Ang | first3 = DC. | last4 = Johnson | first4 = ML. | last5 = D'Angelo | first5 = SP. | last6 = Paik | first6 = PK. | last7 = Brzostowski | first7 = EB. | last8 = Riely | first8 = GJ. | last9 = Kris | first9 = MG. | title = Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. | journal = Clin Cancer Res | volume = 18 | issue = 22 | pages = 6169-77 | month = Nov | year = 2012 | doi = 10.1158/1078-0432.CCR-11-3265 | PMID = 23014527 }}</ref>
* Biomarker for MEK inhibitors selumetinib and trametinib.
==Gross==
In colorectal carcinoma:
*Typically right sided lesions.<ref name=pmid24925349/>


==Microscopic==
==Microscopic==
Features:
Features:
*Typically [[mucinous carcinoma]] in lung.<ref name=pmid25029118>{{Cite journal  | last1 = Kadota | first1 = K. | last2 = Yeh | first2 = YC. | last3 = D'Angelo | first3 = SP. | last4 = Moreira | first4 = AL. | last5 = Kuk | first5 = D. | last6 = Sima | first6 = CS. | last7 = Riely | first7 = GJ. | last8 = Arcila | first8 = ME. | last9 = Kris | first9 = MG. | title = Associations between mutations and histologic patterns of mucin in lung adenocarcinoma: invasive mucinous pattern and extracellular mucin are associated with KRAS mutation. | journal = Am J Surg Pathol | volume = 38 | issue = 8 | pages = 1118-27 | month = Aug | year = 2014 | doi = 10.1097/PAS.0000000000000246 | PMID = 25029118 }}</ref>
*In [[lung adenocarcinoma]]:
*No correlation in [[colorectal carcinoma]].<ref>{{Cite journal  | last1 = Gao | first1 = J. | last2 = Zhang | first2 = J. | last3 = Lu | first3 = T. | last4 = Li | first4 = XY. | last5 = Jia | first5 = N. | last6 = Liang | first6 = ZY. | title = [Correlation between KRAS mutations and clinicopathologic features in colorectal carcinomas]. | journal = Zhonghua Bing Li Xue Za Zhi | volume = 41 | issue = 9 | pages = 595-8 | month = Sep | year = 2012 | doi =  | PMID = 23157826 }}</ref>
**Typically [[mucinous carcinoma]].<ref name=pmid25029118>{{Cite journal  | last1 = Kadota | first1 = K. | last2 = Yeh | first2 = YC. | last3 = D'Angelo | first3 = SP. | last4 = Moreira | first4 = AL. | last5 = Kuk | first5 = D. | last6 = Sima | first6 = CS. | last7 = Riely | first7 = GJ. | last8 = Arcila | first8 = ME. | last9 = Kris | first9 = MG. | title = Associations between mutations and histologic patterns of mucin in lung adenocarcinoma: invasive mucinous pattern and extracellular mucin are associated with KRAS mutation. | journal = Am J Surg Pathol | volume = 38 | issue = 8 | pages = 1118-27 | month = Aug | year = 2014 | doi = 10.1097/PAS.0000000000000246 | PMID = 25029118 }}</ref>
**Associated with tumour-infiltrating leukocytes.<ref name=pmid23619604>{{Cite journal  | last1 = Rekhtman | first1 = N. | last2 = Ang | first2 = DC. | last3 = Riely | first3 = GJ. | last4 = Ladanyi | first4 = M. | last5 = Moreira | first5 = AL. | title = KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma. | journal = Mod Pathol | volume = 26 | issue = 10 | pages = 1307-19 | month = Oct | year = 2013 | doi = 10.1038/modpathol.2013.74 | PMID = 23619604 }}</ref>
*In [[colorectal carcinoma]]:
**No correlation in one study.<ref name=pmid23157826 >{{Cite journal  | last1 = Gao | first1 = J. | last2 = Zhang | first2 = J. | last3 = Lu | first3 = T. | last4 = Li | first4 = XY. | last5 = Jia | first5 = N. | last6 = Liang | first6 = ZY. | title = [Correlation between KRAS mutations and clinicopathologic features in colorectal carcinomas]. | journal = Zhonghua Bing Li Xue Za Zhi | volume = 41 | issue = 9 | pages = 595-8 | month = Sep | year = 2012 | doi =  | PMID = 23157826 }}</ref>
**'''Not''' high-grade based on one study.<ref name=pmid24925349>{{Cite journal  | last1 = Gonsalves | first1 = WI. | last2 = Mahoney | first2 = MR. | last3 = Sargent | first3 = DJ. | last4 = Nelson | first4 = GD. | last5 = Alberts | first5 = SR. | last6 = Sinicrope | first6 = FA. | last7 = Goldberg | first7 = RM. | last8 = Limburg | first8 = PJ. | last9 = Thibodeau | first9 = SN. | title = Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. | journal = J Natl Cancer Inst | volume = 106 | issue = 7 | pages =  | month = Jul | year = 2014 | doi = 10.1093/jnci/dju106 | PMID = 24925349 }}</ref>


==See also==
==See also==
*[[Molecular pathology]].
*[[Molecular pathology]].
*[[Oncogene]].
*[[Oncogene]].
*[[BRAF mutation]].


==References==
==References==

Latest revision as of 15:30, 8 February 2019

KRAS mutation is a re-occuring theme in molecular pathology. KRAS is an oncogene.[1]

General

Kirsten RAS (KRAS) is a member of the Ras gene familiy, which encodes small G proteins with intrinsic GTPase activity.

Seen in:

Not seen in the context of:

Implication

Colorectal cancer

In the context of colorectal carcinoma:[8][9]

  • Patient must have wild type KRAS to get drugs; KRAS mutation predicts resistance to cetuximab (Erbitux) and panitumumab (Vectibix).
  • The vast majority of activating mutations are found in codon 12/13, 61 and 146.[10]
  • KRAS mutations are usually stable between primary and metastatic tumors. [11]
  • KRAS mutation predict poor response to FOLFOX treatment.[12]

Lung cancer

In the context of lung cancer:[13]

  • Mutations are rare in never-smokers.
  • KRAS G12C is the most common G > T transversion mutation in smokers.[14]
  • Biomarker for MEK inhibitors selumetinib and trametinib.

Gross

In colorectal carcinoma:

  • Typically right sided lesions.[7]

Microscopic

Features:

See also

References

  1. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 190070
  2. ↑ Monzon, FA.; Ogino, S.; Hammond, ME.; Halling, KC.; Bloom, KJ.; Nikiforova, MN. (Oct 2009). "The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer.". Arch Pathol Lab Med 133 (10): 1600-6. doi:10.1043/1543-2165-133.10.1600. PMID 19792050.
  3. ↑ Imamura, Y.; Lochhead, P.; Yamauchi, M.; Kuchiba, A.; Qian, ZR.; Liao, X.; Nishihara, R.; Jung, S. et al. (May 2014). "Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.". Mol Cancer 13: 135. doi:10.1186/1476-4598-13-135. PMID 24885062.
  4. ↑ Korpanty, GJ.; Graham, DM.; Vincent, MD.; Leighl, NB. (2014). "Biomarkers That Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1, and KRAS.". Front Oncol 4: 204. doi:10.3389/fonc.2014.00204. PMID 25157335.
  5. ↑ Cuatrecasas, M.; Villanueva, A.; Matias-Guiu, X.; Prat, J. (Apr 1997). "K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases.". Cancer 79 (8): 1581-6. PMID 9118042.
  6. ↑ Gainor, JF.; Varghese, AM.; Ou, SH.; Kabraji, S.; Awad, MM.; Katayama, R.; Pawlak, A.; Mino-Kenudson, M. et al. (Aug 2013). "ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer.". Clin Cancer Res 19 (15): 4273-81. doi:10.1158/1078-0432.CCR-13-0318. PMID 23729361.
  7. ↑ 7.0 7.1 7.2 Gonsalves, WI.; Mahoney, MR.; Sargent, DJ.; Nelson, GD.; Alberts, SR.; Sinicrope, FA.; Goldberg, RM.; Limburg, PJ. et al. (Jul 2014). "Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147.". J Natl Cancer Inst 106 (7). doi:10.1093/jnci/dju106. PMID 24925349.
  8. ↑ Dunn EF, Iida M, Myers RA, et al. (October 2010). "Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab". Oncogene. doi:10.1038/onc.2010.430. PMID 20956938.
  9. ↑ Di Nicolantonio F, Martini M, Molinari F, et al. (December 2008). "Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer". J. Clin. Oncol. 26 (35): 5705–12. doi:10.1200/JCO.2008.18.0786. PMID 19001320.
  10. ↑ Imamura, Y.; Lochhead, P.; Yamauchi, M.; Kuchiba, A.; Qian, ZR.; Liao, X.; Nishihara, R.; Jung, S. et al. (May 2014). "Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.". Mol Cancer 13: 135. doi:10.1186/1476-4598-13-135. PMID 24885062.
  11. ↑ Petaccia de Macedo, M.; Melo, FM.; Ribeiro, HSC.; Marques, MC.; Kagohara, LT.; Begnami, MD.; Neto, JC.; Ribeiro, JS. et al. (2017). "KRAS mutation status is highly homogeneous between areas of the primary tumor and the corresponding metastasis of colorectal adenocarcinomas: one less problem in patient care.". Am J Cancer Res 7 (9): 1978-1989. PMID 28979819.
  12. ↑ Zocche, DM.; Ramirez, C.; Fontao, FM.; Costa, LD.; Redal, MA. (2015). "Global impact of KRAS mutation patterns in FOLFOX treated metastatic colorectal cancer.". Front Genet 6: 116. doi:10.3389/fgene.2015.00116. PMID 25870609.
  13. ↑ Riely, GJ.; Kris, MG.; Rosenbaum, D.; Marks, J.; Li, A.; Chitale, DA.; Nafa, K.; Riedel, ER. et al. (Sep 2008). "Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma.". Clin Cancer Res 14 (18): 5731-4. doi:10.1158/1078-0432.CCR-08-0646. PMID 18794081.
  14. ↑ Dogan, S.; Shen, R.; Ang, DC.; Johnson, ML.; D'Angelo, SP.; Paik, PK.; Brzostowski, EB.; Riely, GJ. et al. (Nov 2012). "Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.". Clin Cancer Res 18 (22): 6169-77. doi:10.1158/1078-0432.CCR-11-3265. PMID 23014527.
  15. ↑ Kadota, K.; Yeh, YC.; D'Angelo, SP.; Moreira, AL.; Kuk, D.; Sima, CS.; Riely, GJ.; Arcila, ME. et al. (Aug 2014). "Associations between mutations and histologic patterns of mucin in lung adenocarcinoma: invasive mucinous pattern and extracellular mucin are associated with KRAS mutation.". Am J Surg Pathol 38 (8): 1118-27. doi:10.1097/PAS.0000000000000246. PMID 25029118.
  16. ↑ Rekhtman, N.; Ang, DC.; Riely, GJ.; Ladanyi, M.; Moreira, AL. (Oct 2013). "KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma.". Mod Pathol 26 (10): 1307-19. doi:10.1038/modpathol.2013.74. PMID 23619604.
  17. ↑ Gao, J.; Zhang, J.; Lu, T.; Li, XY.; Jia, N.; Liang, ZY. (Sep 2012). "[Correlation between KRAS mutations and clinicopathologic features in colorectal carcinomas].". Zhonghua Bing Li Xue Za Zhi 41 (9): 595-8. PMID 23157826.
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