The
management of the colorectal cancer: Perspectives
Type
of article: original
Boumediene Elhabachi, Morsli Doulat, Abderrahman
Blaha, Soumia Zaouag, Hassan Cheheb
Faculty of medicine University of Sidi Bel
Abbes, Algeria
CHU Dr
Hassani A.E.K, Algeria
Abstract
Background: The
progress of scientific research gives new tracks to be exploited for the
management of the colorectal cancers whose the molecular profile study became
fundamental. Aim: the aim of this study was to compare the management of the
colorectal cancer in our patients to the current international recommendations.
Subjects and methods: In a retrospective study, we analysed 256 files between January, 2015
and September 2019. All the adenocarcinoma of colon and rectum were included.
Our patients were divided into two groups: 161
patients with colorectal cancer (63%) and 95 patients with rectum cancer (37%).
We studied if the management of the disease was actually compliant to the
international recommendations.
Results: Our study
showed that the colorectal cancer occured most frequently in young
population, with 45,5% in patients aged
more than 60 years, 44% between 40 -60 years and 10 were under 40 years. The tumor was in T3 or more
stage in 40,3% for colon cancer and 68,4% for rectum cancer. Elsewhere, none of
the patients benefited from a molecular profile study of his tumor.
Discussion:The
colorectal cancer is diagnosed in
relatively young population with 54,5% of patients aged less than 60 years
among whom 10% are less than 40, which explains the diagnostic delay. This
delay is also due to the lack of a screening in general population and high risk subjects. Moreover, the absence
of a molecular examination has a
negative impact on the treatment and on the screening in the apparented,
especially in case of tumor with micro satellite instability.
Conclusion: In order
to improve the prognosis of the colorectal cancers in our patients, a screening
adapted to the groups at risk has to be implemented and a molecular profil
examination achived so that evolution and therapeutics perspectives could be
set.
Keys words:
colorectal cancer; molecular profile, management
Corresponding author: Boumedien Elhabachi,
Faculty of medicine University of Sidi Bel Abbes, Algeria
email: b.elhabachi@yahoo.fr
Received: July 12 2020.
Reviewed: August 17 2020. Accepted: October 3 2020. Published: October 20 2020.
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Colorectal cancers (CRC) are common throughout the
world with over 1 million cases and 500,000 deaths [1] per year. They occupy
the third place among cancers [2].
However, the incidence of these cancers has decreased over the past four
decades [3] particularly in the USA,
thanks to endoscopic screening. It should be noted that it is the cancers of
the left colon that have decreased while those of the right colon have remained
stable. CRC is a serious disease due to its digestive location with its
nutritional impact and its functional impact for cancers of the rectum, close
to the anal sphincter. Adenocarcinomas (ADK) are the most common cancers on
this segment of the digestive tract. This histopathological type is
heterogeneous with a different therapeutic response and course. Immunohistochemistry
and molecular biology have made it possible to define the different biological
profiles of colorectal cancers, the mechanisms of carcinogenesis, the different
signaling pathways, which has led to the development of increasingly effective
targeted therapies. For proper management, it is essential to have certain
informations, mainly the one concerning the presence of a mutation in one or
more genes of the DNA mismatch repair system (MMR system). Indeed,
adenocarcinomas presenting this abnormality are more frequent on the right
colon; they are distinguished from left colon ADKs in terms of precancerous
lesions, prognosis, epidemiology and response to medical treatment.
5% of CRC are hereditary and 30% occur in a context of
family aggregation. In addition to an adequate epidemiological investigation,
screening adapted to the risk group as well as the determination of the
biological profile of the tumor should allow an effective management.
Through a retrospective study, we analyzed the files
of 256 patients with CRC and treated in the general surgery department from
January, 2015 to December, 2019.
Inclusion criteria: all colon cancers (CC) and rectum Cancers (RC) in both sexes treated in
the adult surgical department.
Exclusion criteria: tumors of other histopathological types.
Our workforce consisted of 161 colon ADKs, 20 were
admitted urgently in an occlusion picture and 95 rectal cancers. The
predominance was slightly male and more pronounced for RC (Ratio 1.31). There
are 88 men against 73 women for the CCs and 54 men against 41 women for the RC.
For colon cancers:
Age: only 12
cases were recorded in subjects under the age of 40, ie 7% of colon cancers and
4.5% of all CRCs. The patients are over 60 years old in 52% of CCs (83
patients); 41% of patients (66 patients) are between 40 and 60 years old and
92% are over 40 years old.
The personal history: we find a notion of cancer in 8 patients and in 4
patients when assessing history familial; in 33 patients no history was
specified.
Localization: we find 49
sigmoid localizations, 22 left colic ones, 19 transverse colic and 71 right
colic ones, according to the files.
TNM classification: 54 patients presented with T3 tumors and 69 were T4.
Differentiation: 79 cancers are well differentiated, 30 moderately differentiated and 12
poorly differentiated. In 20 cases, the pathological study was imprecise.
All patients had an extension assessment with a total
colonoscopy, apart from the patients urgently operated and 30 patients
scheduled cold in whom colonoscopy was incomplete or impossible, mainly due to
the evolutionary stage of the lesion and poor preparation.
For rectal cancers:
Age: 34 patients
are over 60 years old (37.5%), 47 patients between 40 and 60 years old (51.5%)
and 14 are under 40 years old.
Personal history : a personal history was found in
11 cases but no family one.
Localization: there were
35 cases on the lower rectum and an equal distribution for the middle and upper
rectum.
Colonoscopy: was only
possible in 55 patients.
TNM: 65 patients
had T3 tumors or more.
Differentiation: ADK was well differentiated in 57 patients, moderately differentiated
in 11 and poorly differentiated in 08. In 10 cases the anatomopathology was inconclusive.
In our series, relatively young and active subjects
have the highest incidence of CRC. Through our analysis, it clearly appears
that the diagnosis is most often late. Indeed, 9.5% of CRCs are admitted and
operated on emergency, in an occlusion picture. This emergency concerns 12% of
CCs and 4.5% of RC.
The diagnostic delay is confirmed by the pathological
study. This delay in diagnosis is probably attributed to the occurrence of this
cancer in a relatively young population which had been healthy until then, and
without seriously affecting the general condition to get the patient and the
physician attention. Regarding age, 45.5% of CRCs are diagnosed in subjects
over 60 years old, 44% of patients were between 40 and 60 years old and 10%
under 40 years old. RCs are developing in an increasingly younger population: 66.5% are
under 60 years old. Elsewhere, this diagnostic delay also seems to be due to
the location of the tumor. Indeed, and according to international
epidemiological studies, 2/3 of colonic cancers are located on the left colon
knowing that the right colon concerns the segment going from the cecum to the
splenic imprint, in other words, up to the left colic angle which is not
included [4]. But in our series we find more ADK of the right colon (90 cases)
than those of the left one (71 cases). These two locations are different, while
patient records do not give great importance to such difference. The tumor
location taken into account is surgical: etiopathogenically, the transverse
colon does not exist, only the right colon and the left one are retained.
serrated polyps, more frequent precancerous lesions on
the right, are difficult to identify by optical or virtual colonoscopy. Our
analysis showed that no screening has been scheduled for first-degree relatives
of these patients operated on for CRC, whereas a colonoscopy is required in
these subjects becoming at high risk.
The diagnosis of CRC should no longer be based on
clinical manifestations that are too often at an advanced stage, as the case is
in our series. It is recommended by learned societies to offer screening in the
general population said to be at average risk from the age of 50 years
[5-8]. In the population at high risk,
screening by optical endoscopy is necessary five years before the age of onset
of cancer in the index case [9-11]. The same is true for chronic inflammatory
bowel diseases that have progressed for 10 years with repeated flare-ups
[12-14]. Syndromic cancers and polyposes are monitored by endoscopy according
to the recommendations of learned societies [15].
Indeed, CRC is one of the best preventable cancers.
This cancer almost always develops on benign lesions such as adenomatous and
serrated polyps. The Adenoma - Cancer sequence is currently well established
[16]. Adenomatous polyps are the precursors of the majority of colorectal
cancers [16]. Up to 80% of colorectal cancers result from the malignant
transformation of an adenomatous polyp with a first stage of genesis of the
adenoma followed by its growth and then its malignant degeneration [17]. The
risk of cancerization increases crescendo with size, the presence of a villous
component and with the presence of severe dysplasia which is more common in
villous polyps [18, 19]. It is obvious that this risk of degeneration is
greater when these risk factors are combined. These polyps are often the site
of a Kras mutation.
Serrated polyps, more common on the right, are a
heterogeneous group made up of three different entities with different
potential for malignant development. According to the WHO classification, a
distinction is made between the hyperplastic polyp, the sessile serrated
adenoma and the traditional serrated adenoma [20-22]. The latter two have a
potential for degeneration, particularly the sessile serrated adenoma which
represents 15 to 20% of serrated polyps and 90% of these polyps are located in
the right colon [23].It is currently recognized as being the initial lesion of
colorectal carcinogenesis according to a new path called “the serrated path”
[21, 22, 24, 25] often with a BRAF mutation [26].
Colorectal carcinogenesis is currently better known
[27, 28] and three main molecular mechanisms of colorectal carcinogenesis are
identified:
1- Chromosomal
instability [29, 30], known as CIN (Chromosomal INstability) or LOH (Loss Of Heterozygoty).
This pathway, involved in at least 80% of CRC, is characterized by allelic
losses associated with frequent mutations of tumor suppressor genes [30].
2-
Micro satellite instability [29]
Involved in about 15% of CCRs. Cancers of the right colon are too often
cancers with micro-satellite instability and called “MIS”. This instability can
be germinal by mutation of one of the genes of the MMR (Mismatch Repair) system
or by methylation. If 15% of sporadic CRCs are of IMS phenotype (dMMR), almost
all CRCs in Lynch syndrome will be of this phenotype. Numerous studies have
shown that the IMS stage II and III phenotype has a better prognosis than MSS
tumors [31, 32]. This prognostic factor seems to be of interest to all stages
with a significant reduction in the risk of death [33, 34].
3- Epigenetic
instability [21, 35, 36] is the third mechanism more recently described, but
which is dependent on the first two ones [36].
Here, there is no mutation, no deletion, no chromosomal instability and
no micro satellite instability by mutation of the genes of the MMR system. DNA
is methylated by adding a methyl group to a cytosine base (CpG islands). The
DNA sequence is nor altered neither modified; we are talking about epigenetic
phenomenon and not genetic one. Depending on the number of markers or the
degree of methylation, CIMP-H tumors (for high) and CIMP-L tumors (for low) are
defined. CIMP-H tumors are often associated with a mutation in the BRAF
proto-oncogene (V600E) [37]. This mutation is too often found in sessile
serrated adenomas (SSA) which are the precursors of these tumors. Indeed, 90%
of tumors that develop from SSA have the BRAF mutation (V600E), whereas this
mutation only very rarely [38]. or never [21]exists in adenomatous polyps.
These findings have clinical implications:
- It is important to look for the phenotype
(dMMR), that is to say a lack of repair of DNA mismatches, and whose
consequence is micro satellite instability and this by searching for protein
extinction ("IHC" immunohistochemistry ) or by biological test. Among
these tumors we should look for those belonging to Lynch syndrome defined by a
mutation in one of the genes of the MMR system. In this case the patient and
his relatives in the first degree become very high risk subjects requiring
specific monitoring. The other tumors are unstable but sporadic. When IHC
reveals a loss of expression of the MLH1 protein with or without PMS2 one, we
must first look for a mutation of the BRAF gene and hypermethylation of the
promoter of the MLH1 gene [39]. The
presence of one of these abnormalities or of both of them indicates the
sporadic character and the sequencing of the genes is no longer indicated
saving time and money.
The search for the unstable MSI phenotype
will be carried out in case of CRC in a subject aged less than 70 years or in
case of several cancers belonging to the spectrum in patients or their first
degree relatives [39, 40].
- The neoadjuvant treatment can be the
cause of an extinction of the MSH6 protein without there being any
micro-satellite instability.
- This same neoadjuvant treatment can give
a complete histological response on an operative specimen. No test will be
possible anymore. - The search for a BRAF and KRAS mutation is very important
in case of metastatic colorectal disease in order to indicate a targeted
therapy by anti EGFR (epidermal growth factor receptor) whose marketing
authorization is conditioned by the absence of mutation [40].
- Tumors of the right colon with MSI
phenotype and BRAF mutation have an excellent prognosis.
- On the other hand, colorectal tumors
which develop along the serrated path, with CIMP-H methylation but MSS
(satellite micro stability) are often diagnosed at an advanced stage.
- CRCs of the CIMP-H and MSS phenotype with
BRAF mutation have a bad prognosis, in particular for stages II, III and IV
[41, 42] with a higher risk of death.
- The MSI phenotype is rare in the rectum
(about 3%) which does not dispense from the same scientific rigor when it comes
to defining the biological profile of the tumor.
- CRC at stage II and III IMS do not seem
to benefit from chemotherapy with 5FU alone, unlike MSS CRC. This molecule, 5
FU, would even be deleterious for CRCs at stage II IMS. IMS would be predictive
of the ineffectiveness of 5FU alone in CRC with sporadic IMS and not in Lynch
syndrome tumors [43].
Determining the tumor IMS or MSS status has become
essential to discuss the indication of adjuvant chemotherapy in a patient
operated on for stage II CRC with bad prognostic factors.
In our patients, the diagnosis of CRC was made by
anatomopathological study of biopsies obtained via endoscopy. Analysis of our
files shows that the biopsies are limited to 3 samples on average and fixed
with formalin. Taking into account the cited elements of modern oncology, it is
imperative to obtain, in the future, 10 to 15 biopsies fixed and included in
paraffin for molecular pathology. An immunohistochemical study or even a
biological test looking for possible micro satellite instability must be carried
out. The two tests are complementary.
The management of CRC requires specialists within a
multidisciplinary team mastering the avenues of modern oncology. Treatment must
be personalized. Each tumor has a specific biological profile. Immunohistochemical
tests and molecular biology in addition to pathology data should allow a
judicious therapeutic choice. This choice guarantees the best chances of
recovery and survival for patients and allows us to spare them a heavy and
expensive treatment and which is sometimes ineffective. The screening is the
only way which allows a reduction of the mortality by colorectal cancer thanks
to an early diagnosis as well as a reduction of the incidence of these
tumors thanks to the diagnosis and
treatment of pre cancerous lesions.
we would like to thank the general surgery
team of the UHC of Sidi Bel Abbès, which allowed us the access to medical
records in order to carry out this critical study.
We certify that there is no conflict of interest
with any financial organization inthe subject matter or materials discussed in
this manuscript.
Professor Boumédiène
ELHABACHI: Gratuated in senology, cancerology and repair
surgery. As a lecturer professor, I work hard and steadily to put implement any new techniques
or actions within our hospital structures, that would allow us to open up to
the future offered by onco-genetic advances and technologies of medical
imagery. This will largery benefit the patients of tomorrow.
Doctor Hassan CHEHEB: Gratuated in general surgery. Assistant master, particularly invested
in hepato-biliary cancerology, we are joining efforts to solve the problems of
a future multidisciplinary management of our patients in a specific
socio-economic and cultural context.
Doulat Morsli:
Resident physicians general surgery faculty of
medecine of sidi bel abbés.
Abderrahman Blaha: Resident physicians general surgery faculty of
medecine of sidi bel abbés.
Soumia Zaouag: Resident physicians general surgery faculty of
medecine of sidi bel abbés.
[1] Corrêa., R.d.S., et al., Rectal cancer survival
in a Brazilian Cancer Reference Unit. JCOL, 2016. 36(4): p. 203-207. https://doi.org/10.1016/j.jcol.2016.04.015
[2] Wright, M., J.S. Beaty, and C.A. Ternent,
Molecular Markers for Colorectal Cancer. Surg Clin North Am, 2017. 97(3): p.
683-701. https://doi.org/10.1016/j.suc.2017.01.014 PMid:28501255
[3] Siegel, R.L., et al., Colorectal cancer
statistics, 2017. CA Cancer J Clin, 2017. 67(3): p. 177-193. https://doi.org/10.3322/caac.21395 PMid:28248415
[4] [Consensus conference: Prevention Screening and
Management of the Colonic Cancers. Paris, France, January 29-30, 1998.
Proceedings]. Gastroenterol Clin Biol, 1998. 22(3 Suppl): p. S1-295.
[5] Bibbins-Domingo, K., et al., Screening for
Colorectal Cancer: US Preventive Services Task Force Recommendation Statement.
JAMA, 2016. 315(23): p. 2564-2575. https://doi.org/10.1001/jama.2016.5989 PMid:27304597
[6] Moore, J.S. and T.H. Aulet, Colorectal Cancer
Screening. Surg Clin North Am, 2017. 97(3): p. 487-502. https://doi.org/10.1016/j.suc.2017.01.001 PMid:28501242
[7] Winawer, S., et al., Colorectal cancer screening
and surveillance: clinical guidelines and rationale-Update based on new
evidence. Gastroenterology, 2003. 124(2): p. 544-60. https://doi.org/10.1053/gast.2003.50044 PMid:12557158
[1]
Winawer, S.J., et al., Prevention of colorectal cancer by colonoscopic
polypectomy. The National Polyp Study Workgroup. N Engl J Med, 1993. 329(27):
p. 1977-81. https://doi.org/10.1056/NEJM199312303292701 PMid:8247072
[2]
National Comprehensive Cancer Network. NCCN clinical practice guidelines
in oncology (NCCN guidelines): colorectal cancer screening., 2018.
[3]
National Comprehensive Cancer Network. Rectal Cancer. Version 3.2018.,
2018.
[4]
Kahi, C.J., et al., Colonoscopy Surveillance after Colorectal Cancer
Resection: Recommendations of the US Multi-Society Task Force on Colorectal
Cancer. Am J Gastroenterol, 2016. 111(3): p. 337-46; quiz 347. https://doi.org/10.1038/ajg.2016.22 PMid:26871541
[5]
Devon, K.M., et al., Cancer of the anus complicating perianal Crohn's
disease. Dis Colon Rectum, 2009. 52(2): p. 211-6. https://doi.org/10.1007/DCR.0b013e318197d0ad PMid:19279414
[6]
Higashi, D., et al., Cancer of the small intestine in patients with
Crohn's disease. Anticancer Res, 2013. 33(7): p. 2977-80.
[7]
Rutter, M.D., et al., Thirty-year analysis of a colonoscopic surveillance
program for neoplasia in ulcerative colitis. Gastroenterology, 2006. 130(4): p.
1030-8. https://doi.org/10.1053/j.gastro.2005.12.035 PMid:16618396
[8]
National Comprehensive Cancer Network.. NCCN Guidelines For Genetic /
familial High-Risk Assessement: Colorectal., 2018.
[9]
Winawer, S.J., et al., Risk of colorectal cancer in the families of
patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med,
1996. 334(2): p. 82-7. https://doi.org/10.1056/NEJM199601113340204 PMid:8531963
[10] Takayama, T., et al., Aberrant crypt foci of the
colon as precursors of adenoma and cancer. N Engl J Med, 1998. 339(18): p.
1277-84. https://doi.org/10.1056/NEJM199810293391803 PMid:9791143
[11] Eide, T.J., Risk of colorectal cancer in
adenoma-bearing individuals within a defined population. Int J Cancer, 1986.
38(2): p. 173-6. https://doi.org/10.1002/ijc.2910380205 PMid:3733258
[12] Morson, B., President's address. The polyp-cancer
sequence in the large bowel. Proc R Soc Med, 1974. 67(6 Pt 1): p. 451-7. https://doi.org/10.1177/00359157740676P115
[13] Bateman, A.C., Pathology of serrated colorectal
lesions. J Clin Pathol, 2014. 67(10): p. 865-74. https://doi.org/10.1136/jclinpath-2014-202175 PMid:24561317
[14] Leggett, B. and V. Whitehall, Role of the
serrated pathway in colorectal cancer pathogenesis. Gastroenterology, 2010.
138(6): p. 2088-100. https://doi.org/10.1053/j.gastro.2009.12.066 PMid:20420948
[15] Saito, S., H. Tajiri, and M. Ikegami, Serrated
polyps of the colon and rectum: Endoscopic features including image enhanced
endoscopy. World J Gastrointest Endosc, 2015. 7(9): p. 860-71. https://doi.org/10.4253/wjge.v7.i9.860 PMid:26240687 PMCid:PMC4515420
[16] Imai, K. and H. Yamamoto, Carcinogenesis and
microsatellite instability: the interrelationship between genetics and
epigenetics. Carcinogenesis, 2008. 29(4): p. 673-80. https://doi.org/10.1093/carcin/bgm228 PMid:17942460
[17] Longacre, T.A. and C.M. Fenoglio-Preiser, Mixed
hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal
neoplasia. Am J Surg Pathol, 1990. 14(6): p. 524-37. https://doi.org/10.1097/00000478-199006000-00003 PMid:2186644
[18] Torlakovic, E. and D.C. Snover, Serrated
adenomatous polyposis in humans. Gastroenterology, 1996. 110(3): p. 748-55. https://doi.org/10.1053/gast.1996.v110.pm8608884 PMid:8608884
[19] Bettington, M., et al., The serrated pathway to
colorectal carcinoma: current concepts and challenges. Histopathology, 2013.
62(3): p. 367-86. https://doi.org/10.1111/his.12055 PMid:23339363
[20] Bae, J.M., J.H. Kim, and G.H. Kang, Molecular
Subtypes of Colorectal Cancer and Their Clinicopathologic Features, With an
Emphasis on the Serrated Neoplasia Pathway. Arch Pathol Lab Med, 2016. 140(5):
p. 406-12. https://doi.org/10.5858/arpa.2015-0310-RA PMid:27128298
[21] Markowitz, S.D. and M.M. Bertagnolli, Molecular
origins of cancer: Molecular basis of colorectal cancer. N Engl J Med, 2009.
361(25): p. 2449-60. https://doi.org/10.1056/NEJMra0804588 PMid:20018966 PMCid:PMC2843693
[22] Laurent-Puig, P., J. Agostini, and K. Maley,
[Colorectal oncogenesis]. Bull Cancer, 2010. 97(11): p. 1311-21. https://doi.org/10.1684/bdc.2010.1216 PMid:21115420
[23] Vogelstein, B., et al., Genetic alterations during
colorectal-tumor development. N Engl J Med, 1988. 319(9): p. 525-32. https://doi.org/10.1056/NEJM198809013190901 PMid:2841597
[24] Ribic, C.M., et al., Tumor
microsatellite-instability status as a predictor of benefit from
fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med, 2003.
349(3): p. 247-57. https://doi.org/10.1056/NEJMoa022289 PMid:12867608 PMCid:PMC3584639
[25] Sargent, D.J., et al., Defective mismatch repair
as a predictive marker for lack of efficacy of fluorouracil-based adjuvant
therapy in colon cancer. J Clin Oncol, 2010. 28(20): p. 3219-26. https://doi.org/10.1200/JCO.2009.27.1825 PMid:20498393 PMCid:PMC2903323
[26] Gryfe, R., et al., Tumor microsatellite
instability and clinical outcome in young patients with colorectal cancer. N
Engl J Med, 2000. 342(2): p. 69-77. https://doi.org/10.1056/NEJM200001133420201 PMid:10631274
[27] Popat, S., R. Hubner, and R.S. Houlston,
Systematic review of microsatellite instability and colorectal cancer
prognosis. J Clin Oncol, 2005. 23(3): p. 609-18. https://doi.org/10.1200/JCO.2005.01.086 PMid:15659508
[28] Boland, C.R. and M. Shike, Report from the
Jerusalem workshop on Lynch syndrome-hereditary nonpolyposis colorectal cancer.
Gastroenterology, 2010. 138(7): p. 2197 e1-7. https://doi.org/10.1053/j.gastro.2010.04.024 PMid:20416305 PMCid:PMC3032350
[29] Colussi, D., et al., Molecular pathways involved
in colorectal cancer: implications for disease behavior and prevention. Int J
Mol Sci, 2013. 14(8): p. 16365-85. https://doi.org/10.3390/ijms140816365 PMid:23965959 PMCid:PMC3759916
[30] Stoffel, E.M. and C.R. Boland, Genetics and
Genetic Testing in Hereditary Colorectal Cancer. Gastroenterology, 2015.
149(5): p. 1191-1203 e2. https://doi.org/10.1053/j.gastro.2015.07.021 PMid:26226567
[31] Jass, J.R., et al., Advanced colorectal polyps
with the molecular and morphological features of serrated polyps and adenomas:
concept of a 'fusion' pathway to colorectal cancer. Histopathology, 2006.
49(2): p. 121-31. https://doi.org/10.1111/j.1365-2559.2006.02466.x PMid:16879389 PMCid:PMC1619718
[32] Vasen, H.F., et al., Revised guidelines for the
clinical management of Lynch syndrome (HNPCC): recommendations by a group of
European experts. Gut, 2013. 62(6): p. 812-23. https://doi.org/10.1136/gutjnl-2012-304356 PMid:23408351 PMCid:PMC3647358
[33] Allegra, C.J., et al., American Society of
Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations
in patients with metastatic colorectal carcinoma to predict response to
anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin
Oncol, 2009. 27(12): p. 2091-6. https://doi.org/10.1200/JCO.2009.21.9170 PMid:19188670
[34] Samowitz, W.S., et al., Poor survival associated
with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer
Res, 2005. 65(14): p. 6063-9. https://doi.org/10.1158/0008-5472.CAN-05-0404 PMid:16024606
[35] Ward, R.L., et al., Adverse prognostic effect of
methylation in colorectal cancer is reversed by microsatellite instability. J
Clin Oncol, 2003. 21(20): p. 3729-36. https://doi.org/10.1200/JCO.2003.03.123 PMid:14551292
[36] Sinicrope, F.A., et al., DNA mismatch repair
status and colon cancer recurrence and survival in clinical trials of
5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst, 2011. 103(11): p.
863-75. https://doi.org/10.1093/jnci/djr153 PMid:21597022 PMCid:PMC3110173