Molecular Subtyping of Colorectal Cancer: Time to Explore Both Intertumoral and Intratumoral Heterogeneity to Evaluate Patient Outcome
2014; Elsevier BV; Volume: 148; Issue: 1 Linguagem: Inglês
10.1053/j.gastro.2014.11.024
ISSN1528-0012
AutoresEric R. Fearon, John M. Carethers,
Tópico(s)Colorectal Cancer Treatments and Studies
ResumoSee "Association between molecular subtypes of colorectal cancer and patient survival," by Phipps AI, Limburg PJ, Baron JA, et al, on page 77; and "Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes," by Sinicrope FA, Shi Q, Smyrk TC, et al, on page 88. See "Association between molecular subtypes of colorectal cancer and patient survival," by Phipps AI, Limburg PJ, Baron JA, et al, on page 77; and "Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes," by Sinicrope FA, Shi Q, Smyrk TC, et al, on page 88. Over the past 3 decades—since molecular analyses of somatic gene alterations in primary human cancer specimens first became tractable—many of the recurrent somatic genetic and epigenetic defects present in colorectal cancers (CRCs) have been identified. The accumulation of multiple loss-of-function defects in selected tumor suppressor genes and gain-of-function defects in selected oncogenes, together with epigenetic alterations, such as DNA methylation changes, is believed to be critical in initiating colorectal tumorigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions.1Fearon E.R. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (10481) Google Scholar, 2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar, 3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar, 4Sehagiri S. Stawiski E.W. Durinck S. et al.Recurrent R-spondin fusions in colon cancer.Nature. 2012; 488: 660-664Crossref PubMed Scopus (794) Google Scholar Among the most common tumor suppressor gene mutations in CRCs are those in APC (which encodes the adenomatous polyposis coli [APC] protein) and TP53 (which encodes the p53 protein).2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar, 3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar, 4Sehagiri S. Stawiski E.W. Durinck S. et al.Recurrent R-spondin fusions in colon cancer.Nature. 2012; 488: 660-664Crossref PubMed Scopus (794) Google Scholar The most common oncogene mutations in CRC include point mutations activating the functions of the KRAS, PI3KCA (phosphoinositide-3-kinase, catalytic, alpha polypeptide), BRAF, and NRAS proteins.2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar, 3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar, 4Sehagiri S. Stawiski E.W. Durinck S. et al.Recurrent R-spondin fusions in colon cancer.Nature. 2012; 488: 660-664Crossref PubMed Scopus (794) Google Scholar The oncogene missense mutations found in the KRAS and NRAS genes in about 40%-45% of CRCs most commonly affect codons 12 and 13, but a subset of CRCs have KRAS or NRAS codon 61 missense mutations.2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar, 3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar Substitution of glutamic acid for the wild-type valine at codon 600 (V600E) accounts for the vast majority of BRAF activating mutations in CRC.2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar, 3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar Mutations activating KRAS or NRAS are mutually exclusive with BRAF activating mutations.2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar, 3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar, 4Sehagiri S. Stawiski E.W. Durinck S. et al.Recurrent R-spondin fusions in colon cancer.Nature. 2012; 488: 660-664Crossref PubMed Scopus (794) Google Scholar Recent comprehensive sequencing studies suggest that approximately 25 different genes are commonly affected by somatic mutations in CRCs, with tumor suppressor genes outnumbering oncogenes by about 4 to 1 on this list.3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar, 4Sehagiri S. Stawiski E.W. Durinck S. et al.Recurrent R-spondin fusions in colon cancer.Nature. 2012; 488: 660-664Crossref PubMed Scopus (794) Google Scholar Nearly 16% of CRCs manifest a hypermutation phenotype, with a median of 700 subtle somatic mutations that go beyond the above 25 driver genes, and are predicted to alter protein products.3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar About three-fourths of the hypermutation CRC cases—roughly 12%–13% of all CRCs—are constituted by the CRCs that manifest the high frequency of microsatellite instability (MSI-H) phenotype, owing to mutation or inactivation of one of several different key proteins functioning in DNA mismatch repair (MMR), most prominently including MLH1, MLH3, and MSH2.3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar The remaining one-quarter of the hypermutation CRC cases—about 3%–4% of all CRCs—do not manifest the MSI-H phenotype and usually harbor somatic mutations in the gene encoding DNA repair polymerase POLε or ≥1 MMR genes.3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar In the remaining 84% of CRCs that do not manifest the hypermutation phenotype (including both the so-called microsatellite stable [MSS] and microsatellite instability low [MSI-L] cases), the median number of subtle somatic mutations in exons predicted to alter protein products is about 60 mutations per tumor.3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar Prior work has established that the MSS and MSI-L CRCs often display aneuploidy, albeit with certain recurrent chromosome and subchromosome gains and losses seen in considerable fractions of CRCs.2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar In mammalian genomes, DNA methylation covalently modifies the cytosine residue in the majority of 5′-CpG-3′ dinucleotide sequences, except for CpG islands, which are localized regions of high CpG content often found in the promoter and upstream regulatory regions of a large fraction of genes.5Deaton A.M. Bird A. CpG islands and the regulation of transcription.Genes Dev. 2011; 25: 1010-1022Crossref PubMed Scopus (2200) Google Scholar Hypermethylation of these CpG islands is associated with gene silencing.5Deaton A.M. Bird A. CpG islands and the regulation of transcription.Genes Dev. 2011; 25: 1010-1022Crossref PubMed Scopus (2200) Google Scholar A subset of CRCs shows extensive DNA hypermethylation at many different CpG islands scattered around the genome, and this phenotype has been termed the high frequency CpG island hypermethylation phenotype (CIMP-H).6Toyota M. Ahuja N. Ohe-Toyota M. et al.CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Crossref PubMed Scopus (2182) Google Scholar, 7Weisenberger D.J. Siegmund K.D. Campan M. et al.CpG island methylator underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1590) Google Scholar About 20%-25% of CRCs manifest the CIMP-H phenotype and a similar fraction of CRCs manifest a lower frequency CIMP (CIMP-L) phenotype, with the remaining 50% of CRCs lacking CIMP.8Hinoue T. Weisenberger D.J. Lange C.P.E. et al.Genome-scale analysis of aberrant DNA methylation in colorectal cancer.Genome Res. 2012; 22: 271-282Crossref PubMed Scopus (512) Google Scholar Many CIMP-H and a few CIMP-L CRCs have hypermethylation of the promoter region of the MLH1 MMR gene, and this group of CRCs constitutes the majority of the MSI-H CRCs.7Weisenberger D.J. Siegmund K.D. Campan M. et al.CpG island methylator underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1590) Google Scholar, 8Hinoue T. Weisenberger D.J. Lange C.P.E. et al.Genome-scale analysis of aberrant DNA methylation in colorectal cancer.Genome Res. 2012; 22: 271-282Crossref PubMed Scopus (512) Google Scholar Of note, the hypermutation CRC subset, including many of the CIMP-H CRCs displaying MSI-H, is almost invariably the subset of CRCs that harbors the BRAFV600E oncogenic mutation.7Weisenberger D.J. Siegmund K.D. Campan M. et al.CpG island methylator underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1590) Google Scholar, 8Hinoue T. Weisenberger D.J. Lange C.P.E. et al.Genome-scale analysis of aberrant DNA methylation in colorectal cancer.Genome Res. 2012; 22: 271-282Crossref PubMed Scopus (512) Google Scholar The vast majority of these CRCs with BRAFV600E mutations arise in the right colon.7Weisenberger D.J. Siegmund K.D. Campan M. et al.CpG island methylator underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1590) Google Scholar, 8Hinoue T. Weisenberger D.J. Lange C.P.E. et al.Genome-scale analysis of aberrant DNA methylation in colorectal cancer.Genome Res. 2012; 22: 271-282Crossref PubMed Scopus (512) Google Scholar The specific tumor suppressor and oncogenic somatic mutations as well as the chromosome and subchromosomal copy number changes and the epigenetic alterations that have critical roles in promoting the outgrowth and/or sustaining the survival of neoplastic cells have been termed "driver" gene lesions. Those gene lesions that do not contribute in a functionally significant fashion to the origin and/or persistence and expansion of the cancer cell population, but may have instead arisen as bystander events during tumorigenes, are often termed "passenger" gene lesions. Many CRCs have multiple somatic driver gene mutations, often including ≥1 oncogene mutations together with several different tumor suppressor gene mutations.1Fearon E.R. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (10481) Google Scholar, 2Fearon E.R. Molecular genetics of colorectal cancer.Ann Rev Pathol. 2011; 6: 479-507Crossref PubMed Scopus (1318) Google Scholar, 3The Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (6294) Google Scholar, 4Sehagiri S. Stawiski E.W. Durinck S. et al.Recurrent R-spondin fusions in colon cancer.Nature. 2012; 488: 660-664Crossref PubMed Scopus (794) Google Scholar, 9Vogelstein B. Papadopoulos N. Velculescu V.E. et al.Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5616) Google Scholar Not unexpectedly, in light of the many different possible combinations arising simply from consideration of the commonly mutated oncogenes and tumor suppressor genes and the common chromosome and subchromosomal gains and losses, coupled with the very high number of patient-specific somatic mutations seen in any given CRC, essentially no 2 CRCs share the same somatic mutation profiles in the bulk of the cancer cells. Moreover, this extensive genetic complexity in a given CRC coexists with similarly extensive epigenetic complexity in the CRC. Despite the tremendous complexity and diversity seen in CRC genomes and epigenomes, prior strategies for attempting to define molecular alterations in CRC that may have utility for likelihood of cancer recurrence and outcome and/or response to conventional or novel therapeutic agents in patients have frequently emphasized efforts to implicate single oncogene or tumor suppressor gene defects or quite limited combinations of gene defects as prognostic or predictive markers. To date, although most single gene mutation markers have modest prognostic or predictive value, BRAFV600E mutation has been associated with poorer survival in CRC, and there are convincing data to indicate that the presence of a KRAS mutation in a CRC are associated with resistance to therapies targeting the epidermal growth factor receptor.10Herzig D.O. Tsikitis V.L. Molecular markers for colon diagnosis, prognosis and targeted therapy.J Surg Oncol. 2014; ([Epub ahead of print])http://dx.doi.org/ 10.1002/jso.23806PubMed Google Scholar Arguably, the most robust prognostic molecular classifier for CRC has been the MSI-H phenotype. The MSI-H phenotype has been linked to improved survival in stage II and stage III CRC patients,11Popat S. Hubner R. Houlston R.S. Systematic review of microsatellite instability and colorectal cancer prognosis.J Clin Oncol. 2005; 23: 609-618Crossref PubMed Scopus (1492) Google Scholar although the use of 5-fluorouracil–based adjuvant chemotherapy did not seem to show any survival benefit in survival for patients with MSI-H CRC.12Carethers J.M. Smith E.J. Behling C.A. et al.Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer.Gastroenterology. 2004; 126: 394-401Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 13Kim G.P. Colangelo L.H. Wieand H.S. et al.Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study.J Clin Oncol. 2007; 25: 767-772Crossref PubMed Scopus (316) Google Scholar, 14Sargent D.J. Marsoni S. Monges G. 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: 3219-3226Crossref PubMed Scopus (1259) Google Scholar The papers from Phipps et al15Phipps A.I. Limburg P.J. Baron J.A. et al.Association between molecular subtypes of colorectal cancer and patient survival.Gastroenterology. 2015; 148: 77-87Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar and Sinicrope et al16Sinicrope F.A. Shi Q. Smyrk T.C. et al.Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes.Gastroenterology. 2015; 148: 88-99Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar in this issue of Gastroenterology advance some new and important associations between molecular alterations and patient survival. Their analyses stem in part from prior work from Jeremy Jass, which suggested determination of MSI and CIMP status might be very useful for defining distinct histopathologic and molecular subsets of CRC, and the distinct subsets of CRC might have significant variations in the prevalence of somatic mutations affecting the APC and TP53 tumor suppressor genes and the KRAS and BRAF oncogenes.17Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.Histopathology. 2007; 50: 113-130Crossref PubMed Scopus (1137) Google Scholar In his work on the use of MSI- and CIMP-status to define CRC subsets, Jass also emphasized the view that the key precursor lesions for sporadic CRCs manifesting the CIMP-H phenotype were most likely to manifest a serrated morphology, including sessile serrated adenomas and traditional serrated adenomas.17Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.Histopathology. 2007; 50: 113-130Crossref PubMed Scopus (1137) Google Scholar In their studies of very large numbers of CRC patients, both the Sinicrope and Phipps groups emphasized the analysis of MSI and CIMP status in the CRC specimens, as well as analysis for mutations of codons 12 and 13 of KRAS and codon 600 of BRAF.15Phipps A.I. Limburg P.J. Baron J.A. et al.Association between molecular subtypes of colorectal cancer and patient survival.Gastroenterology. 2015; 148: 77-87Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 16Sinicrope F.A. Shi Q. Smyrk T.C. et al.Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes.Gastroenterology. 2015; 148: 88-99Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar Both groups found, with remarkably similar percentages for subgroups, that analysis of MSI status (MMR function) and CIMP status along with KRAS and BRAF mutations were informative for CRC-specific mortality (Table 1). Both groups also reported that MMR-proficient CRCs with KRAS mutations or especially BRAF mutations had poorer outcomes than MMR-proficient tumors that were wild type for either gene (Table 1). As the authors appropriately note, the findings offer further evidence that studies of the intertumor molecular heterogeneity of CRCs has merit and value.Table 1Summary of Genotypes, Their Percentages, and Relative Patient Outcome From Phipps et al15Phipps A.I. Limburg P.J. Baron J.A. et al.Association between molecular subtypes of colorectal cancer and patient survival.Gastroenterology. 2015; 148: 77-87Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar and Sinicrope et al16Sinicrope F.A. Shi Q. Smyrk T.C. et al.Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes.Gastroenterology. 2015; 148: 88-99Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar Among Primary Colorectal CancersCancer GenotypeMSSMSS/BRAFV600E MutantMSS/KRAS MutantMSI-H/BRAFV600E Mutant or hMLH1 HypermethylationMSI-H Without BRAFV600E Mutant or hMLH1 HypermethylationApproximate phenotypeTraditional/CINSerrated/CIMPTraditional/CIN/KRASSerrated/Sporadic CIMP/MSIFamilial MSIPhipps et al (N = 2,080; % of cancers)(Type 4)47%(Type 2)4%(Type 3)26%(Type 1)7%(Type 5)4%Sinicrope, et al. N = 2720 (% of cancers)49%6.9%35%6.8%2.6%Relative patient survival outcomeReferentPoor1.5-2X worsePoor1.5X worseFavorableFavorable0.3XCommentsMore likely distalMore likely proximal, female, older ageSlightly more proximal; high representation among African AmericansMore likely proximal, female, older ageMore likely proximal, young ageNOTE. The Phipps et al percentages do not add perfectly up to 100% owing to imputed data used in the study.CIMP, CpG island methylator phenotype; CIN, chromosomal instability; MSI-H, microsatellite instability-high; MSS, microsatellite stable. Open table in a new tab NOTE. The Phipps et al percentages do not add perfectly up to 100% owing to imputed data used in the study. CIMP, CpG island methylator phenotype; CIN, chromosomal instability; MSI-H, microsatellite instability-high; MSS, microsatellite stable. Despite the utility of defining molecular phenotypes based on clonal genetic alterations shared by all or nearly all neoplastic cells in a patient's primary CRC, it seems increasingly likely that in-depth and comprehensive analyses of intratumoral molecular heterogeneity in each patient's primary CRC may have major ramifications for understanding how molecular defects may contribute individually and collectively to clinical outcomes in CRC patients. Comprehensive, sequence-based analyses of cancer cell populations from individual patients where the cancer cell populations were spatially and/or temporally distinct have indicated that significant intratumoral genetic heterogeneity in primary cancer lesions and metastases may be the "rule" in cancer, rather than an exception.9Vogelstein B. Papadopoulos N. Velculescu V.E. et al.Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5616) Google Scholar, 18Hiley C. de Bruin E.C. McGranahan N. et al.Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine.Genome Biol. 2014; 15: 453-462Crossref PubMed Scopus (164) Google Scholar Critical initiating genetic and epigenetic lesions might be shared (ie, clonally) among all neoplastic clones in a primary cancer, but geographically distinct regions of primary tumors may have distinct mutation and epigenetic profiles from those in other regions of the tumor. Similarly, metastatic cell populations in a patient may have genetic and epigenetic divergence from the nonmetastatic cells, and there may be heterogeneity among different metastatic lesions in a patient and within individual metastases.9Vogelstein B. Papadopoulos N. Velculescu V.E. et al.Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5616) Google Scholar, 18Hiley C. de Bruin E.C. McGranahan N. et al.Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine.Genome Biol. 2014; 15: 453-462Crossref PubMed Scopus (164) Google Scholar Branched evolutionary growth may be an important feature in both primary tumors and metastatic lesions, with multiple competing clonal populations evolving over time and in space. This more recent view of the potentially extensive intratumoral genetic heterogeneity in any given cancer and the contributions of intratumoral heterogeneity to tumor progression contrasts with some earlier views. Before the recent studies,9Vogelstein B. Papadopoulos N. Velculescu V.E. et al.Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5616) Google Scholar, 18Hiley C. de Bruin E.C. McGranahan N. et al.Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine.Genome Biol. 2014; 15: 453-462Crossref PubMed Scopus (164) Google Scholar it was suspected that the cell populations in many primary cancers might be more homogeneous, where somatic mutations were accumulated in a more stepwise fashion as a result of multiple sequential clonal sweeps of each variant cell populations in the primary cancer, with metastases perhaps often arising from the clonally dominant cell population in the primary tumor. Consistent with the notion that rare variant cell populations may have important roles in clinical outcome, a recent study indicated that in some CRC patients where the primary cancer cell population was wild type for KRAS, there is strong biological selection for outgrowth of CRCs with mutations in KRAS or other mitogen-activated protein kinase pathway proteins when epidermal growth factor receptor blockade is used therapeutically.19Diaz Jr., L.A. Williams R.T. Wu J. et al.The molecular evolution of acquired resistance to targeted EGFR blockage in colorectal cancers.Nature. 2012; 486: 537-540Crossref PubMed Scopus (1391) Google Scholar, 20Bettegowda C. Sausen M. Leary R.J. et al.Detection of circulating tumor DNA in early and late-stage human malignancies.Science Transl Med. 2014; 6: 224ra24Crossref PubMed Scopus (3372) Google Scholar New strategies, such as future deep sequencing of primary CRC cell populations, comprehensive single-cell analyses, and/or analyses of circulating tumor-derived DNA will likely be needed for future molecular approaches to better define prognosis and predict likely responses to existing and new targeted therapies in patients with CRC. Association Between Molecular Subtypes of Colorectal Cancer and Patient SurvivalGastroenterologyVol. 148Issue 1PreviewColorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. Full-Text PDF Molecular Markers Identify Subtypes of Stage III Colon Cancer Associated With Patient OutcomesGastroenterologyVol. 148Issue 1PreviewCategorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes. Full-Text PDF Open AccessCovering the CoverGastroenterologyVol. 148Issue 1PreviewCrohn's disease is a chronic process that displays great variability among patients. Instruments for measuring disease activity have largely focused on patient symptoms and physical signs. An assessment of structural changes that result from Crohn's disease represents another potential approach to measure the disease's accumulated effects. In this issue of Gastroenterology, Pariente et al report on a new instrument produced by the International Program to develop New Indexes in Crohn's disease (IPNIC) that focuses on structural criteria. Full-Text PDF
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