Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients.
Methods
A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family.
Results
Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006).
Conclusions
Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.
de la ChapelleA.: Genetic predisposition to colorectal cancer.Nat Rev Cancer, 4: 769–780, 2004.
2.
LynchH.T., de la ChapelleA.: Hereditary colorectal cancer.N Engl J Med, 348: 919–932, 2003.
3.
VasenH.F., MecklinJ.P., Meera KhanP., LynchH.T.: The International Collaborative Group on Hereditary Non-Polyposis Colorectal cancer (ICG-HNPCC).Dis Colon Rectum, 34: 424–425, 1991.
4.
VasenH.F., WatsonP., MecklinJ.P., LynchH.T.: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology, 116: 1453–1456, 1999.
KinzlerK.W., VogelsteinB.: Lessons from hereditary colorectal cancer.Cell, 87: 159–170, 1996.
8.
PopatS., HubnerR., HoulstonR.S.: Systematic review of microsatellite instability and colorectal cancer prognosis.J Clin Oncol, 23: 609–618, 2005.
9.
AlbanoW.A., RecabarenJ.A., LynchH.T., CampbellA.S., MailliardJ.A., OrganC.H., LynchJ.F., KimberlingW.J.: Natural history of hereditary cancer of the breast and colon.Cancer, 50: 360–363, 1982.
10.
FujitaS., MoriyaY., SugiharaK., AkasuT., UshioK.: Prognosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the role of Japanese criteria for HNPCC.Jpn J Cancer Res, 26: 351–355, 1996.
11.
MyrhøjT., BisgaardM.L., BernsteinI., SvendsenL.B., SøndergaardJ.O., BülowS.: Hereditary non-polyposis colorectal cancer: clinical features and survival. Results from the Danish HNPCC register.Scand J Gastroenterol, 32: 572–576, 1997.
12.
AarnioM., MustonenH., MecklinJ.P., JärvinenH.J.: Prognosis of colorectal cancer varies in different high-risk conditions.Ann Med, 30: 75–80, 1998.
PercesepeA., BenattiP., RoncucciL., SassatelliR., FanteR., GanazziD., BellacosaA., GenuardiM., NeriG., VielA., Ponz de LeonM.: Survival analysis in families affected by hereditary non-polyposis colorectal cancer.Int J Cancer, 71: 373–376, 1997.
15.
BertarioL., RussoA., SalaP., EboliM., RadiceP., PresciuttiniS., AndreolaS., Rodriguez-BigasM.A., PizzettiP., SpinelliP.: Survival of patients with hereditary colorectal cancer: comparison of HNPCC and colorectal cancer in FAP patients with sporadic colorectal cancer.Int J Cancer, 80: 183–187, 1999.
16.
BermejoJ.L., EngC., HemminkiK.: Cancer characteristics in Swedish families fulfilling criteria for hereditary nonpolyposis colorectal cancer.Gastroenterology, 129: 1889–1899, 2005.
17.
FarringtonS.M., McKinleyA.J., CarothersA.D., CunninghamC., BubbV.J., SharpL., WyllieA.H., DunlopM.G.: Evidence for an age-related influence of microsatellite instability on colorectal cancer survival.Int J Cancer, 98: 844–850, 2002.
18.
SankilaR., AaltonenL.A., JärvinenH.J., MecklinJ.P.: Better survival rates in patients with MLH1-associated hereditary colorectal cancer.Gastroenterology, 110: 682–687, 1996.
19.
BarnetsonR.A., TenesaA., FarringtonS.M., NichollI.D., CetnarskyjR., PorteousM.E., CampbellH., DunlopM.G.: Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.N Engl J Med, 354: 2815–2817, 2006.
PensottiV., RadiceP., PresciuttiniS., CalistriD., GazzoliI., Grimalt PerezA., MondiniP., BuonsantiG., SalaP., RossettiC., RanzaniG.N., BertarioL., PierottiM.A.: Mean age of tumor onset in hereditary non-polyposis colorectal cancer (HN-PCC) families correlates with the presence of mutations in DNA mismatch repair gene.Genes Chromosomes Cancer, 19: 135–142, 1997.
22.
VielA., GenuardiM., CapozziE., LeonardiF., BellacosaA., Paravatou-PetsotasM., PomponiM.G., FornasarigM., PercesepeA., RoncucciL., TamassiaM.G., BenattiP., Ponz de LeonM., ValentiA., CovinoM., AntiM., FolettoM., BoiocchiM., NeriG.: Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer.Genes Chromosomes Cancer, 18: 8–18, 1997.
MonteraM., RestaN., SimoneC., GuantiG., MarcheseC., CivitelliS., ManciniA., PozziS., De SalvoL., BruzzoneD., DonadiniA., RomioL., MareniC.: Mutational germline analysis of hMSH2 and hMLH1 genes in early onset colorectal cancer patients.J Med Genet, 40: 472, 2000.
25.
WijnenJ., VasenH., Meera KhanP., MenkoF.H., Van Der KliftH., Van LeeuwenC., Van Den BroekM., Van Leeuwen-CornelisseI., NagengastF., Meijers-HeijboerA., LindhoutD., GriffioenG., CatsA., KleibeukerJ., VarescoL., BertarioL., BisgaardM.L., MohrJ., FoddeR.: Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient gel electrophoresis.Am J Hum Genet, 56: 1060–1066, 1995.
26.
WijnenJ., KhanP.M., VasenH., MenkoF., van der KliftH., van den BroekM., van Leeuwen-CornelisseI., NagengastF., Meijers-HeijboerE.J., LindhoutD., GriffioenG., CatsA., KleibeukerJ., VarescoL., BertarioL., BisgaardM.L., MohrJ., KolodnerR., FoddeR.: Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16.Am J Hum Genet, 58: 300–307, 1996.
27.
Holinski-FederE., Müller-KochY., FriedlW., MoesleinG., KellerG., PlaschkeJ., BallhausenW., GrossM., Baldwin-JedeleK., JungckM., MangoldE., VogelsangH., SchackertH.K., LohseaP., MurkenJ., MeitingerT.: DHPLC mutation analysis of the hereditary nonpolyposis colon cancer (HNPCC) genes hMLH1 and hMSH2.J Biochem Biophys Methods, 47: 21–32, 2001.
28.
VielA., PetronzelliF., Della PuppaL., Lucci-CordiscoE., FornasarigM., PucciarelliS., RovellaV., QuaiaM., Ponz de LeonM., BoiocchiM., GenuardiM.: Different molecular mechanisms underlie genomic deletions in the MLH1 Gene.Hum Mutat, 20: 368–374, 2002.
29.
PastrelloC., BaglioniS., TibilettiM.G., PapiL., FornasarigM., MorabitoA., AgostiniM., GenuardiM., VielA.: Stability of BAT26 in tumours of hereditary nonpolyposis colorectal cancer patients with MSH2 intragenic deletion.Eur J Hum Genet, 14: 63–68, 2006.
30.
De LellisL., CuriaM.C., CatalanoT., De ToffolS., BassiC., MareniC., BertarioL., BattistaP., Mariani-CostantiniR., RadiceP., CamaA.: Combined use of MLPA and non-fluorescent multiplex PCR analysis by high performance liquid chromatography (NFMP-HPLC) for the detection of genomic rearrangements.Hum Mutat, 27: 1047–1056, 2006.
31.
BolandC.R., ThibodeauS.N., HamiltonS.R., SidranskyD., EshlemanJ.R., BurtR.W., MeltzerS.J., Rodriguez-BigasM.A., FoddeR., RanzaniG.N., SrivastavaS.: A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.Cancer Res, 58: 5248–5257, 1998.
32.
CanzianF., SalovaaraR., HemminkiA., KristoP., ChadwickR.B., AaltonenL.A., de la ChapelleA.: Semiautomated assessment of loss of heterozygosity and replication error in tumors.Cancer Res, 564: 3331–3337, 1996.
33.
BertarioL., AsteH., ArrigoniA., FracassoP., RossiniF.P., RossettiC., ValanzanoR.: Clinical aspects and management of hereditary non-polyposis colorectal cancer (HNPCC).Tumori, 82: 117–121, 1996.
34.
ClarkA.J., BarnetsonR., FarringtonS.M., DunlopM.G.: Prognosis in DNA mismatch repair deficient colorectal cancer: are all MSI tumours equivalent?Fam Cancer, 3: 85–91, 2004.
35.
BenattiP., RoncucciL., GanazziD., PercesepeA., Di GregorioC., PedroniM., BorghiF., SalaE., ScarselliA., MenigattiM., RossiG., GenuardiM., VielA., Ponz De LeonM.: Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer.Int J Cancer, 95: 323–328, 2001.
36.
RibicC.M., SargentD.J., MooreM.J., ThibodeauS.N., FrenchA.J., GoldbergR.M., HamiltonS.R., Laurent-PuigP., GryfeR., ShepherdL.E., TuD., RedstonM., GallingerS.: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.N Engl J Med, 349: 247–257, 2003.
37.
CarethersJ.M., SmithE.J., BehlingC.A., NguyenL., TajimaA., DoctoleroR.T., CabreraB.L., GoelA., ArnoldC.A., MiyaiK., BolandC.R.: Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer.Gastroenterology, 126: 394–401, 2004.
38.
de Vos tot Nederveen CappelW.H., MeulenbeldH.J., KleibeukerJ.H., NagengastF.M., MenkoF.H., GriffioenG., CatsA., MorreauH., GelderblomH., VasenH.F.: Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer.Int J Cancer, 109: 468–471, 2004.
39.
BenattiP., GafàR., BaranaD., MarinoM., ScarselliA., PedroniM., MaestriI., GuerzoniL., RoncucciL., MenigattiM., RoncariB., MaffeiS., RossiG., PontiG., SantiniA., LosiL., Di GregorioC., OlianiC., Ponz de LeonM., LanzaG.: Microsatellite instability and colorectal cancer prognosis.Clin Cancer Res, 11: 8332–8340, 2005.
40.
WarusavitarneJ., RamanathanP., KaufmanA., RobinsonB.G., SchnitzlerM.: 5-fluorouracil (5FU) treatment does not influence invasion and metastasis in microsatellite unstable (MSI-H) colorectal cancer.Int J Colorectal Dis, 21: 625–631, 2006.
41.
DolcettiR., VielA., DoglioniC., RussoA., GuidoboniM., CapozziE., VecchiatoN., MacrìE., FornasarigM., BoiocchiM.: High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability.Am J Pathol, 154: 1805–1813, 1999.
42.
Michael-RobinsonJ.M., Biemer-HüttmannA., PurdieD.M., WalshM.D., SimmsL.A., BidenK.G., YoungJ.P., LeggettB.A., JassJ.R., Radford-SmithG.L.: Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status.Gut, 48: 360–366, 2001.
43.
SmyrkT.C., WatsonP., KaulK., LynchH.T.: Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma.Cancer, 91: 2417–24222001.
44.
WynterC.V., SimmsL.A., ButtenshawR.L., BidenK.G., YoungJ., LeggettB.A., ConradR.J., SchochE.M., JassJ.R., Praga PillayS.: Angiogenic factor VEGF is decreased in human colorectal neoplasms showing DNA microsatellite instability.J Pathol, 189: 319–325, 1999.
45.
WendumD., BoëlleP.Y., RigauV., SebbaghN., OlschwangS., MourraN., ParcR., TrugnanG., MasliahJ., FléjouJ.F.: Mucinous colon carcinomas with microsatellite instability have a lower microvessel density and lower vascular endothelial growth factor expression.Virchows Arch, 442: 111–117, 2003.
46.
InoueY., MikiC., WatanabeH., OjimaE., KusunokiM.: Genomic instability and tissue expression of angiogenic growth factors in sporadic colorectal cancer.Surgery, 139: 305–311, 2006.
47.
BuckowitzA., KnaebelH.P., BennerA., BläkerH., GebertJ., KienleP., von Knebel DoeberitzM., KloorM.: Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases.Br J Cancer, 92: 1746–1753, 2005.
48.
ChungD., RustgiA.K.: The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications.Ann Intern Med, 138: 560–570, 2003.
49.
GrazianoF., CascinuS.: Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes’ B colorectal cancer patients: how much evidence is enough?Ann Oncol, 14: 1026–1038, 2003.
50.
KlumpB., NehlsO., OkechT., HsiehC.J., GacoV., GittingerF.S., SarbiaM., BorchardF., GreschniokA., GruenagelH.H., PorschenR., GregorM.: Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature.Int J Colorectal Dis, 19: 23–42, 2004.
Abdel-RahmanW.M., OllikainenM., KariolaR., JärvinenH.J., MecklinJ.P., Nyström-LahtiM., KnuutilaS., PeltomäkiP.: Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations.Oncogene, 24: 1542–1551, 2005.
53.
LlorX., PonsE., XicolaR.M., CastellsA., AlendaC., PiñolV, AndreuM., Castellví-BelS., PayáA., JoverR., BessaX., GirósA., RocaA., GassullM.A.: Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway.Clin Cancer Res, 11: 7304–7310, 2005.
54.
Mueller-KochY., VogelsangH., KoppR., LohseP., KellerG., AustD., MudersM., GrossM., DaumJ., SchiemannU., GrabowskiM., ScholzM., KerkerB., BeckerI., HenkeG., Holinski-FederE.: Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer.Gut, 54: 1733–1740, 2005.
55.
LynchH.T., BolandC.R., GongG., ShawT.G., LynchP.M., FoddeR., LynchJ.F., de la ChapelleA.: Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications.Eur J Hum Genet, 14: 390–402, 2006.
56.
Dove-EdwinI., de JongA.E., AdamsJ., MesherD., LiptonL., SasieniP., VasenH.F., ThomasH.J.: Prospective results of surveillance colonscopy in dominant familial colorectal cancer with and without Lynch syndrome.Gastroenterology, 130: 1995–2000, 2006.
57.
TravisL.B., RabkinC.S., BrownL.M., AllanJ.M., AlterB.P., AmbrosoneC.B., BeggC.B., CaporasoN., ChanockS., DeMicheleA., FiggW.D., GospodarowiczM.K., HallE.J., HisadaM., InskipP., KleinermanR., LittleJ.B., MalkinD., NgA.K., OffitK., PuiC.H., RobisonL.L., RothmanN., ShieldsP.G., StrongL., TaniguchiT., TuckerM.A., GreeneM.H.: Cancer survivorship - genetic susceptibility and second primary cancers: research strategies and recommendations.J Natl Cancer Inst, 98: 15–25, 2006.
