FaCD Online Syndrome Fact Sheet

Last updated: 3 Jun 2003

Name: Hereditary Non-Polyposis Colorectal Cancer NOT VISIBLE

Synonym: HNPCC, Lynch syndromes 1 and 2 (= Cancer Family Syndrome), Hereditary Mismatch Repair Deficiency syndrome, HMRDS

Mode of Inheritance: AD

OMIM number: 114500   114400   120435   120436   600678   600259  

Genes

EXO1, mapped to 1q42-q43
MLH1, mapped to 3p21.3
MLH3, mapped to 14q24.3
MSH2, mapped to 2p21-p22
MSH6, mapped to 2p16
PMS2, mapped to 7p22
TGFBR2, mapped to 3p22

Tumor features

adenomatous polyps in the small intestine
biliary tract cancer (incl. gallbladder)
breast cancer, male
endometrial cancer
gastrointestinal adenomas
gastrointestinal cancer
gastrointestinal polyps
glioma of the brain
hepatocellular cancer (hepatoma)
keratoacanthoma
malignant fibrous histiocytoma
ovarian cancer (i.e. epithelial origin)
pancreatic adenocarcinoma
renal pyelum cancer
sebaceous adenoma
sebaceous carcinoma
sebaceous epithelioma
ureter cancer

Tumor features (possible)

breast cancer
Hodgkin disease (Hodgkin's lymphoma)
laryngeal cancer
non-Hodgkin lymphoma
sarcoma
urinary bladder cancer

Comment

HNPCC is an autosomal dominant disorder characterized by a 70%-90 % cumulative life-time risk of colorectal cancer, often with an early onset (average 40-50 years), proximal location, and an increased risk of various other tumors. More than 5-10 colorectal adenomatous polyps are unusual in HNPCC. These include endometrial cancer, with a cumulative life-time risk of 30-60 %, ovarian cancer (12%), gastric cancer (13 % in one series[1], as in familial adenomatous polyposis, this risk may be strongly influenced by exogenous risk factors; majority is of intestinal type[2]), cancer of the small intestine and also cancer of the upper urinary tract, brain, hepatobiliary tract and pancreas[1;3-10]. Multiple primary colorectal tumors regularly occur in HNPCC. Lin et al.[11] reported a 96% colorectal cancer risk and 34% extra-colonic cancer risk in male hMSH2 (see below) mutation carriers compared to 39% colorectal cancer risk and 69% extra-colonic cancer risk in female carriers. These authors reported a lifetime extra-colonic cancer risk of 48% and 11% in hMSH2 and hMLH1 mutation carriers (men + women), respectively. With the exception of one study[12] which showed differently, breast cancer risk does not appear to be clearly increased in HNPCC, however, in some individual cases molecular studies have suggested that the occurrence of breast cancer (including male breast cancer) was causally linked to the presence of a germline HNPCC gene mutation[13;14]. Malignant fibrous histiocytoma ia another tumor which on rare occasions may be part of the HNPCC phenotype[15]. Wang et al.[16] and Ricciardone et al.[17] reported a remarkable association between the development of neurofibromatosis type I, hematological malignancy (NHL, acute leukemia) and the presence of homozygous deletions of the HNPCC gene hMLH1 (see below).

At the molecular level, HNPCC is characterized by germline mutations in genes responsible for the repair of DNA replication errors, the mismatch repair (MMR) genes and is has therefore been suggested to refer to the disease as hereditary mismatch repair deficiency syndrome[18]. Several MMR genes have been identified in the human and germline mutations in HNPCC patients have been found in 5 of them: hMLH1, hMSH2, hMLH3, hMSH6, hPMS1 and hPMS2[19-28]. Germline mutations in these genes (mainly in hMSH2 and hMLH1) have been detected in approximately 60 % of HNPCC families[29]. A de novo hMSH2 germline mutation has been reported[30].

Deficiency of MMR genes causes replication errors (mismatches) in repetitive DNA segments, known as microsatellites. If the resulting microsatellite instability (MSI) damages genes critical for cell growth control and other genes which contribute to genomic stability, this in turn may lead to tumor development[31-34]. Loss of other functions of the mismatch repair genes, especially those involved in the repair of DNA damage caused by environmental agents, are possibly important for tumorigenesis as well [32;35-37].

It has been shown that MSI is not a unique feature of tumors in HNPCC patients[38], but occurs in different percentages in the majority of solid neoplasms[39]. The tumors of some families with clustering of non-polyposis colorectal cancer do not show MSI[40] and these families may still have HNPCC, e.g. due to mutations in hMSH6[25] or other genes, which may include TGFBR2, the gene encoding the TGF-beta type II receptor[41]. Overall contribution of TGF-beta type II receptor gene germline mutations to HNPCC is probably low[42]. There is some evidence to suggest that tumor risks may depend on the type of MMR gene involved (hMSH2 vs hMLH1)[7;43]. Penetrance and tumor location associated with HNPCC MMR gene mutations may be modified by polymorphisms in other genes[44;45]. Mismatch repair has an important function in meiosis and analysis of aneuploidy frequencies in sperm from 10 HNPCC patients with an hMSH2 mutation has revealed a significantly increased frequency of disomy 13, 21 and XX, as well as diploidy compared with controls, although the magnitude of increase was not large (1.4-1.8 times control values)[46].

The classical criteria for HNPCC, known as the Amsterdam criteria, were initially developed for research purposes and did not include these molecular data. They were as follows:

  • (a) the presence of at least 3 relatives with histologically verified colorectal cancer, one of the relatives being a first-degree relative of the other two,
  • (b) colorectal cancer involving at least 2 successive generations,
  • (c) at least one case of colorectal cancer diagnosed before age 50 and
  • (d) exclusion (on clinical grounds) of Familial Adenomatous Polyposis.


These criteria have been criticized as being to strict for clinical purposes since they did not take into account the wide range of tumors associated with HNPCC and presence or absence of tumor microsatellite instability[47-49]. Recently the Amsterdam criteria have been revised (Amsterdam criteria II)[50]:
  • a) the presence of at least 3 relatives with histologically verified
  • colorectal cancer,
  • endometrial cancer,
  • small bowel cancer,
  • ureter cancer or
  • renal pelvis cancer;
  • one of these relatives should be a first-degree relative of the other two,
  • (b) at least 2 successive generations should be affected,
  • (c) at least one case of these cancers diagnosed before age 50 and
  • (d) exclusion (on clinical grounds) of Familial Adenomatous Polyposis.


Germline mutations in the HNPCC genes have indeed been demonstrated in patients with early onset colorectal cancer, featuring MSI, in the absence of a strong family history of colorectal cancer[51-53]. Although cancer risks associated with these mutations found outside classical HNPCC families may differ from those found in families fulfilling the Amsterdam HNPCC criteria, these risks may still be high, especially if those families ascertained through young CRC patients[54].

The Bethesda guidelines try to incorporate insights based on the molecular studies of patients and families with colorectal cancer and other HNPCC associated tumors, and aim at providing clinicians with practical criteria to select patients and their families for tumor MSI testing[55](modified after the original table; see also:[56-58]):
  • 1) Individuals with cancer of any type at any age, in families meeting the Amsterdam criteria. Preferably, colorectal tumors should be tested, or, if not available, any HNPCC associated extra-colonic tumor (endometrial, ovarian, gastric, hepatobiliary, small-bowel cancer, transitional cell carcinoma of renal pelvis or ureter). If these are also unavailable, then test any other tumor, preferably those with the earliest age at diagnosis.
  • 2) Individuals with colorectal or endometrial cancer diagnosed at age <45 (any colorectal cancer type, but especially tumors with > 50% signet-ring-cell-type, or right-sided location and undifferentiated histological pattern)
  • 3) Individuals with colorectal adenomas diagnosed at age <40
  • 4) Individuals with two HNPCC related cancers diagnosed at any age: colorectal cancer or any of the HNPCC associated extra-colonic tumors (listed under item 1.) Preferably the colorectal tumor should be tested. (The importance of testing patients with multiple HNPCC spectrum tumors has been stressed[59;60].
  • 5) Individual with colorectal cancer at any age + a first-degree relative with colorectal cancer and/or colorectal adenoma and/or HNPCC related extra-colonic cancer (see 1. for listing). One of the cancers diagnosed at age <45 or adenoma at age <40. Preferably the colorectal tumor should be tested. (Early onset colorectal cancer and endometrial cancer are independent predictors of hMLH1/hMSH2 mutations[61].


Finding MSI increases the chance that the studied patient/family has indeed HNPCC and warrants testing for germline MMR gene mutations[62]. However, the absence of MSI cannot be used as an exclusionary criterion for HNPCC[63], since not all HNPCC associated tumors show MSI and particularly those associated with germline mutations in the MMR gene hMSH6 (GTBP)[25;64]. Tumor immunohistochemistry for MMR gene expression, rather than MSI testing, may turn out to be a more simple first test in the clinic to select for possible HNPCC patients[65]. Although colorectal cancer in HNPCC at the histological level is often of a mucinous, highly proliferative type[6], which is generally associated with less favorable prognosis, survival in HNPCC appeared to be better than in sporadic colorectal cancer cases with similar staging[66-69]. However, studies by Percepe et al.[70] and Bertario et al.[71] could not demonstrate any significant difference in survival.

Links

International Society for Gastrointestinal Hereditary Tumours (InSiGHT) 18 1 08

References

[1] Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomaki P, Mecklin JP, Jarvinen HJ. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81[2], 214-218. 1999.
[2] Aarnio M, Salovaara R, Aaltonen LA, Mecklin JP, Jarvinen HJ. Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome. Int J Cancer 74[5], 551-555. 1997.
[3] Watson P, Lynch HT. The tumor spectrum in HNPCC. Anticancer Res 1994; 14:1635-1639.
[4] Mecklin JP, Jarvinen HJ. Tumor spectrum in Cancer Family Syndrome (Hereditary Nonpolyposis Colorectal Cancer). Cancer 1991; 68:1109-1112.
[5] Watson P, Lynch HT. Extracolonic cancer in Hereditary Nonpolyposis Colorectal Cancer. Cancer 1993; 71:677-685.
[6] Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome) - An updated review. Cancer 78[6], 1149-1167. 1996.
[7] Vasen HFA, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijers-Heijboer EH, Bertario L, Varesco L, Bisgaard ML, Mohr J, Fodde R, Khan PM. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. GASTROENTEROLOGY 110[4], 1020-1027. 1996.
[8] Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 1995; 87(15):1114-1125.
[9] Sijmons RH, Kiemeney LALM, Witjes JA, Vasen HFA. Urinary tract cancer and hereditary nonpolyposis colorectal cancer: Risks and screening options. J Urol 160[2], 466-470. 1998.
[10] Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999; 36:801-818.
[11] Lin KM, Shashidharan M, Thorson AG, Ternent CA, Blatchford GJ, Christensen MA, Watson P, Lemon SJ, Franklin B, Karr B, Lynch J, Lynch HT. Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer. J Gastrointest Surg 1998; 2(1):67-71.
[12] Itoh H, Houlston RS, Harocopos C, Slack J. Risk of cancer death in first-degree relatives of patients with hereditary non-polyposis cancer syndrome (Lynch type II): a study of 130 kindreds in the United Kingdom. Br J Surg 77, 1367-1370. 1990.
[13] Risinger JI, Barrett JC, Watson P, Lynch HT, Boyd J. Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer 77[9], 1836-1843. 1996.
[14] Boyd J, Rhei E, Federici MG, Borgen PI, Watson P, Franklin B, Karr B, Lynch J, Lemon SJ, Lynch HT. Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 1999; 53(1):87-91.
[15] Sijmons R, Hofstra R, Hollema H, Mensink R, van Der Hout A, Hoekstra H, Kleibeuker J, Molenaar W, Wijnen J, Fodde R, Vasen H, Buys C. Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer. Genes Chromosomes Cancer 2000; 29:353-355.
[16] Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, Ruano E, Puisieux A. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res 59[2], 294-297. 1999.
[17] Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, Uzunalimoglu O, Cetinkaya H, Tanyeli A, Erken E, Ozturk M. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59[2], 290-293. 1999.
[18] Jass JR. Diagnosis of hereditary non-polyposis colorectal cancer. Histopathology 32[6], 491-497. 1998.
[19] Fishel R, Lescoe MK, Rao MRS, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75:1027-1038.
[20] Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Dunlop MG, Hamilton SR, Petersen GM, Delachapelle A, Vogelstein B, Kinzler KW. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994; 371:75-80.
[21] Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M, Guan XY, Zhang J, Meltzer PS, Yu JW, Kao FT, Chen DJ, Cerosaletti KM, Keith Fournier RE, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin JP, Jarvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, de la Chapelle A, Kinzler KW, Vogelstein B. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75:1215-1225.
[22] Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Hamilton SR, Petersen GM, Watson P, Lynch HT, Peltomaki P, Mecklin JP, de la Chapelle A, Kinzler KW, Vogelstein B. Mutation of a mutL homolog in hereditary colon cancer. Science 1994; 263:1625-1629.
[23] Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Lipford J, Lindblom A, Tannergard P, Bollag RJ, Godwin AR, Ward DC, Nordenskjold M, Fishel R, Kolodner R, Liskay RM. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994; 368:258-261.
[24] Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17[3], 271-272. 1997.
[25] Wu Y, Berends MJW, Mensink RGJ, Kempinga C, Sijmons RH, van der Zee AGJ, Hollema H, Kleibeuker JH, Buys CHCM, Hofstra RMW. Association of herediatry nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet 1999; 65:1291-1298.
[26] Kolodner RD, Tytell JD, Schmeits JL, Kane MF, Gupta RD, Weger J, Wahlberg S, Fox EA, Peel D, Ziogas A, Garber JE, Syngal S, Anton-Culver H, Li FP. Germ-line msh6 mutations in colorectal cancer families. Cancer Res 1999; 59(20):5068-5074.
[27] Wijnen J, de Leeuw W, Vasen H, Van der Klift H, Moller P, Stormorken A, Meijers-Heijboer H, Lindhout D, Menko F, Vossen S, Moeslein G, Tops C, Brocker-Vriends A, Wu Y, Hofstra R, Sijmons R, Cornelisse C, Morreau H, Fodde R. Familial endometrial cancer in female carries of MSH6 germline mutations. Nat Genet 1999; 23:142-144.
[28] Wu Y, Berends MJW, Mensink RGJ, Verlind E, Sijmons RH, van der Zee AGJ, Hollema H, Kleibeuker JH, Buys CHCM, Hofstra RMW. Germline hMLH3 mutations in patients with suspected HNPCC. Am J Hum Genet 67[4 (suppl. 2)], 17. 2000. Ref Type: Abstract
[29] Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomaki P, de la Chapelle A, Hamilton SR, Vogelstein B, Kinzler KW. Analysis of mismatch repair genes in hereditary non- polyposis colorectal cancer patients. Nat Med 1996; 2:169-174.
[30] Kraus C, Kastl S, G√ľnther K, Klessinger S, Hohenberger W, Ballhausen WG. A proven de novo germline mutation in HNPCC. J Med Genet 1999; 36:919-921.
[31] Rhyu MS. Molecular mechanisms underlying hereditary nonpolyposis colorectal carcinoma. J Natl Cancer Inst 1996; 88:240-251.
[32] Umar A, Kunkel TA. DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur J Biochem 238[2], 297-307. 1996.
[33] Parsons R, Myeroff LL, Liu B, Willson JKV, Markowitz SD, Kinzler KW, Vogelstein B. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 1995; 55:5548-5550.
[34] Eshleman JR, Markowitz SD. Mismatch repair defects in human carcinogenesis. Hum Mol Genet 5, 1489-1494. 1996.
[35] Mellon I, Rajpal DK, Koi M, Boland CR, Champe GN. Transcription-coupled repair deficiency and mutations in human mismatch repair genes. Science 272[5261], 557-560. 1996.
[36] Holzman D. Mismatch repair genes matched to several new roles in cancer. J Natl Cancer Inst 1996; 88(14):950-951.
[37] Parsons R, Li GM, Longley M, Modrich P, Liu B, Berk T, Hamilton SR, Kinzler KW, Vogelstein B. Mismatch repair deficiency in phenotypically normal human cells. Science 1995; 268:738-740.
[38] Aaltonen LA, Peltomaki P, Mecklin JP, Jarvinen H, Jass JR, Green JS, Lynch HT, Watson P, Tallqvist G, Juhola M, Sistonen P, Hamilton SR, Kinzler KW, Vogelstein B, de la Chapelle A. Replication errors in benign and malignant tumors from hereditary nonpolyposis celorectal cancer patients. Cancer Res 1994; 54:1645-1648.
[39] Eshleman JR, Markowitz SD. Microsatellite instability in inherited and sporadic neoplasms. Curr Opin Oncol 1995; 7:83-89.
[40] Brown SR, Finan PJ, Cawkwell L, Quirke P, Bishop DT. Frequency of replications errors in colorectal cancer and their association with family history. Gut 1998; 43:553-557.
[41] Lu SL, Kawabata M, Imamura T, Akiyama Y, Nomizu T, Miyazono K, Yuasa Y. HNPCC associated with germline mutation in the TGF-beta type II receptor gene. Nat Genet 19[1], 17-18. 1998.
[42] Shin KH, Park YJ, Park JG. Mutational analysis of the transforming growth factor beta receptor type II gene in hereditary nonpolyposis colorectal cancer and early-onset colorectal cancer patients. Clin Cancer Res 2000; 6(2):536-540.
[43] Lin KM, Shashidharan M, Ternent CA, Thorson AG, Blatchford GJ, Christensen MA, Lanspa SJ, Lemon SJ, Watson P, Lynch HT. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum 1998; 41(4):428-433.
[44] Moisio AL, Sistonen P, Mecklin JP, Jarvinen H, Peltomaki P. Genetic polymorphisms in carcinogen metabolisms and their association to hereditary nonpolyposis colon cancer. GASTROENTEROLOGY 115, 1387-1394. 1998.
[45] Maillet P, Chappuis PO, Vaudan G, Heinimann K, Dobbie Z, Hutter P, Sappino AP. An ATM polymorphism modulates HNPCC penetrance. Eur J Hum Genet 1999; 7(1).
[46] Martin RH, Green J, Ko E, Barclay L, Rademaker AW. Analysis of aneuploidy frequencies in sperm from patients with hereditary nonpolyposis colon cancer and an hMSH2 mutation. Am J Hum Genet 2000; 66(3):1149-1152.
[47] Jass JR, Cottier DS, Jeevaratnam P, Pokos V, Holdaway KM, Bowden ML, van de Water NS, Browett PJ. Diagnostic use of microsatellite instability in hereditary non- polyposis colorectal cancer. Lancet 1995; 346:1200-1201.
[48] Moslein G, Tester DJ, Lindor NM, Honchel R, Cunningham JM, French AJ, Halling KC, Schwab M, Goretzki P, Thibodeau SN. Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. Hum Mol Genet 5[9], 1245-1252. 1996.
[49] Baba S. Clinical applications of genetic studies in hereditary colorectal cancer. In: Muller H, Scott RJ, Weber W, editors. Hereditary Cancer. Basel: Karger, 1996: 173-190.
[50] Vasen HFA, Watson P, Mecklin JP, Lynch HT, ICG-HNPCC. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) proposed by the International Collaborative Group on HNPCC. GASTROENTEROLOGY 116, 1453-1456. 1999.
[51] Liu B, Farrington SM, Petersen GM, Hamilton SR, Parsons R, Papadopoulos N, Fujiwara T, Jen J, Kinzler KW, Wyllie AH, Vogelsten B, Dunlop MG. Genetic instability occurs in the majority of young patients with colorectal cancer. Nat Med 1995; 1:348-352.
[52] Farrington SM, Lin-Goerke J, Ling J, Wang YT, Burczak JD, Robbins DJ, Dunlop MG. Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. Am J Hum Genet 63[3], 749-759. 1998.
[53] Chan TL, Yuen ST, Chung LP, Ho JW, Kwan KY, Chan AS, Ho JC, Leung SY, Wyllie AH. Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer. J Natl Cancer Inst 1999; 91(14):1221-1226.
[54] Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, Liu B, Kinzler KW, Vogelstein B. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6[1], 105-110. 1997.
[55] Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Meera Khan P, Lynch H, Perucho M, Smyrk T, Sobin L, Srivastava S. A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: Meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89[23], 1758-1762. 1997.
[56] Perucho M. Correspondence re: C. R. Boland et al., 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. Cancer Res 59[1], 249-253. 1999.
[57] Lamberti C, Kruse R, Ruelfs C, Caspari R, Wang Y, Jungck M, Mathiak M, Malayeri HRH, Friedl W, Sauerbruch T, Propping P. Microsatellite instability - a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer. Gut 44, 839-843. 1999.
[58] Cravo ML, Fidalgo PO, Lage PA, Albuquerque CI, Chaves PP, Claro I, Gomes T, Gaspar C, Soares JO, NobreLeitao C. Validation and simplification of Bethesda guidelines for identifying apparently sporadic forms of colorectal carcinoma with microsatellite instability. Cancer 85[4], 779-785. 1999.
[59] Brown SR, Finan PJ, Bishop DT. Are relatives of patients with multiple HNPCC spectrum tumours at increased risk of cancer? Gut 43, 664-668. 1998.
[60] Lynch HT, Watson P. Multiple HNPCC tumours: ask the family! Gut 43[5], 596-597. 1998.
[61] Wijnen JT, Vasen HFA, Meera Khan P, Zwinderman AH, Van der Klift H, Mulder A, Tops C, Moller P, Fodde R, Menko F, Taal B, Nagengast F, Brunner H, Kleibeuker J, Sijmons R, Griffioen G, Brocker-Vriends A, Bakker E, Van Leeuwen-Cornelisse I, Meijers-Heijboer A, Lindhout D, Breuning M, Post J, Schaap C, Apold J, Heimdal K, Bertario L, Bisgaard ML, Goetz P. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339[8], 511-518. 1998.
[62] Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P, Chadwick RB, Kaariainen H, Eskelinen M, Jarvinen H, Mecklin JP, de la Chapelle A. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998; 338(21):1481-1487.
[63] Lynch HT, Smyrk TC. Identifying hereditary nonpolyposis colorectal cancer. N Engl J Med 1998; 338(21):1537-1538.
[64] Parc YR, Halling KC, Wang L, Christensen ER, Cunningham JM, Burgart LJ, Price-Troska TL, Thibodeau SN. hMSH6 alterations in patients with MSI-L colorectal cancer. Am J Hum Genet 65[4], A65. 1999. Ref Type: Abstract
[65] Cawkwell L, Gray S, Murgatroyd H, Sutherland F, Haine L, Longfellow M, O'Loughlin S, Cross D, Kronborg O, Fenger C, Mapstone N, Dixon M, Quirke P. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut 1999; 45:409-415.
[66] Lynch HT, Smyrk T. Colorectal cancer, survival advantage, and hereditary nonpolyposis colorectal carcinoma. GASTROENTEROLOGY 1996; 110:943-947.
[67] Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. GASTROENTEROLOGY 1996; 110:682-687.
[68] Aarnio M, Mustonen H, Mecklin JP, Jarvinen HJ. Prognosis of colorectal cancer varies in different high-risk conditions. Ann Med 30[1], 75-80. 1998.
[69] Watson P, Lin KM, Rodriguez-Bigas MA, Smyrk T, Lemon S, Shashidharan M, Franklin B, Karr B, Thorson A, Lynch HT. Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 1998; 83:259-266.
[70] Percesepe A, Benatti P, Roncucci L, Sassatelli R, Fante R, Ganazzi D, Bellacosa A, Genuardi M, Neri G, Viel A, Ponz de leon M. Survival analysis in families affected by hereditary non- polyposis colorectal cancer. Int J Cancer 71[3], 373-376. 1997.
[71] Bertario L, Russo A, Sala P, Eboli M, Radice P, Presciuttini S, Andreola S, RodriguezBigas MA, Pizzetti P, Spinelli P. Survival of patients with hereditary colorectal cancer: Comparison of HNPCC and colorectal cancer in FAP patients with sporadic colorectal cancer. Int J Cancer 80[2], 183-187. 1999.