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