It is estimated that a high genetic predisposition is the cause of 10-20% of all colon cancers (CRC) (1-5).

Among the well known syndromes of inherited predisposition to tumours manifesting with CRC such syndromes showing mendelian pattern of inheritance can be included like: hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome), familial adenomatous polyposis (FAP); Gardner, Zankas, Turcot, Peutz-Jaghers syndromes and juvenile polyposis.

HNPCC has been described by Lynch (6) in 60's and is the cause of around 5% of all CRC. It has been shown that HNPCC is caused by mutations within several genes such as: MSH2, MLH1, MSH6, EPCAM, PMS2. Mutation within the two first are the most frequent cause of the Lynch syndrome (7-10). Characteristic clinical feature of Lynch syndrome include:

– early age of CRC diagnosis (about 45 yrs),

– more frequent right site tumour localization,

– two and more CRC cases among I° relatives,

– many syn- and meta-chronous CRC tumours

– occurrence of disease in consecutive generations (vertical transmissions)

– increased frequency of occurrence among relatives of cancers of the endometrium, small bowel and urinary tract

According to international group of experts (International Collaborative Group on HNPCC – ICG-HNPCC) Lynch syndrome can be definitively diagnosed, if constitutional mutation within one of genes connected with HNPCC, such as MSH2 or MLH1 is identified or if the following pedigree-clinical criteria are matched (tab. 1) (11, 12).

A family matching definitive criteria of HNPCC according to ICG-HNPCC is presented on figure 1.

Due to incomplete penetrance of genes what is typical for dominant mendelian disorders, deaths caused by various diseases, or due to difficulties in achieving full information about all of relatives, the large proportion – perhaps majority – of families actually with HNPCC, can not be diagnosed using Amsterdam criteria summarized in table 1.

Therefore several authors is using another type of criteria, fulfillment of which is not allowing definitive diagnosis of HNPCC, however it is useful in identification of families with highly increased risk (12-15). According to our experience criteria summarized in table 2 are of a particular value in identification of cases suspected of HNPCC.

Examples of families matching criteria of "suspected HNPCC” are presented on figures 2-3.

DNA testing is recommended in families fulfilling at least "suspected HNPCC” criteria. After exclusion of FAP (characteristic FAP features include polyposis, congenital hypertrophy of the retinal pigment epithelium, cysts and osteomata of bones of the maxilla and mondible desmoid tumors) immunohistochemical analyses (IHC) of MLH1, MSH2, MSH6expression in malignant tissues should be performed (absence of the protein may indicate the mutated gene).

Results of several studies performed in our center characterised the frequencies and spectrum of MSH2 and MLH1 mutations in Poland (16). Similary to other populations, the most frequent causes of HNPCC in Poland are MLH1 and MSH2 mutations, constituting 90% of all mutations associated with this syndrome. MLPA detects 10% of these mutations. In over 60% of all HNPCC families recurrent mutations can be found. Thus, after IHC MLPA, for MSH2 and MLH1 should be performed. Next, with MLPA negative, DNA tests searching for recurrent mutations, characteristic for Polish population, should be applied. Last step should include DHPLC (17) and sequencing of the cases indicated by DHPLC results.

Another promising method is the designer iPLEX/TaqMan test plexes, which comprised seven mutations of the APC gene and 29 mutations of three of the mismatch repair genes andseems to be an an outstanding tool for identification of recurrent mutations among hereditary colorectal cancer patients, including HNPCC. (18).

Detection of marker mutation for family with HNPCC is of clinical importance because: A. allows exclusion around 50% relatives from high risk group, B. facilitates decision about surgery extension, for example instead of classical – tumour resection the colectomy with prophylactic hysterectomy and ovariectomy when such resection is performed in diagnosed carriers of mutation – females at perimenopausal age.

Our present knowledge on this syndrome is indicting that special prevention and treatment should be applied. Different programs are performed by particular centres (4, 19, 20). According to the guidelines for the clinical management of Lynch syndrome established by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group) relatives from families fulfilling Amsterdam criteria II or revised Bethesda criteria 1) CRC diagnosed in a patient aged 50 years; 2) Presence of synchronous, metachronous colorectal or other Lynch syndrome-related tumours, *regardless of age; 3) CRC with MSI-H phenotype diagnosed in a patient aged 60 years; 4) patient with CRC and a first-degree relative with a Lynch syndrome-related tumour, with one of the cancers diagnosed at age 50 year; 5) patient with CRC with two or more first-degree or second degree relatives with a Lynch syndrome-related tumour, regardless of age) (21) with Lynch syndrome should consider the following options of medical managements:

Persons with high risk of CRC should consider low fat diet with limitations concerning red meat, but with bran and rich in cellulose (22).

There are reports that group of drugs lowering the risk of CRC include: aspirin, sulindac, prioxicam, calcium, vitamin C. Real value of such drugs in cancer prevention in HNPCC is still under investigations. Especially promising data have been achieved with aspirin (20, 22, 23, 24).

Full colonoscopy is recommended beginning from age of 20-25 yrs every one – two years. In families in which CRC has been diagnosed at earlier age colonoscopy should begin 5 years earlier than age of the youngest person with CRC. In cases were endoscopy of the colon could not be assessed properly, barium enema is indicated (20, 25).

Due to increased frequency of female genital tract tumours in families with HNPCC, it is recommended to perform, beginning at the age of 35 years, annual clinical gynecologic examinations with transvaginal ultrasonography (USG) and histopatological examination of endometrium. Additionally, in some cases it is indicated to perform examination aimed to detect other tumours more frequently observed in a given family (for example stomach, urinary tract, breast) (5, 20).

Endoscopic polypectomy is recommended in case of polyps which are benign and non recurrent. However in patients with adenomas: multiple and/or recurrent and/or of significant degree of displasia and/or villous, prophylactic colectomy should be considered (25). Most of experts believe that prophylactic surgery is not recommended to patients without any pathologic changes of the colon even if such persons are carries of mutated HNPCC gene (17). High proportion of synchronous tumours (more than 15% of patients at the time of diagnosis) or metchachronous tumours (about 45% during 10 years following surgery of the primary tumour) is suggesting that for preventive surgery as for surgery in patients from HNPCC families with histopathology diagnosed CRC the following types of surgical treatment can be recommended (20, 26):

– proctocolectomy with ileostomy,

– colectomy with ileo-rectal anastomosis,

– proctocolectomy with ileo-anal "pouch” – S, J, W or H.

The first from proposed procedures is the most radical but later the risk of recurrence is very low, however such treatment is highly traumatising and frequently leading to urinary tract abnormalities and sexual disfunction.

Colectomy with ileorectal anastomosis is not leading to such complications however should be followed by frequent examinations due to the risk of cancer in unresected fragment of bowel.

Proctocoloctomy with ileo-anal "pouch” S, J, W or H is the method with relative short history so it is difficult to conclude about it definitely.

In females with Lynch syndrome undergoing surgery due to CRC and at perimenopausal age or older, due to increased risk of primary endometrial and ovarian cancers, it is recommended to consider extension of the surgery by hysterectomy and adnexectomy (20, 27).

All of above procedures are characterized by increasing frequency of complications. However they are recommended in the treatment of HNPCC because the really important problem for this patient is the high risk of second primary CRC.

It has been shown that the application of appropriate programs of management in families with HNPCC is leading to increased detection of early asymptomatic CRC. Additionally, prospective studies has confirmed that due to appropriate management the lifetime risk of CRC is going down from 80 to 30% and there is higher proportion of healing and longer survival time of patients with CRC from families with Lynch syndrome. The right management applied in carriers of MSH2/MLH1 mutations is making that such person can not die due to CRC (28).