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Lynch Syndrome I


Alternative Names
Colorectal Cancer, Hereditary Nonpolyposis, Type 1
HNPCC1
Colon Cancer, Familial Nonpolyposis, Type 1
FCC1
COCA1
Lynch Syndrome II

WHO International Classification of Diseases
Neoplasms > Malignant neoplasms

OMIM Number
120435

Gene Map Locus
2p22-p21

Mode of Inheritance
Autosomal dominant (2p16)

Med. Sea

Tunisia

Med. Sea

Lebanon

X

Syria

X

Iraq

Asia

Morocco

Algeria

Libya

Egypt

Palestine

Jordan

Kuwait

The Gulf

Mauritania

Sudan

KSA

Bahrain

Qatar

Eritrea

Red Sea

Yemen

Oman

UAE

Africa

Djibouti

Somalia

Comoros

Indian

Ocean

Description

Lynch syndrome is a hereditary non-polyposis colorectal cancer (HNPCC) characterized by the development of colon cancer at an early age, an excess of multiple primary colon cancer, and a predominance of proximal colon cancer. HNPCC accounts for about 1% of colorectal cancers, and its prevalence is of the order of 1:3000. Some populations, e.g. Finns, show a founder effect. HNPCC can be classified into two types: HNPCC-I and HNPCC-II. HNPCC-I is the site specific Lynch syndrome.

An International Collaborative Group on hereditary non-polyposis colorectal cancer (ICG-HNPCC) unified definitions and update criteria for HNPCC. Families diagnosed with Lynch syndrome-II develop an increased incidence of cancer of the endometrium, ovary, stomach, pancreas, breast, and other sites.

Despite the availability of genetic tests for Lynch syndrome, family history remains the most important tool in the diagnosis of this disease. If the cancer onset starts in early age in an individual with Lynch syndrome, targeted cancer surveillance should be extended to all first-degree relatives at an early age.

Molecular Genetics

HNPCC is an autosomal dominantly inherited predisposition to develop colorectal cancer. HNPCC is defined as inactivating germline mutations in genes encoding components of the DNA mismatch repair (MMR) system. The single germline mutation in an MMR gene in an individual with HNPCC does not result in MMR deficiency. However, a second hit in the functional allele in a tumor does then result in loss of MMR. This leads to failure to repair errors introduced into DNA during DNA replication. Cells with defective MMR have very high rates of somatic mutation, and accumulate mutations randomly in many genes as well as non-coding DNA. Mutations may arise from inactivate tumor suppressor genes or activate cellular oncogenes, and therefore in turn give rise to cancer development.

To date germline mutations in four genes encoding components of the mismatch repair pathway have been shown to underlie HNPCC, these are: Homolog of MutS E. coli 2 (MSH2), Homolog of MutL E. coli 1 (MLH1), S. cerevisiae Postmeiotic Segregation Increased 2 (PMS2), and Homolog of MutS E. coli 6 (MSH6). However, mutations in MSH2 and MLH1 account for approximately 90% of HNPCC and service provision is generally based on analysis of only these two genes. Less than 1% of patients with HNPCC have mutations in the PMS2 gene.


Epidemiology in the Arab World

Lebanon

Farah et al. (2001) studied the history of a Lebanese family consisting of ten siblings with Lynch syndrome type II. The father died at the age of 51 years from colon cancer and nine of the siblings (90%) presented varied spectrum of tumors in addition to that in the colon. One of these siblings presented at the age of 69 a metachronous colonic adenocarcinoma at the splenic flexure, and an ampullary adenocarcinoma. Four years later, he presented an obstructing metachronous tumor of the descending colon. Another sibling was admitted at 40 years of age for surgery to remove an adrenocarcinoma of the right colon. Seventeen years later, he had a subtotal colectomy with ileo-rectal anatomosis for a metachronous tumor in the descending colon. Two years later, he developed a third metachronous adenocarcinoma in the rectal remnant. Two more years later, he showed a mass in the region of the rectum, and erosion of the sacrum anteriorly with thickening of the mesenteries and fluid in the pelvis suggestive of mesenteric seeding. He died at the age of 63. Three of the other siblings had carcinoma of the colon resected, one also had a gastric leimyoma, and a fourth underwent colonic removal of polyps. Some of the siblings also suffered from kidney tumor, breast and uterus, and hepatic tumor [See also: Syria > Farah et al., 2001].

Syria

Farah et al. (2001) discovered a Syrian "Cancer Family" residing in Lebanon by studying its pedigree. The father and the four siblings showed many features of Lynch syndrome I. The father died at the age of 71 because of colon cancer. The index case was 41 years old when she became pregnant and presented a transverse colon tumor. Follow-up colonoscopy revealed a metachronous splenic fleure tumor. The eldest brother had an ascending colon carcinoma and presented symptoms of post-prandial crampy abdominal pain and distension. The other sibling died prior to the time of analysis. However, sigmoidoscopy with biopsies showed adenocarcinoma of the colon 8 cm from the anal verge. This tumor was not completely respectable because of adherence to the bony pelvis posteriorly. The fourth sibling was 50 years old and revealed three polyps which were removed. Two of the polyps showed mild to moderate dysplasia. The third polyp from the sigmoid colon had adenocarcinoma in situ with a free base and pedicle.

References

  1. Farah S, Abyad A, Mourad FH, Uthman S. Lynch syndrome: report of two Families from Lebanon and clinical review. Emirates Med J. 200; 19(3):181-5.

Links
http://ftp.infobiogen.fr/services/chromcancer/Kprones/HNPCCLynchID10049.html
http://ghr.nlm.nih.gov/condition=hereditarynonpolyposiscolorectalcancer
http://www.cmgs.org/BPG/Guidelines/2002/HNPCC.htm
http://www.colorectal-cancer.net/colorectal.htm
http://www.genetests.org/profiles/hnpcc
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=144

Contributors
Ghazi O. Tadmouri: 24.5.2006
Abeer Fareed: 24.5.2006

Edit History
Pratibha: 16.9.2009
Tasneem: 19.3.2008
Abeer: 6.3.2007
Pratibha: 28.12.2006
Sarah: 27.5.2006

Notes
To contribute with your findings to the content of this record, please fill the CTGA Database Information Submission Form and email it, along with supportive documents, to cags@emirates.net.ae.




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