Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications.
We estimate that 5-10% of virtually all forms of cancer are due to a primary hereditary etiology. However, a hereditary cancer diagnosis is often missed because the family history of cancer is given short shrift in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC) certainly fits this estimate, although some studies suggest that a minimum of 2% with a range as high as 10% of the total colorectal cancer burden is due to HNPCC. Mutations in one of the four mismatch repair genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of HNPCC kindreds. Other germ-line mutations are likely to be identified to account for the remainder of HNPCC patients. By far the most common HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting for only about 3% of such families. Prior to these molecular genetic discoveries, the genetic counselor could only provide the patient with an estimate of a 50% likelihood of manifesting HNPCC based on the counselee having one or more first-degree relatives manifesting syndrome cancers in their direct genetic lineage. Because DNA testing has become available in families with known mutations, we have provided pretest group education in the form of a family information service with intensive education about the natural history, genetic risk, surveillance, and options for management of HNPCC, as well as discussion of the potential for fear, anxiety, apprehension, and insurance or employer discrimination that might impact on this DNA testing. Following informed consent, these relatives were then counseled on a one-to-one basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we have provided this service to four extended HNPCC kindreds. Details of this genetic counseling experience on these four kindreds will be discussed.
Lynch
H T
HT
Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Lemon
S J
SJ
Karr
B
B
Franklin
B
B
Lynch
J F
JF
Watson
P
P
Tinley
S
S
Lerman
C
C
Carter
C
C
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000209:etiology / Q000235:genetics* / Q000523:psychology / Q000628:therapy; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D005817:Genetic Counseling; D005819:Genetic Markers; D005820:Genetic Testing; D006801:Humans; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D005819:Genetic Markers; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes