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July 2016

Genetics of Hereditary Colon, Uterine and Ovarian (Lynch syndrome)

The majority of cancer cases are not attributable to hereditary causes. However, cancer can be hereditary in some families. There are many factors that can increase the probability that in a family may be hereditary. Some of these factors are: early onset of cancer (colon cancer or uterine cancer <50), more than one primary (new) cancer in an individual, the same cancer in two or more close relatives, unusual presentation of cancer, and related cancers (such as colon/uterine/ovarian/other gastrointestinal cancers) found in the same family. In addition, abnormal results on screening tests performed on a tumor (i.e. microsatellite instability (MSI) or immunohistochemistry (IHC)) may also suggest a higher likelihood that the tumor is due to a hereditary cause.

Several changes (mutations) have been discovered which predispose individuals to cancer. In review, the genetic instructions for our bodies are stored in our cells in tiny structures called . A normal individual has 23 pairs of chromosomes: one from each pair is normally inherited from the mother, and the other from the father. The most common form of hereditary is called Lynch syndrome (also called hereditary non- polyposis colorectal cancer (HNPCC)). Clinical testing is available for several involved in Lynch syndrome, including MLH1 (on chromosome 3), MSH2 (on ), MSH6 (on chromosome 2), EPCAM (on chromosome 2), and PMS2 (on chromosome 7).

Lynch syndrome is passed down in families in an autosomal dominant pattern of inheritance. This means that an individual who carries a mutation has a 50% chance of passing the mutation on to each of their children. It also means that siblings of an individual who carries a mutation have a 50% chance of carrying the same mutation.

Individuals with Lynch syndrome are at risk for several types of cancer. Both men and women with Lynch syndrome are at increased risk to develop colon cancer. It is estimated that the lifetime risk for colon cancer is as high as ~65-80%. Individuals with Lynch syndrome are also at increased risk for a second primary colon cancer. The available data suggest that women with Lynch syndrome have a ~20-60% lifetime risk of uterine cancer, and a ~9-12% lifetime risk of . Individuals with Lynch syndrome may also be at some increased risk for a variety of other types of cancers, including other gastrointestinal cancers, urinary tract cancers, hepatobiliary tract cancers, sebaceous skin cancers, and brain tumors. However, the overall lifetime risks for many of these other cancers are relatively small.

Individuals who learn they have Lynch syndrome are offered special surveillance and risk reduction options. Genetic counseling is particularly important as the cancer risks can vary greatly between the several genes associated with Lynch syndrome.

Smilow Cancer Genetics and Prevention 330 Orchard Street, Suite 107 New Haven, CT 06510 Phone: 203-200-4362 Fax: 203-200-1362 [email protected] http://yalecancercenter.org/patient/specialty/genetics/ Page 2 of 2

References

Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995;64:430–3.

Chen S, Wang W, Lee S, Nafa K, Lee J, Romans K, Watson P, Gruber SB, Euhus D, Kinzler KW, Jass J, Gallinger S, Lindor NM, Casey G, Ellis N, Giardiello FM, Offit K, Parmigiani G. Colon Cancer Family Registry. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA. 2006;296:1479–87.

Kohlmann and Gruber. (2014) Lynch syndrome. Retrieved December 23, 2015 from http://www.ncbi.nlm.nih.gov/books/NBK1211/

Rahner N, Steinke V, Schlegelberger B, Eisinger F, Hutter P, Olschwang S. Clinical utility gene card for: Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) - update 2012. Eur J Hum Genet. 2013;21(1)

Smilow Cancer Genetics and Prevention 330 Orchard Street, Suite 107 New Haven, CT 06510 Phone: 203-200-4362 Fax: 203-200-1362 [email protected] http://yalecancercenter.org/patient/specialty/genetics/