Unusual Symptoms

Doctor's File Notes Genetic Consulting November 4, 2015

I had the pleasure of seeing [patient] in our Cancer Genetics and Prevention Program Gastrointestinal Cancer Prevention Clinic today to discuss his personal and family history of cancer. He was alone.

As you know, {patient} is a 73 y.o. Eastern European Jewish male who has had three primary cancers. The first was prostate cancer, followed by esophageal cancer and most recently cecal colon cancer, all at the age of 72. He has a 40 year history of chronic fatigue syndrome.

Molecular tissue analysis is recommended as a screening test for Lynch Syndrome. At UCSF it includes immunohistochemical (IHC) staining of all colorectal cancers for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. These tests were completed on this patient's cecal colon tumor. The tumor showed absent expression of both MLH1 and PMS2. Expression of MSH2 and MSH6 was present. This pattern may arise sporadically due to hypermethylation of the MLH1 promoter, or as a result of a germ line mutation in MLH1 or PMS2 (Lynch syndrome). Further tumor testing, including MLH1 promoter methylation is recommended, as well as germ line genetic testing for Lynch syndrome given the family history of mother and aunt with colon cancer.

Paternal: Germany, Lithuania. {Patient} reports Ashkenazi Jewish ancestry. Maternal: Germany. {Patient} reports Ashkenazi Jewish ancestry. No reports of consanguinity.

We discussed the fact that cancer is a common disease and the majority of the time, it is a sporadic occurrence. Hereditary predisposition to cancer is relatively rare, accounting for 5-10% of common cancers. There are many genes in the human body that are important for controlling cell growth and preventing cancer. A person who has a mutation (change) in the genetic code of one of these genes has an increased chance of developing certain types of cancer. Features suggestive of a hereditary cancer diagnosis, multiple primary tumors in the same individual, multiple affected family members on the same side of the family, and rare tumor types associated with known hereditary cancer syndromes.

In other cases, there may be a moderately increased risk for cancer that is multifactorial, due to a combination of genetic and non-genetic (environmental, hormonal, etc.) risk factors that act together to determine cancer risk.

The types and ages of cancer in the family are suggestive of hereditary cancer predisposition syndrome caused by a mutation in a single gene. These features include colon cancer with evidence of mismatch repair deficiency, specifically a tumor with loss of expression of MLH1 and PMS2, and a family history of colon cancer in his mother and maternal aunt. Based on these features, the following differential was discussed. Lynch syndrome vs. sporadic (acquired) mismatch repair deficient colon cancer. Based on data currently available, the probability Lynch syndrome is around 20% and the probability of a sporadic mismatch repair deficient tumor is around 80%. Because of the markedly increased risks for colorectal and other cancers associated with Lynch syndrome, germ line genetic testing is recommended. If the patient is found to have Lynch syndrome, annual colonoscopy will be recommended. The patient's close relatives would also be at increased risk for Lynch syndrome and it's associated cancers.

He also has a maternal first cousin with breast cancer and is of Ashkenazi Jewish ancestry. We now recognize that individuals with BRCA1 or BRCA2 mutations are at elevated risk for prostate cancer, and there is more recent data to suggest an association with esophageal and colorectal cancer. For this reason, I recommend that we also rule out a mutation in the BRCA1/BRCA2 pathway genes.

Lynch syndrome was reviewed in detail, including the fact that men and women with the condition have up to a 75% lifetime risk to develop colorectal cancer. Moreover, this syndrome is associated with a 39% risk of a second primary colorectal cancer arising within 10 years of the first. Women also have up to a 71% lifetime risk for endometrial cancer. Persons with Lynch syndrome are also at increased risk for other cancers that include cancer of the urinary tract, ovary, stomach, small intestine, hepatobiliary tract, skin, and brain. The molecular genetics of Lynch syndrome are will understood. The condition is caused by a germ line mutation in one of the mismatch repair genes, most often MLH1, MS2, MSH6, or PMS2. Germ line deletions in EPCAM can also cause Lynch syndrome. Several hundred mutations in the mismatch repair genes that predispose people to colorectal cancer and other Lynch syndrome-associated cancers have been found. These mutations may cause the production of an abnormally short or inactivated mismatch repair protein that cannot perform its normal function. When the mismatch repair protein is absent or ineffective, the number of mistakes that are left unrpaired during cell division increases substantially. If the cells continue to divide, errors accumulate in DNA; the cells become unable to function properly and may form a tumor in the colon, endometrium or another part of the body. Mutations in mismatch repair genes are inherited in an autosomal dominant manner, meaning each first degree relative (parent, child, and sibling) of an individual with this condition has a 50% chance of inheriting the disease causing mutation.