Lynch Syndrome Diagram of a gene associated with Lynch syndrome5 Anatomy & Physiology August 31 2015
What is Lynch Syndrome? • Lynch syndrome is a genetic disorder that dramatically increases the risk of obtaining certain cancers at a relatively young age1 • Lynch syndrome is the leading cause of hereditary colon cancer1 • Experts project that between 600,000 – 1,000,000 people in the United States have Lynch syndrome … but that less than 5% of these people have been diagnosed.3 Did you know? Lynch syndrome was previously known as HNPCC (hereditary non-polyposis colorectal cancer) and as family cancer syndrome.2 Visualization of a colon tumor4
What causes Lynch Syndrome? • Lynch syndrome is caused by a mutation in any one of several DNA mismatch repair (MMR) genes.2 • Although DNA replication is very accurate, mistakes do occur. The MMR genes make proteins whose job is to correct any mismatched bases that occur after DNA replication. If these proteins don’t work, then mutations can accumulate in cells, leading to cancer.5 A simplified diagram of DNA mismatch repair.6
Inheritance of Lynch Syndrome • Vocab! • Autosomal means the gene occurs on one of the 22 ‘regular’ chromosomes (not the X or Y) • Dominant means that a person will have the trait (disorder) if they have the gene. • Lynch syndrome is an autosomal dominant disorder.3 • This means that Lynch syndrome occurs equally in both genders, and that a person with Lynch syndrome has a 50% chance of passing on the disorder to each of his or her children. An example pedigree of a family with Lynch Syndrome7
Lynch syndrome cancers Lynch syndrome increases the risk of many different cancers. These tumors tend to be fast-growing and tend to occur at relatively young ages (e.g. 30s and 40s, rather than 60s and 70s).
Lynch syndrome cancers Lynch syndrome increases the risk of many different cancers. These tumors tend to be fast-growing and tend to occur at relatively young ages (e.g. 30s and 40s, rather than 60s and 70s). The digestive system and female reproductive systems are most at risk of developing cancer, and thus are most impacted by this disorder. Cancer can disrupt the functioning of these systems due to the excessive growth of mutated (and usually non- or poorly-functioning) cells.
Signs, Symptoms, and Diagnosis Lynch syndrome is first suspected when a family exhibits multiple early-onset cancers.3,8 These families may then undergo a family history screening, genetic testing, and/or tissue sampling. Family history The “Amsterdam Criteria” state that Lynch Syndrome can be diagnosed if ALL of the following conditions are met:3, • 3 immediate family members have a Lynch Syndrome cancer (e.g. colorectal, urinary, endometrial, or ovarian) • At least 2 generations are affected • At least 1 of the cancers must occur before age 50 • Another colorectal disorder (FAP) must be ruled out Meeting the Amsterdam Criteria is sufficient for a diagnosis of Lynch syndrome. Genetic testing need not be done… but, usually, it is encouraged. Can you think of why?
Signs, Symptoms, and Diagnosis Genetic Testing Individuals whose family history indicates Lynch syndrome may be referred for genetic testing. Blood is drawn at a doctor’s office and sent to a lab. Usually, 5 MMR (mismatch repair) genes associated with Lynch syndrome will be sequenced. 3 The results may come back4 • normal (no mutation in the MMR genes) • Inconclusive (a mutation has been found, but there is no current medical knowledge about the impact of that mutation) • Positive for Lynch syndrome (a mutation known to cause Lynch syndrome has been found) Researchers don’t believe they have discovered all the Lynch syndrome mutations yet4
Signs, Symptoms, and Diagnosis Case study! Diagram of the colon and picture of colon tumor 1 Other signs indicative of Lynch syndrome • Lynch cancers are fast growing1,3 • Conversely, Lynch colon cancers tend to have increased survivability3,7 • Lynch colon cancers are more likely to occur on the ascending colon3 • Lynch tumors exhibit microsatellite instability – a tendency for a lot of variation in non-coding genes. This can be identified by examining the DNA of tumor cells.3
Management of Lynch Syndrome Lynch syndrome cannot be treated or prevented, but it can be managed through surveillance and risk-reduction. Surveillance2,7 The goal of surveillance is to detect cancer early, while it is still treatable. People with Lynch syndrome are recommended to begin yearly cancer screenings, including: • Colonoscopy (age 25+) • Renal ultrasound and cytology (for urinary cancers) (age 25+) • Endometrial biopsy (age 35+) • Transvaginal ultrasound & CA-125 (for ovarian cancer) (age 35+) Based on family history, doctors may also recommend yearly screens for breast cancer, stomach cancer, and brain cancer) Diagram of colonoscopy procedure and polyp8
Management of Lynch Syndrome Prophylatic means “intended to prevent disease” Risk Reduction7 • Prophylatic removal of the colon – eliminates risk of colon cancer. Recommended for people who develop many colon tumors. • Prophylatic removal of uterus and ovaries – eliminates the risk of ovarian and endometrial cancers. Recommended for women with Lynch syndrome after childbearing is complete. • Daily high-dose aspirin – may reduce cancer risk by 30%, but comes with risk (digestive & bleeding issues). Recommended to discuss with doctor. • Hormonal birth control – To reduce endometrial cancer risk in women who have not yet had their uterus removed. • Don’t smoke and maintain healthy BMI – both shown in multiple studies to moderately reduce cancer risk. • Healthy diet (high fruit, low sugar, maybe low meat) – weak, but significant effect in multiple studies
Prognosis The risk and age of onset of Lynch syndrome cancers are relatively well known, but the overall effect on life expectancy is less clear, and likely varies considerable depending: • What steps are taken to reduce or manage cancer risk • Which cancers develop • How quickly the cancers are caught and treated
Works Cited • Mayo Clinic Staff. Lynch syndrome. 2014 http://www.mayoclinic.org/diseases-conditions/lynch-syndrome/basics/definition/con-20025651 • Vasen HFAQ, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch Syndrome (HNPCC): recommendations by a group of European Experts. Gut 2013; 1-13. • Lynch Syndrome International. Mutation of a single gene dramatically increases the chances of contracting cancer. 2014. http://www.lynchcancers.com/ • KCE Belgian Health care knowledge center. [KCE] Press release : KCE Reports 220 Oncogenetic testing for Lynch syndrome and familial adenomatous polyposis. 2014. http://kce.fgov.be/press-release/kce-press-release-kce-reports-220-oncogenetic-testing-for-lynch-syndrome-and-familial- • Memorial Newfoundland University Hospital. Mismatch repair genes DNA database. 2006. http://www.med.mun.ca/mmrvariants/thegenes.aspx • Sadava D, Sadava DE, Hillis DM, Orians GH, Heller HC, Purves WK, Bernebaum M. Life: The Science of Biology. 8th edition. 2007, Sinaur Associates.
Works Cited • Wikipedia. Hereditary non-polyposis colorectal cancer. 2014. http://en.wikipedia.org/wiki/Hereditary_nonpolyposis_colorectal_cancer • Hereditary Cancer Institute. Living with hereditary colon cancer. 2005, Creighton University Press. • American Gastroenterological Association. Preparing for your colonoscopy. 2014. http://www.gastro.org/patient-center/procedures/colonoscopy