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Hereditary non- polyposis colorectal cancer (Lynch syndrome)

Morning Report May 20, 2009 Bridger Clarke. Hereditary non- polyposis colorectal cancer (Lynch syndrome). Henry T Lynch, MD. Born in Lawrence, Massachusetts, on 4 January 1928. Dropped out of high school at the age of fourteen and joined the Navy during WWII.

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Hereditary non- polyposis colorectal cancer (Lynch syndrome)

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  1. Morning Report May 20, 2009 Bridger Clarke Hereditary non-polyposis colorectal cancer (Lynch syndrome)

  2. Henry T Lynch, MD • Born in Lawrence, Massachusetts, on 4 January 1928. • Dropped out of high school at the age of fourteen and joined the Navy during WWII. • Discharged from the Navy in 1946, he became a professional boxer in upper New York State • Obtained his GED and attended the University of Oklahoma, graduating in 1951. • Eventually attended medical school at UT Galveston and residency at University of Nebraska, completed in 1964.

  3. History • In 1962, Charles Magnuson, a gastroenterologist at the Omaha VA, asked Lynch to consult on a patient with a strong family history of CRC. • Lynch presumed FAP, but discovered a strong familial predilection for CRC in the absence of multiple polyps. • He presented his findings at a meeting of the American Society of Human Genetics in 1964.

  4. History • The story goes that his presentation reminded Marjorie Shaw, a medical geneticist at the University of Michigan, of another family with similar characteristics. • In 1966, she and Lynch published their first report of these two families, family N from Nebraska, and family M from Michigan. • Initially called “cancer family syndrome” (CFS), it is now kn0wn as Lynch Syndrome.

  5. Lynch Syndrome • Most common of the inherited colon cancer susceptibility syndromes (FAP, JP). • “HNPCC” can be misleading as the disorder predisposes to a variety of other cancers. • The designation of “Lynch Syndrome I and II” is also going out of favor.

  6. Mean age of diagnosis is 47 years old, as opposed to 64 years old in patients without the syndrome. • 10% have multiple tumors at the time of diagnosis • Accounts for 2-3% of colorectal cancers and ~2% of uterine cancers. • Approximately 4,000 new cases of Lynch Syndrome each year.

  7. CRC in Lynch Syndrome • Lifetime risk of colorectal cancer is ~70% • CRCs in Lynch Syndrome evolve from adenomas, but differ from sporadic cancers: • More proximal • Larger • Flatter • More high grade dysplasia and villous histology • The adenoma-carcinoma sequence progresses more rapidly, and new cancers can occur within 2-3 yrs of a negative colonoscopy.

  8. Extra-colonic Cancers • Endometrial cancer is the most common, occurring in up to 70% of women who are gene carriers. • Other sites include: • Ovarian, gastric, small bowel, renal pelvis, ureter, pancreatic, and brain cancers. • Debate about whether prostate and breast cancer are part of Lynch Syndrome.

  9. Genetics • Caused by a mutation in one of several DNA mismatch repair (MMR) genes (MLH-1, MSH-2, MSH-6). • The MMR system recognizes base-pair mismatches that occur during DNA replication and repairs them. • DNA mismatches commonly occur in repetitive sequences called microsatellites. • Loss of MMR leads to expansion/contraction of microsatellite region, termed ‘microsatellite instability’, and an increased rate of mutation.

  10. Amsterdam II Criteria: • Three or more family members with HNPCC-related cancers, one of whom is a first degree relative of the other two • Two successive affected generations • One or more of the HNPCC-related cancers • Diagnosed under age 50 years • FAP has been excluded.

  11. Who should be tested? • 1. CRC in pt <50 years old. • 2. Any patient with synchronous/metachronous CRC or HNPCC-associated tumors, regardless of age. • 3. CRC with the MSI-H-like histology in a pt <60 yo. • 4. CRC in a patient with one or more first-degree relatives with a HNPCC-related tumor diagnosed <50 yo. • 5. CRC in a patient with >1 first- or second-degree relatives with HNPCC-related tumors, regardless of age.

  12. Screening and Surveillance • Screening recommendations for patients with MMR gene mutations: • Colonoscopy every 1-2 years beginning at age 20, or 10 years earlier than the youngest age of colon cancer diagnosis in the family (whichever comes first). • In families with MSH6 mutations, recommendation is to start at age 30 since the age of onset of colon cancer is later in these families

  13. Screening and Surveillence • Endometrial and Ovarian cancer: • Annual screening at age 30, or 5 to 10 years before the earliest age of diagnosis in the family (whichever is earlier). Pelvic exam and endometrial aspirate and transvaginal ultrasound are recommended. • Discussion of prophylactic TAH-BSO at 35 years old. • Annual urinalysis with cytology at age 25-35. • Annual skin exam • Periodic upper endoscopy

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