Download Hereditary non-polyposis colorectal cancer

Morning Report
May 20, 2009
Bridger Clarke
Henry T Lynch, MD
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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.
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In 1962, Charles Magnuson, a gastroenterologist at
the Omaha VA, asked Lynch to consult on a patient
with a strong family history of CRC.
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Lynch presumed FAP, but discovered a strong
familial predilection for CRC in the absence of
multiple polyps.
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He presented his findings at a meeting of the
American Society of Human Genetics in 1964.
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The story goes that his presentation reminded
Marjorie Shaw, a medical geneticist at the University
of Michigan, of another family with similar
characteristics.
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In 1966, she and Lynch published their first report of
these two families, family N from Nebraska, and
family M from Michigan.
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Initially called “cancer family syndrome” (CFS), it is
now kn0wn as Lynch Syndrome.
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Most common of the inherited colon cancer
susceptibility syndromes (FAP, JP).
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“HNPCC” can be misleading as the disorder
predisposes to a variety of other cancers.
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The designation of “Lynch Syndrome I and II” is
also going out of favor.
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Mean age of diagnosis is 47 years old, as opposed to 64
years old in patients without the syndrome.
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10% have multiple tumors at the time of diagnosis
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Accounts for 2-3% of colorectal cancers and ~2% of
uterine cancers.
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Approximately 4,000 new cases of Lynch Syndrome each
year.
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Lifetime risk of colorectal cancer is ~70%
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CRCs in Lynch Syndrome evolve from adenomas, but
differ from sporadic cancers:
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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.
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Endometrial cancer is the most common, occurring
in up to 70% of women who are gene carriers.
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Other sites include:
 Ovarian, gastric, small bowel, renal pelvis, ureter,
pancreatic, and brain cancers.
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Debate about whether prostate and breast cancer
are part of Lynch Syndrome.
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Caused by a mutation in one of several DNA mismatch
repair (MMR) genes (MLH-1, MSH-2, MSH-6).
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The MMR system recognizes base-pair mismatches that
occur during DNA replication and repairs them.
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DNA mismatches commonly occur in repetitive
sequences called microsatellites.
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Loss of MMR leads to expansion/contraction of
microsatellite region, termed ‘microsatellite instability’,
and an increased rate of mutation.
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Three or more family members with HNPCC-related
cancers, one of whom is a first degree relative of the
other two
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Two successive affected generations
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One or more of the HNPCC-related cancers
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Diagnosed under age 50 years
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FAP has been excluded.
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1. CRC in pt <50 years old.
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2. Any patient with synchronous/metachronous CRC or
HNPCC-associated tumors, regardless of age.
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3. CRC with the MSI-H-like histology in a pt <60 yo.
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4. CRC in a patient with one or more first-degree relatives
with a HNPCC-related tumor diagnosed <50 yo.
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5. CRC in a patient with >1 first- or second-degree
relatives with HNPCC-related tumors, regardless of age.
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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
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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.
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Annual urinalysis with cytology at age 25-35.
Annual skin exam
Periodic upper endoscopy