Gastroenterology Board Review for hereditary syndromes including Lynch syndrome, MAP, and Peutz-Jeghers syndrome.

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Douglas Riegert-Johnson
Assistant Professor of Medicine
riegertjohnson.douglas@mayo.edu
Place Presenter
Photo Here

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Hereditary Colon Cancer Syndromes
and cars
Douglas Riegert-Johnson, MD

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No conflicts of interest.
No off label drug indications discussed.

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Learning Objectives
• Compare and contrast Lynch syndrome and Serrated
Polyposis Syndrome.
• Recall the features of Peutz-Jeghers Syndrome and
Cronkhite Canada Syndrome.
• Be able to analyze a cancer family history to diagnosis
the type of polyposis.

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Which of the following statements is TRUE regarding genetic
discrimination and genetic privacy?
A. The terms of use for direct to consumer genetic testing companies
(eg 23andme) includes language that gives the testing company
rights to your anonymized data in perpetuity.
B. In most places in the United States, there are civil and criminal
penalties for performing genetic testing on an individual without their
consent.
C. Provisions of the ACA prevent direct to consumer genetic testing
companies from selling customer data to third parties.
D. It is not possible to re identify individuals who have anonymously
donated DNA for scientific studies.
E. Individuals with hereditary cancer syndromes (eg Lynch syndrome)
can enlist in the United States Armed Forces.

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Which of the following statements is TRUE regarding genetic
discrimination and privacy?
A. The terms of use for direct to consumer genetic testing companies
include language that gives the testing company rights to your
anonymonized data in perpetuity. You CAN request all of your data
be deleted from 23andme and other DTC companies.
B.  In most places in the United States, there are civil and criminal
penalties for performing genetic testing on an individual without their
consent.
C. Provisions of the ACA prevent direct to consumer genetic testing
companies from selling customer data to third parties. False.
D. It is not possible to re identify individuals who have anonymously
donated DNA for scientific studies. It is possible in some cases.
E. Individuals with hereditary cancer syndromes (eg Lynch syndrome)
can enlist in the United States Armed Forces. False.
Re identification of Anonymous Individuals Science 2016.

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Which direct to consumer genetic test will sequence
genes associated with Lynch syndrome, familial
adenomatous polyposis, BRCA1/2 and hereditary
pancreatic cancer?
A. 23andme
B. Ancestry.com
C. Color.com genetics
D. National Geographic
E. OneGenome

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A. 23andme
B. Ancestry.com
C.  Color.com genetics
D. National Geographic
E. OneGenome
Which direct to consumer genetic test will sequence
genes associated with Lynch syndrome, familial
adenomatous polyposis, BRCA1/2 and hereditary
pancreatic cancer?

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• Dr. Riegert-Johnson has no relationship with and DTC GTC.
• Color.com direct to consumer test, ordered by a medical doctor. Either
your own or a MD working with Color.com establishing a doctor patient
relationship.
• HIPPA compliant as a health care provider.
• Cost includes a telephone consultation with a genetic counselor.

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The 1957 Aurora
contained many
innovative safety
features. Who was it
designed and built by?
A. A postal worker.
B. A police officer.
C. A priest.
D. A gastroenterologist.

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Question
The number of individuals with Lynch syndrome in the United
States is estimated to be closest to which number?
A. 1,000
B. 10,000
C. 100,000
D. 500,000
E. 1,000,000
The Search for Unaffected Individuals with Lynch Syndrome. Hampel and Chapelle. 2011.

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Question
The number of individuals with Lynch syndrome in the United
States is estimated to be closest to which number?
A. 1,000
B. 10,000
C. 100,000
D. 500,000
E.  1,000,000. The prevalence of Lynch syndrome in the general
population is estimated at 1 in 370. Given a population of
307,000,000 it is estimated that 830,000 individuals in the US have
Lynch syndrome. The Search for Unaffected Individuals with Lynch Syndrome. Hampel and Chapelle. 2011.

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Testing taking skills for
GI genetics Board Questions:
A + B = C
A. Identify the
syndrome
based on
clues in the
stem
B. Know next
appropriate
step in
diagnosis or
management
C. Select the
correct answer

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Question.
Identical twins present with anemia and abdominal pain.

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Question
Which test is most likely to identify the cause of the twin’s anemia and
abdominal pain?
A. Upper endoscopy.
B. Colonoscopy.
C. Testing of the STK11 gene.
D. CT scan of the abdomen and pelvis.
E. Wireless capsule endoscopy.

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Strategy
Identify the syndrome
based on clues in the stem
You recognize the
characteristic melanotic
macules of
Peutz-Jeghers syndrome
(also twins).
Know next appropriate
step in diagnosis or
management
Patients with PJS should
be evaluated for small
bowel polyps.
Answer Correctly!
Wireless capsule
endoscopy
A + B = C

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Answer
Identical twins present to the office with anemia and abdominal pain
(shown below). Which test is most likely to identify the cause of the
patient’s anemia.
A. Upper endoscopy
B. Colonoscopy
C.Testing of the STK11 gene. STK11 is the gene associated with Peutz-
Jeghers syndrome. Testing of the STK11 gene only identifies a
mutation in about 3 of 4 patients with Peutz Jeghers syndrome. So 1
in 4 patients with Peutz-Jeghers syndrome will have a negative
genetic test.
D.CT scan of the abdomen and pelvis
E.  Wireless capsule endoscopy

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Question
The identical twins who presented to the office were diagnosed with
Peutz-Jeghers syndrome based on the characteristic melanotic
macules and small bowel polyps. If they maintain appropriate GI follow
up, which cancer prevention test is most important to recommend?
A. Urinalysis
B. Endoscopic Ultrasound
C. Mammography
D. MRCP
E. CT chest

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Strategy
Identify the syndrome
based on clues in the
stem. Photo showing
characteristic melanotic
macules of Peutz
Jeghers syndrome.
Know next appropriate
step in diagnosis or
management. BREAST
CANCER is the most
common cancer in
women with Peutz-
Jeghers syndrome.
Answer Correctly!
The test most likely to
identify breast cancer is
mammography.

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Cumulative cancer risk by site and age from a study of 416
Peutz-Jeghers syndrome patients (Clinical Cancer Res. 2006)
Site Age
40 yrs 50 yrs 60 yrs 70 yrs
GI (sans f/u) 9 15 33 57
Breast 8 13 31 45
GYN 3 8 18 18
Pancreas 3 5 7 11
Lung
males
1 4 13 17

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Question
WCE was performed and showed characteristic Peutz-Jeghers
syndrome small intestinal polyps. If they maintain appropriate GI
follow up, which cancer prevention test is most important to
recommend?
A. Urinalysis
B. Endoscopic Ultrasound
C.  Mammography
D. MRCP
E. CT chest

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Illustration of the identical twins reported by Conner as rendered by Sir Jonathan Hutchinson’s artist. Connor’s report was published
in Lancet(1895;2:1169) and the illustration was published in Archives of Surgery (London 7:290,1896). Note the perioral melanotic
macules. The text of Connor’s report reads, “Dr. J. T. Connor showed two cases of Pigmentation, of the Lips and the Mouth, in twins,
both girls, aged twelve years, of dark complexion and anaemic. The pigment spots, which were only noticed two years ago, were ink
black in colour, mostly of very small size and scattered over the lips, (especially the lower), gums, hard palate, and not on the
tongue.” Later in life, the twins developed additional features of PJS – one died of intussusception at age 20, the other died of breast
cancer at age 52 (5, 18). Courtesy of Victor McKusick, MD, Johns Hopkins Hospital.

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Question.
Which of the following disorders is most prevalent in the
United States?
A. Achalasia
B. Esophageal cancer
C. Primary biliary cirrhosis
D. Lynch syndrome
E. Pancreatic cancer

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Answer.
Which of the following disorders is most prevalent in
the United States?
A. Achalasia
B. Esophageal cancer
C. Primary biliary cirrhosis
D.  Lynch syndrome
E. Pancreatic cancer
The Search for Unaffected Individuals with Lynch Syndrome. Hampel and Chapelle. 2011.
Achalasia in England. Gut 2018.
SEER esophageal cancer.

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Question
A 43 year old man presented to the ED with abdominal pain. CT showed abnormal right colon and a
mass was found in the right colon on colonoscopy. No polyps were seen. The patient underwent
right colon hemicolectomy. Pathology was reported as adenocarcinoma with lymphocytic tumor
infiltration.
The patient’s mother (65 yo) had a hysterectomy in her 50s for bleeding, indication unclear. The
patient’s father (66yo), brother (45 yo) and sister (41yo) are alive and well.
Which test is the most appropriate?
A. Sequencing the APC and MUTYH genes.
B. Testing the patient’s tumor for microsatellite instability with immunohistochemisty.
C. Examination of the buccal mucosa and tips of the fingers.
D. Sequencing of the MSH2 gene.
E. Examination of the finger nails.

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Strategy
Identify the syndrome
based on clues in the
stem. Lynch syndrome,
next slide.
Know next appropriate
step in diagnosis or
management.
Evaluate tumor for
micro satellite instability.
Answer Correctly!
Immunohistochemisty
test of tumor for
microsatellite instability.

28. Question
• 43 year old man presented to the ED with abdominal pain. CT showed abnormal right colon (70% LS
Cas) and a mass was found in the right colon on colonoscopy. No polyps were seen (Lynch
syndrome also known as Hereditary NON Polyposis Colon Cancer, HNPCC). The patient underwent
right colon resection. Pathology was reported adenocarcinoma with lymphocytic tumor infiltration.
• The patient’s mother had a hysterectomy (LS=endometrial cancer) in her 50s for bleeding. Otherwise
she has no history of cancer. Father, and a brother (45) and sister (41) are alive and well.
Which test is the most appropriate?
A. Sequencing of the APC and MUTYH genes. These genes are defective in polyposis.
B. Tumor testing for microsatellite instability with IHC. MSI testing has > 90 sensitivity for Lynch
syndrome.
C. Examination for peri oral pigmentation. This would be seen in Peutz-Jeghers syndrome.
D. Sequencing of the MSH2 gene. MSH2 is one of the most common genes defective in Lynch
syndrome. However, defects in four other genes can cause Lynch syndrome (MLH1, PMS2, MSH6,
EPCAM) and testing for only MSH2 mutations would miss >50% of cases.
E. Examination of the patient’s finger nails. Oncolysis is associated with the inflammatory, non genetic
condition, Cronkhite Canada syndrome.
Clues for Lynch syndrome

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Question
Which definition is most accurate for the term microsatellite instability?
A. The fluctuations in orbit of small (<1m) Russian spybots.
B. Unstable protein complexes that encircle a the nucleus of a cell.
C. Changes in length of short repetitive DNA sequences in cancers.
D. The title of a Dave Mathews song that peaked at #18 in 1995.
E. The shortening of chromosomes that occurs with age.

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Question
Which definition is most accurate for the term microsatellite instability?
A. The fluctuations in orbit of small (<1m) Russian spybots.
B. Unstable protein complexes that encircle a the nucleus of a cell.
C. Changes in length of short repetitive DNA sequences in tumors.
D. The title of a Dave Mathews song that peaked at #18 in 1995.
E. The shortening of chromosomes that occurs with age.

31. HIGH YEILD FACTS: What is micro satellite instability!?
3. Then it was found that there are many smaller repetitive DNA sequences through
out the entire genome, microsatellite.
4. How are they unstable?
“Instability” refers to the change of micro satellite length in tumors. Usually
lengthening.
Big A tract 26 (BAT 26) > 29 in the tumor tissue
AAAAAAAAAAAAAAAAAAAAAAAAAAAAA
Micro satellites
length varies greatly
in the population.
CODIS uses 13
micro satellites to
develop DNA profiles
for law enforcement.
1. The very tips of chromosomes appeared to be appendenges or
satellites.
2. It was determined that these satellites were repetitive DNA.

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How does microsatellite instability happen in Lynch
syndrome?
• Mutations in 5 genes (DNA Mismatch repair) cause micro
satellite instability
• MLH1
• MSH2
• PMS2
• MSH6
• EPCAM

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We test for the presence of the Lynch syndrome
gene proteins (MLH1, MSH2, MSH6, PMS2) in
the tumor using.
(This is more widely available, faster (24 hours) and less expensive than
testing the actual DNA.)
How to test for micro satellite instability?

34. LS Dx: Staining of tumor tissue (IHC) to determine if the Lynch
syndrome Mismatch repair (MMR) genes are expressed: If the IHC
screening test staining is abnormal further workup is needed
Retained MLH1
Retained PMS2
Retained MSH2
Retained MSH6
EXAMPLE OF NORMAL STAINING

35. An example of a positive test for Lynch syndrome using
immunohistochemistry.
Retained MLH1
Retained PMS2
Retained MSH2
Loss of MSH6

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Which of the following, groups should be tested for
Lynch syndrome?
• A. Patients with colorectal cancer or endometrial cancer
under the age of 50.
• B. Patients with colorectal cancer or endometrial cancer
under the age of 60, or with a family history of colon cancer.
• C. All patients with colorectal cancer or endometrial cancer.
• D. All patients with a first degree relative with colorectal
cancer under the age of 40.
• E. All patients with a first degree relative with colorectal and
endometrial cancer under the age of 50.

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• A. Patients with colorectal cancer or endometrial cancer
under the age of 50. Testing under age 50 or 60 will
decrease sensitivity.
• B. Patients with colorectal cancer or endometrial cancer
under the age of 60, or with a family history of colon cancer.
• C.  All patients with colorectal cancer or endometrial
cancer.
• D. All patients with a first degree relative with colorectal
cancer under the age of 40. Recommend testing relative
with cancer, rather than unaffected patient.
• E. All patients with a first degree relative with colorectal and
endometrial cancer under the age of 40.

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Current standard of care is Universal Screening for
Lynch Syndrome. No need to memorize screening
criteria.
Lynch syndrome testing in the past could be costly and complex.
Many different criteria based on age, family history and other factors
were used to limit testing to those most likely to be positive. These
included Amsterdam 1, Amsterdam 2, Bethesda, and revised Bethesda
criteria.
However, the Achilles heal of all the criteria was limited sensitivity, i.e.
cases of Lynch syndrome were missed. The Bethesda criteria miss
about 12% of Lynch syndrome cases.
Identification of Lynch syndrome among patients with colorectal cancer. EPICOLON
consortium. JAMA 2012.

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Which one of the following options was developed,
but never went into production?
A. Glove box mini bar.
B. Swivel front seats.
C. “Jump seats” in the bed of a pickup truck.
D. Illuminated tires.
E. Passenger seat road flares.

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Question
A 55 year old longshoreman has moved to your area and
comes to establish care. He smokes 2 packs of cigarettes a
day and drinks 2 cans of beer a day. There is no family
history of colon or endometrial cancer. On examination,
BMI is 41 kg/m2.
He had a colonoscopy by his previous gastroenterologist
three years ago. Polyps were removed but no further details
are available. He received a letter telling him he should
have a follow up colonoscopy at this time.
Next slide show findings of the follow up colonoscopy.

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Five polyps were removed: three 2 cm polyps in the ascending colon and two 5 mm
polyps in the transverse colon. Also, a large scar with tattoo and regrowth was
noted.

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Characteristic
photomicrography of the
polyps removed.

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Question
Which is the next most appropriate recommendation for the
patient.
A. Upper endoscopy.
B. Testing polyp tissue for micro satellite instability by
immunohistochemistry.
C. Yearly colonoscopy.
D. Wireless capsule endoscopy.
E. Direct to consumer genetic testing for Lynch syndrome.

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StrategyIdentify the syndrome based
on clues in the stem. Mucus
covered right colon polyps
with “boot” pathology =
Serrated Polyposis
Syndrome
(formal criteria on following
slides)
Know next appropriate step in
diagnosis or management.
SPS patients are at risk for
fast growing interval colon
cancers.
Answer Correctly!
Yearly colonoscopy.
“Boot” shaped crypts of a sessile serrated polyp.

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Answer
Which is the next most appropriate recommendation for the
patient.
A. Upper endoscopy. SPS patients do not need to be followed
for upper GI tract cancers.
B. Testing polyp tissue for micro satellite instability.
C. Yearly colonoscopy
D. Wireless capsule endoscopy.
E. Direct to consumer genetic testing for Lynch syndrome.

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Serrated Polyposis Syndrome.
Who has it?
Part 1: What is a serrated polyp?
Any of the three types of serrated polyps qualify for
WHO criteria,
sessile serrated polyp
hyperplastic
traditional serrated adenoma.

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Serrated Polyposis Syndrome
Who has it? Part 2: Number and size. Memory Aid.
World Health Organization Has Three Criteria
5 ✕ 2 = 10
5 serrated polyps
proximal to
sigmoid
2 are
> than 10 mm
Patients close to meeting criteria on
initial colonoscopy, usually do on follow
up.
>20
More than
>20
serrated
polyps
through the
colon
1 serrated
polyp in an
individual with a
1 st degree
relative with
SPS
1/ 1st

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Q: Does Serrated Polyposis Syndrome mimic Lynch Syndrome?
Do SPS patients need to be tested for Lynch syndrome?
A: No.
Lynch syndrome does not commonly present as serrated polyposis.
LS patient DO NOT have serrated polyps more often than the general
population. LS serrated polyps.

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What causes SPS?
1.Unknown.
It is not caused by heritable traits with a strong
effect. Unlike Lynch syndrome and FAP, single gene disorders with high
penetrance.
2. Smoking.
Typically hyperplastic polyp predominant (not sessile serrated polyps)
If smoking is stopped, polyps regress.
3. Genetic traits with a weak effect.
Genetic testing is not recommended for SPS.

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What are the colonoscopy recommendations for family
members of SPS patients?
• Colonoscopy IS recommended. First degree relatives of SPS
patients should have colonoscopy at age 40 or 10 years prior to
index patient’s diagnosis of SPS.
• Only 1 in 7 first degree relatives of SPS patients will have SPS. Most
SPS patients will not have a relative with SPS. Serrated polyposis family
member reference.

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Question
Which of the following car facts is FALSE?
A. The original Honda CRV had an optional shower.
B. The MINI has an optional dashboard gauge that measures
how much time you drive with the top down.
C. Sperm whale oil was used as transmission fluid until the
passage of the Endangered Species Act of 1972.
D. One option on the original Renault Chic was a “scent
scelector” .

53. Question
• A 65 year old man comes for screening colonoscopy. He
takes no medications. He has never had surgery.
Colonoscopy found 50 adenomas through out the colon, 5
mm to 30 mm.
• His parents are both 82 and they both have had
colonoscopy within the last 5 years without polyps.
• He has six siblings. A younger sister, 53, had surgery for
colon cancer at 49 with “many polyps”, an older brother has
been told he is a “polyp farm” and has colonoscopy yearly.
• The patient has three sons, 45, 43, 40. All three have had
colonoscopy in the last 5 years for abdominal pain or
hematochezia and no polyps were found.

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What test is most likely to make the diagnosis?
A. Testing of the APC gene.
B. Wireless capsule endoscopy.
C. Testing of polyp tissue for microsatellite instability by IHC.
D. Testing of the MUTYH associated polyposis gene.
E. Thyroid ultrasound.

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Colon cancer syndromes are classified by the
number of adenomatous polyps
Number of Polyps
20 100 1000
Lynch syndrome Familial
adenomatous
Polyposis
APC gene mutation
0
Lynch Syndrome and familial adenomatous polyposis (FAP) are the most common colon
cancer syndromes. MUYTH associated polyposis is rare.
Recessive
MUTYH
associated
Polyposis

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Visual representation of family history.

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Strategy
Identify the syndrome based
on clues in the stem.
Adenomatous polyposis
#20 -100
Only sibs affected =
MUTYH associated
polyposis
Know next appropriate step in
diagnosis or management.
MUTYH genetic testing is
sensitive and specific.
Answer Correctly!
Testing of the MUTYH gene.

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Question
• 65 year old retired military engineer presents with 12 months of
gradual weight loss and watery diarrhea. He has a history of
hypertension and gout. Medications include aspirin, olmesartan, and
simvastatin.
• On examination, BMI 16.5 kg/m2. He appears chronically ill. Hair is
thinning. Heart rate is regular, there are no murmurs. Lungs are clear
to auscultation. Abdomen is soft and non tender. Some nails have
separated from nail beds.
• The patients has two brothers they are both well. Both of his parents
died over the age of 80 from dementia.
• Laboratories: Albumin 2.4.
• A photograph from a recent colonoscopy is shown on the next slide.

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Question
Which is the next most appropriate option?
A. Testing the APC gene for mutations.
B. Discontinuing olmesartan.
C. TB Quantiferion, Hepatitis serologies, and HIV test.
D. Referring the patient for colectomy.
E. Initiation of total parental nutrition.

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Strategy
Identify the syndrome based on
clues in the stem. Diarrhea
(protien losing), hair loss,
oncholysis, no family history,
inflammatory polyps =
Cronkhite Canada
syndrome
Know next appropriate step in
diagnosis or management.
Cronkhite Canada syndrome
is a rare NON GENETIC
inflammatory disorder. The
treatment is
immunosuppression with
steroids and thiopurines.
Answer Correctly!
Before initiation of
immunosuppression, patient
needs to be evaluated for
concurrent infections.

63. ©2018 MFMER | 3741122-63
Question
Which is the next most appropriate option
• A. Testing the APC gene for mutations.
• B. Discontinuing olmesartan.
• C.  TB Quantiferion, Hepatitis serologies, and stool tests.
• D. Referring the patient for colectomy.
• E. Initiation of total parental nutrition.

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Type Gene (inheritance) Onset Cancers Clinical associations
Adenomatous
FAP APC (AD) 2nd-3rd decade CRC (small
bowel/ampullary),
brain, desmoids
Gardner’s syndrome, CHRPE,
osteomas
A-FAP APC (AD) 5th-6th decade Similar to FAP
MYH MutYH (AR) 5th-6th decade CRC, duodenum,
ovaries, bladder,
thyroid, and skin
Desmoids, CHRPE, osteoma,
sebaceous
Hamartomatous
Peutz-Jeghers STK11/LKB1 (AD) 2nd-3rd decade GI lumen, pancreas,
GU (gonads, cervix),
breast, thyroid
Mucocutaneous pigmentation
Respiratory/nasal and urinary
epithelial polyps
Juvenile polyposis BMPR1A and
SMAD4 (AD)
2nd-3rd decade Colon, gastric Bleeding/obstruction
Hereditary telangiectasias
Cowden PTEN1 (AD) Young adults Breast, endometrial,
thyroid, kidney, CRC
Trichilemmomas
Oral fibromas
Palmoplantar karatoses

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Question
What is the most expensive car ever sold?

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a. 1962 Ferrari GTO
c. MB w196 Monza
b. Aston Martin DBR1
d. 1937 Bugatti Atalante

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a. 1962 Ferrari GTO – 52 mil US$
b. MB w196 Monza – $31.4 mil US$
c. Aston Martin DBR1 – 22.5 mil US$
d. Mclaren P1d. 1937 Bugatti Atalante – 40 mil US$

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• THE END
Good Luck!

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Thank you

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