Download - 2015 fellows lecture version d
2
RESOURCESAND BACKGROUND
3
Genetics = the study of single gene disorders and genetic testing the testing of single genes.
Genomics = the study of multiple genetic disorders simultaneously and the testing of multiple genes
GENOMICS VERSUS GENETICS
BRCA1
BRCA2
ATM
BARD1*MSH2*MSH6 *MLH1
PALB2
NF1
CHEK2
CDH1TP53
RAD50
*PMS2
Genetics 2 genes $4200 12 weeks
Genomics 14 genes
$2000 ($100 out of poc)
4 weeks
Lynch syndrome associatedDNA mismatch repair genes
Drag picture to placeholder or click icon to add
GENOMIC COUNSELING AS A
SPECIALTY
Under Graduate 4 years + Post Graduate 2 years
Specialty Number
Internists 189,587
Family medicine specialists 114,000
Genomic counselors 3,200
Medical geneticists 1,509 (all time)
How do I find a genomic counselor? www.nsgc.org
Collaborative Group of the Americas on Inherited Colorectal Cancer In 1995, the Collaborative Group of the Americas on Inherited
Colorectal Cancer (CGA-ICC) was established to improve understanding of the basic science of inherited colorectal cancer and the clinical management of affected families.
The CGA focuses on families with rare forms of inherited colorectal cancer: familial adenomatous polyposis (FAP), MYH-associated polyposis, Peutz- Jeghers syndrome, juvenile polyposis, other hamartomatous polyposes, serrated polyposis, and hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome.
www.polyppolyp.com - Polyposis note toolkit.
RESOURCES FOR PROVIDERS
Lynch Syndrome InternationalThe Hereditary Colon Cancer
Foundation (FAP)Peutz Jeghers Syndrome Discussion Gro
up
PATIENTS CAN FIND SUPPORT GROUPS VALUABLE
10
HEREDITARY COLON CANCER CASE
CASE FROM THE CLINIC
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 resection. Pathology was reported adenocarcinoma with lymphocytic tumor infi ltration.
The patient’s mother had a hysterectomy in her 50s for bleeding, unclear if due to endometrial cancer or not. Otherwise she has no history of cancer. Father, and a bother (45) and sister (41) are alive and well.
Which test is the most appropriate?A. Sequencing and testing for large deletions of the
APC gene.B. Tumor testing for microsatellite instability.C. Examination for peri oral pigmentation. D. Sequencing of the MSH2 gene.
CASE FROM THE CLINIC
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 resection. Pathology was reported adenocarcinoma with lymphocytic tumor infi ltration.
The patient’s mother had a hysterectomy in her 50s for bleeding. Otherwise she has no history of cancer. Father, and a bother (45) and sister (41) are alive and well.
Which test is the most appropriate?A. Sequencing and testing for large deletions of APC.
(FAP)B. Tumor testing for microsatellite instability. (Sensitive
for LS) C. Examination for peri oral pigmentation. (PJS, small
int polyp) D. Sequencing of the MSH2 gene. (Will miss mutations
in the other LS genes, MLH1, MSH6, PMS2)
Clues for Lynch syndrome
13
Hereditary non polyposis colon cancer proposed by Dr. Lynch.
HNPCC no longer as cancer risks outside of the colon are also elevated in Lynch syndrome (endometrial, biliary, pancreatic, and others)
LYNCH SYNDROMEHEREDITARY NON POLYPOSIS
COLON CANCER (HNPCC)
Q: WHY IS MICRO SATELLITE INSTABILITY IMPORTANT?
A: ALMOST ALL LYNCH SYNDROME COLON AND ENDOMETRIAL CAS DEMONSTRATE MICRO SATELLITE
INSTABILITY.
So the presence of micro satellite instability is used as a sensitive (but not specific) screen for Lynch syndrome.
Colon Cancer
Unstable 20% of CRCs
Lynch2% of CRCs
WHAT IS MICRO SATELLITE INSTABILITY!?
What is a micro satellite? Tips of chromosomes were termed “satellites” and
later determined to be repetitive DNA. Subsequently short areas of repetitive DNA found through out the genome , these were termed “micro satellites.”
Example:Big A tract 26 (BAT 26)
AAAAAAAAAAAAAAAAAAAAAAAAAA
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
How do they become unstable in LS?The genes that repair micro satellite errors are nonfunctional in LS tumor tissue. These are the DNA mismatch repair, Lynch syndrome, genes – MSH2>, MLH1> MSH6> PMS2> EPCAM. (Also known as the MMR genes. )
Micro satellites
length varies greatly in the population. CODIS uses
13 micro satellites to
develop DNA profiles for
law enforcement.
16
Direct testing on the tumor DNA can be done from paraffi n embedded tissues. This test is clinically available.
In practice, we test for the presence of the LS DNA MMR gene proteins (MLH1, MSH2, MSH6,PMS2). This is more widely available, faster (24 hours) and less expensive ($250) than direct DNA tumor testing.
TESTING FOR MICROSATELLITE INSTABILITY
LS DX: STAINING OF TUMOR TISSUE (IHC) TO DETERMINEIF 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
AN EXAMPLE OF A POSITIVE MMR-IHC LS TEST:
STAINING MLH1 AND PMS2 ABSENT. INDICATING FURTHER WORK UP POSSIBLY INCLUDING BLOOD DNA BASED TESTING OF MLH1 /
PMS2.
Loss MLH1
Loss PMS2
Retained MSH2
Retained MSH6
Colon Cancer, Second Colon Cancer, precancerous polyp
IN PATIENTS WITH LYNCH SYNDROME, MOST COMMON LOCATION OF COLORECTAL CANCER IS
IN THE ASCENDING COLON OR CECUM
Järvinen HJ, Gastroenterology 2000.
AppendixRectum
A clue for LS
Courtesy: M. Krishna
INTRA TUMORLYMPHOCYTES
1%
%Lynch
Syndrome25%
CRC 72 CRC<50 CRC<50
7%<0.2%
Mother(1st deg)
Son
50-75%
AmCriteria(3 fam mem)
PROBABILITY OF LYNCH SYNDROME RELATED TO AGE OF CANCER DX AND
FAHX
22
• Primary CRC treatment • IRA preferred for LS (from historical records there is a 1-2% chance of second colon cancer per year)
• Secondary CRC Prevention (follow up)• Yearly c-scopy for LS
• Primary Prevention of CAs other than CRC• Endometrial
• Identification of other affected family members (sons, daughters)
WHY IDENTIFY PATIENTS WITH LYNCH SYNDROME?
COLONOSCOPY IS EFFECTIVE IN DECREASING CANCER IN LYNCH SYNDROME
PATIENTS
Outcome Colonoscopy No Colonoscopy
Colon Cancer 8 (18%) 19 (41%)
Colon Cancer Deaths 0 4
Total Deaths 4 (9%) 12 (26%)
Järvinen HJ, Gastroenterology 2000.
90 Lynch syndrome patients
44 Colonoscopy (every 3 years)
46 No colonoscopy
15 years
TESTING FOR LYNCH S., OR DIAGNOSING LYNCH S. BASED ON CLINICAL CRITERIA IS
INSENSITIVE (MISSES CASES).
Targeted testing (Revised Bethesda OR
AMSTERDAM)
Test if any criteria meet, • CRC before the age of 50 years;• Colorectal cancer with
Synchronous or metachronous colorectal cancer or history of LS tumors
A high-microsatellite-instability morphology (infiltrating lymphocytes) that was diagnosed before the age of 60 years
Family history. *One or more fi rst-degree relatives with colorectal cancer or other LS tumours. One of the cancers must have been diagnosed before the age of 50 years (this includes adenoma, which must have been diagnosed before the age of 40 years); Colorectal cancer with two or more relatives with colorectal cancer or other HNPCC-related tumours, regardless of age.
Universal ( or close) TUMOR testing
A) Micro satellite instability testing on all colon cancers
ORB) Micro satellite
instability testing on most colon cancers
All CRC cases less than 70
Any patient regardless of age who has any Bethesda criteria. (95% sensitive and
requires 35% fewer tests)
Moreira and others. JAMA 2012. 23073952
NOW
SCREENING ALL COLORECTAL CANCER PATIENTS FOR LS BY IHC HAS A YIELD
OF AT LEAST 2%
Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). An additional 52 family members with Lynch syndrome were identified. Therefore, 14 patients were tested for each LS case identified.
Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer.
Hampel, NEJM 2008
Mutation in the Lynch syndrome PMS2 gene (p.G559X)
Colon cancer age 59 yo
Died 86 2nd colon cancer immediately
after patient dx.
Colon cancer found to be micro satellite unstable
(lacking PMS2 gene)
THE NEW PARADIGM: PROGRAMATIC SCREENING OF ALL COLON CANCERS FOR LYNCH SYNDROME EX.
PATIENTS WITH LYNCH SYNDROME WHO HAVE COLONOSCOPIES LIVE LONGER
Outcome Colonoscopy No Colonoscopy
Colon Cancer 8 (18%) 19 (41%)
Colon Cancer Deaths 0 4
Total Deaths 4 (9%) 12 (26%)
Järvinen HJ, Gastroenterology 2000.
90 Lynch syndrome patients
44 Colonoscopy (every 3 years)
46 No colonoscopy
15 years
COLONOSCOPY FOR LYNCH SYNDROME: MISSED DEADLINES
Link to Canadian study of colonoscopy in patients with Lynch syndrome (MSH2)
68 Women with Lynch syndrome (MSH2) Colonoscopy 1-2 years
28 Colonoscopy on schedule
14% Colon CA
Age at Colon Cancer diagnosis
79 years
Median survival 80 years
40 Colonoscopy not on schedule
17% Colon CA
Age at Colon cancer diagnosis 57 years
Median survival 63 years
MISSED DEADLINES : 5 COLON CANCER > 2YR FOLLOW UP FAST GROWING: 4 COLON CANCERS IN THE 1 TO 2 YEAR INTERVAL.
M ISSED POLYPS? : 2 COLON CANCERS IN THE 1 YEAR INTERVAL . ? M ISSED RAP ID OR RAP ID GROWTH
0
1
2
3
4
5
6
7
A B C D E F G H I J K
Interval between last colonoscopy and 11 colon cancer diagnoses (years) for female patients
CASE
A 52 year old woman presented with hematochezia. She had no personal or family history of cancer. A colonoscopy 2 years ago was performed for colon cancer prevention. The preparation was good. A 4 mm tubular adenoma in the transverse colon, a 10 mm hyperplastic polyp in the ascending colon and an 5 mm hyperplastic polyp were all removed.
A second colonoscopy found a rectal mass, biopsied and found to be adenocarcinoma. The results of third colonoscopy performed with chromoendoscopy are on the next slide (2gm indigo carmine in 500 mL NS).
CASE
Mismatch repair gene immunohistochemistry showed loss of PMS2. MLH1, MSH2 and MSH6 were all present.
Germline testing identified a known disease causing mutation in PMS2.
Some interval colon cancers will be explained by Lynch syndrome.
FOLLOW UP.
Loss PMS2
34
Studies suffer fromSmall numbersFew operatorsWhite light then chromoendoscopy design, so are you testing a second examination or the chromoendoscopy?
Also withdrawal time much longer from chromoendoscopy, 10 vs 20 min, so are just testing a longer withdrawal time.
CHROMOENDOSCOPY FOR LYNCH SYNDROME? DATA QUALITY IS POOR.
American J of Gastroenterology 2015. 10 French centers.
“The percentage of patients in whom at least one additional adenoma was detected during the chromoscopy was 31% (24/78).”
+Indigo carmine chromoendoscopy 45 year old female Lynch
syndrome patient (MLH1): Ascending colon polyp before injection with saline.
+Indigo carmine chromoendoscopy 45 year old female Lynch
syndrome patient (MLH1): Ascending colon polyp after injection with saline.
38
LS is a hereditary colorectal, endometrial and other cancer syndrome caused by mutation in the DNA MMR genes.
First line for testing is mismatch repair gene immunohistochemistry. MMR IHC.
Universal screening for Lynch syndrome is now recommended by NCCN.
Amsterdam criteria are not sensitive or specific for Lynch syndrome
Yearly colonoscopy (?with chromoendoscopy) is recommended.
LYNCH SYNDROME SUMMARY
39
CASE
A 45 year-old man presented for medical genetics evaluation. Between the ages of 20 and 30 years, the patient had nasal polyps and several large stalked colon polyps removed. At 43 years-old, he was diagnosed with jejunal adenocarcinoma (T1N0).
Upper endoscopy following surgery showed several stomach and small bowel polyps. A genetic test for familial adenomatosis polyposis (APC gene) was negative. There was no family history of cancer.
CASE
RRIR
Arborizing smooth muscle in an intestinal polyp is almost pathognomic for PJS. Often missed in pathology!
Melanotic macules often fade and the last place they can be seen in the buccal mucosa.
Nasal Polyposis as a feature of PJS Originally published in Dutch as: Peutz J. “Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane.” Nederl Maandschr Geneesk. 1921; 10:134-146.
MELANOTIC MACULES FADE
Originally published in Dutch as: Peutz J. Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. Nederl Maandschr Geneesk. 1921; 10:134-146.
Peutz-Jeghers syndrome is associated with melanotic macules, polyps and cancer
Died age 20 Intussusception
Connor. Archives of Surgery (London 7:290,1896).
Died age 50Breast Cancer
PEUTZ-JEGHERS
90% Adenocarcinoma / 90% Intussception Cancer surveillance tests 5 slides
SESSILE SERRATED POLYPOSIS
Douglas Riegert- Johnson, MDMayo Clinic FloridaGastroenterology and Genetics
Open access other slide sets on slideshare.net
Hyperlink
THERE ARE THREE TYPES OF SERRATED POLYPS
Classification is a relatively recent construct.HyperplasticSessile serrated adenoma/polyp (1996)
SS adenoma = SS adenoma/polypTraditional serrated adenoma (1990)
Serrated polyposis syndrome to be discussed at end of talk (WHO criteria 2000)
Burt R, Jass JR. Hyperplastic polyposis. In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System. Vol 2. Lyon, France: IARC; 2000:35–136.
292; 72%
112; 28%
Adenomas Serrated polyps
Complete Adenoma Resection Study (CARE): Gastroenterology 2013
64; 57%
6; 5%
42; 38%
Hyperplastic
Traditional serrated ade-nomaSessile serrated adenoma/polyp
About 3 in 10 polyps are serrated polyps, about 1 in 10 are sessile
serrated adenomas
Hyperplastic polyp Sessile Serrated Adenoma
“The boot”Must have at least one
horizontally branched crypt
Traditional Serrated Adenoma
Lifetime odds of
colorectal cancer
diagnosis
Postulated lower limit (1/400 individuals have a hereditary syndrome pre disposing to rapid polyp growth eg Lynch
syndrome)
1/400
1/10
1/166
Lifetime risk with no screening
Lifetime risk for patients in colonoscopy program
All odds are approximation
WHY ARE SSAS IMPORTANT?PLUMBING THE DEPTHS OF
COLORECTAL CANCER PREVENTION
Not seen lesionsOther lesionsIncompletely resection
SSA
Risk Stratification
NOT SEEN (AND NOT CLASSIFIED) LESIONS:
THE PROPORTION OF COLOSCOPIES WITH SESSILE SERRATED ADENOMAS VARIES
BASED ON CENTER (COLONOSCOPIST AND PATHOLOGIST).
2014 USA Septin 9 trial data on SAs per center
Mean % of colonoscopies with
SSAPs = 2.8%Range (0-9.8%)
WHO CRITERIA FOR SERRATED POLYPOSIS SYNDROME
* ANY TYPE OF SERRATED POLYP.
WHO Criterion 1. At least 5 serrated polyps proximal to the sigmoid colon, of which 2 measure at least 10 mm in diameter). 5 × 2 = 10.
WHO Criterion 2. Any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with SPS.
*WHO Criterion 3. >20 serrated polyps spread throughout the colon. * About 80% of patients meet this criterion.
SERRATED POLYPOSIS IS UNCOMMON (BUT NOT RARE) AND REQUIRES YEARLY FOLLOW UP
1:151 – 1:294 of patients in FIT based colorectal cancer prevention programs.
1-year surveillance interval for these patients recommended by US Multi-Society Task Force on Colorectal Cancer and the European Society of Gastrointestinal Endoscopy.
Serrated lesions: Recommendations from an expert panel.
FOR SERRATED POLYPOSIS, COLONOSCOPY OF FAMILY MEMBERS HAS HIGH YIELD BUT GENETIC TESTING
OF PATIENTS HAS A LOW YIELD
First degree relatives of SPS should have colonoscopy at age 40 or 10 years prior to proband’s diagnosis of SPS
(4/10 significant polyp, 1/7 will have serrated polyposis Reference).
Genetic evaluation recommended by the European guidelines. Yield is low. DRJ “less than 5%”. Genetic DDX includes
Lynch syndrome (mutation in the DNA mismatch repair genes) MYH associated polyposis (MAP) Mutations in the RNAF4 gene.
Patients can be referred to a genetic counselor using an online database (www.nsgc.org)
SUMMARY
SSAs represent 1 in 10 colon polyps, and have a “boot” histopathology.
Interval colon cancers are rare, SSAs may be canary signal to the causative missed lesions, new lesions, and incomplete polypectomies.
Evidence suggests that SSA themselves may not play a direct role in colorectal cancer.
Current recommendations for SSA surveillance are consensus only and similar to those for adenomas Piecemeal follow up 3 to 6 months SSA more than 10 mm in size, follow up in 3 years
Sessile serrated polyposis syndrome requires yearly follow up colonoscopy and colonoscopy is recommended for family members.
THE END
ADDENDUM
Neoplastic polyps, n (%) 346 (82.8)
Adenomas 292 (69.9)
Tubular adenomas 260 (62.2)
Tubulovillous adenomas 21 (5.0) Villous adenomas 5 (1.2) Traditional serrated adenomas 6 (1.4)
Sessile serrated adenomas/polyps 42 (10.1)
Cancer 1 (0.2)
Hyperplastic polyps 64 (15.3)
Complete Adenoma Resection Study (CARE): Gastroenterology 2013
HYPERPLASTIC POLYP FOLLOW UP
Lesion Size Number Location Follow up
HP <10 mm Any numberb Rectosigmoid 10c
HP ≤5 mm ≤3 Proximal to sigmoid 10
HP Any ≥4 Proximal to sigmoid 5
HP >5 mm ≥1 Proximal to sigmoid 5
4 years old. Alive and well.
28 years oldAlive and well
48 years oldThyroid disease
50 years oldAlive and well
25 yo dx with transverse CRC.
25 tubular adenomas in left colon (right colon not seen due to obstruction).A few stomach polyps. At 22 yo dx left temporal lobe glioblastoma.“Freckles in Eye”.
CASE
4 years old. Alive and well.
28 years oldAlive and well
48 years oldThyroid disease
50 years oldAlive and well
25 yo dx with transverse CRC, 25 tubular adenomas in left colon (right colon not seen due to obstruction)A few stomach polyps. At 22 yo dx left temporal lobe glioblastoma.“Freckles in Eye”.DX: ? FAP NEW MUTATION TURCOT
FAP + brain tumor (usually meduloblastoma) = Turcot syndrome
LS + brain tumor (usually glioblastoma) = Turcot syndrome
TERM “TURCOT SYNDROME” AS CURRENTLY USED
Numerous CAL macules
PHYSICAL EXAMINATION
4 years old. Alive and well.
28 years oldAlive and well
48 years oldThyroid disease
50 years oldAlive and well
PMS2 gene mutation (Pro246Cysfsx3)
PMS2 gene mutation (Ile611Asnfsx3)
PMS2 gene wildtype(normal)
25 yo dx with
transverse CRC.
or
GENETIC TEST RESULTS: “DOUBLE LYNCH” ONE LYNCH SYNDROME
MUTATION FROM EACH PARENT
First described in 1999 in two simultaneously publishedreports (Ricciardone et al. 1999; Wang et al. 1999)
Synonyms.Childhood cancer syndrome (CCS)
Lynch III syndrome ‘‘CoLoN’’, Colon tumours or/and Leukaemia/Lymphoma
CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY“DOUBLE LYNCH”
Constitutional mismatch repair-deficiency syndrome:have we so far seen only the tip of an iceberg?
All CMMRD patients with available clinical data (n = 18) had café-au-lait spots (>6 spots) and three patients had hypopigmentation. Three individuals had axil lary freckles, and one had a plexiform neurofi broma; meeting the criteria for NF-1, but lacked germline NF-1 mutations.
CMMR OVERLAPS WITH NF1: CASE 2 WITH 50 CALM.
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium.. 24440087.
Cancer Number Median age (range) of diagnosis
Hematological 30 6 (0.4-17)
Brain tumor 44 8 (2-35)
Colorectal cancer
37 16 (8-35)
Small bowel 9 26 (11-42)
TUMOR SPECTRUM OF CMMRD IN 92 PATIENTS
2010 CMMRD Review of 92 patients.
SUPPLEMENTAL SLIDES
Described in 1959 by Jacques Turcot in Diseases of the Colon and Rectum
Hôtel Dieu de Quebec hospital (1640) and the Laval University2 teenage siblings with numerous colorectal polyps. The brother (15 years old) with meduloblastoma of the spinal cord and adenocarcinomas of the sigmoid colon and rectum. The sister (13 years old) with cerebral glioblastoma and pituitary adenoma.Mckusick and Osler communicated that parents were third cousins.
“Every case of familial polyposis should be followed and explored, not only looking for new occurrences of polyps in the colon and rectum, when they are not removed by also for the appearance of other tissue tumors elsewhere in the body.”
Colon Cancer, Second Colon Cancer, precancerous polyp
IN PATIENTS WITH LYNCH SYNDROME THE PREDOMINANCE OF COLON POLYPS AND
CANCERS ARE LOCATED IN THE RIGHT COLON.
Järvinen HJ, Gastroenterology 2000.
Appendix
Rectum
Cancer Surveillance strategy
Children
Colon Colonoscopy annuallya
Upper GI tract and small bowel
EGD annuallya, video capsule endoscopy annuallya
Brainb Ultrasound at birth then MRI brain every 6 months
Leukemiab, Lymphomab Complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase every 4 months
Adults
Colon Colonoscopy annuallya
Upper GI tract and small bowel
EGD annuallya, video capsule endoscopy annuallya
Brainb Ultrasound at birth then MRI brain every 6 months
Leukemiab, Lymphomab Complete blood count, erythrocyte sedimentation rate, lactate dehydrogenase every 4 months
Uterus Ultrasound annually
Upper urinary tract Ultrasound and urine cytology annually
Surveil lance protocol for patient with for Bial lel ic MMR mutations.
EGD-esophagogastroduodenoscopy. a To start at 3 years of age or at diagnosis;
b Brain, leukemia/lymphoma screening should commence at birth if diagnosed prenatally.
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium. 24440087.
PMS2 dominates, followed by MSH6 and MLH1.“MSH2 mutations which are most commonly found
in Lynch syndrome are less common to absent in CMMRD, while PMS2 and MSH6 are more commonly observed in the syndrome. A possible explanation for this phenomenon is low penetrance of heterozygous mutations in MSH6 and PMS2 found in CMMRD and the deleterious functional consequence of homozygous mutations. Highly penetrant mutations in MSH2, may be embryonically lethal when homozygous leading to the lower prevalence observed in CMMRD.”
CMMRD MUTATION SPECTRUM
There were several cafr-au-lait spots on theskin of the chest, back, abdomen, and extremities,but there were no nodules on the body surface.
H Itoh and others, Gut 1979. Kyushu University Faculty of Medicine, Fukuoka, Japan.“There were several cafe-au-lait spots on theskin of the chest, back, abdomen, and extremities, but there were no nodules on the body surface.”
Proband. 13 yo from Brazil. Youngest in a family of 7 children.
No gastric or extracolonic features
of FAP.
Compared with familial polyposis coli, colonic polyps in Turcot’s syndrome are fewer in number and larger in size.
(1)In Turcot's syndrome the manifestations of brain tumour and colonic polyposis are signifi cantly associated and are not merely coincidental, although the association of brain tumour is only incidental in the few cases of famil ial polyposis coli .
(2)Moreover, an autosomal recessive mode of transmission is most l ikely in this syndrome.
(3)The number of colonic polyps in Turcot's syndrome was frequently less than 100, in contrast with the study of Bussey (1975) who noted that the average number of polyps in famil ial polyposis coli was about 1000 and rarely less than 200. The analysis of macroscopic fi ndings of colonic polyps showed that they were fewer in number and larger in size in Turcot's syndrome compared with famil ial polyposis coli .
(4)Therefore, we present the hypothesis that Turcot's syndrome is genetical ly dist inct from famil ial polyposis col i .
FEATURES OF TURCOT BY ITOH AND OTHERS
Turcot syndrome and its characteristic colonic manifestations.Itoh H, Ohsato K. Dis Colon Rectum. 1985 Jun;28(6):399-402.
DIFFERENCES IN TUMOR SPECTRUM BASED ON GENOTYPE IN CMMRD
PMS2/MSH6>
MLH1/MSH2
n 65 24
Median age of dx 9 years 4 years
Hematological (#1 Non Hodgkins Lymphoma Tcell)
29% 46%
Brain 35% 8%
Lynch syndrome cancer(colon, endometrial)
68% 29%
Described in 1959 by Jacques Turcot in Diseases of the Colon and Rectum Hôtel Dieu de Quebec hospital (1640) and the Laval
University 2 teenage siblings with numerous colorectal polyps. The
brother (15 years old) with meduloblastoma of the spinal cord and adenocarcinomas of the sigmoid colon and rectum. The sister (13 years old) with cerebral glioblastoma and pituitary adenoma.
Mckusick and Osler communicated that parents were third cousins.
Crail Syndrome case report (1949) Adenomatous polyposis, mebullastoma of the brain stem,
and papillary thyroid cancer.
TURCOT SYNDROME
New England Journal Medicine article describing molecular phenotype.Turcot original report 1959. 13839882.
Normal Staining of PMS2 in tumor.Both copies of PMS2 present.
Lynch syndrome. No staining in tumor. (Both copies of PMS2 inactivated, one inherited, one acquired in tumor) Staining
in tumor lymphocytes and normal tissue.
Patient Results: Constitutional mismatch repair deficiency. No staining in tumor and normal tissue.
(Both copies of PMS2 inactivated in tumor and normal by inherited mutations.)
DNA measurements of microsatellite instability based on comparing normal and tumor tissue MS. In LS, the tumor MS change, so a difference can be seen. (I think) in CMMRD normal and tumor both change so no difference can be seen.
Only one out of the 14 brain tumours
exhibited an MSI-high genotype.
MICRO SATELLITE INSTABILITY UNRELIABLE IN CMMRD
Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium. 24440087.
87
SSAS
TRADITIONAL SERRATED ADENOMA SHOULD BE RENAMED AS CONFUSED WITH SSA
Much higher rate of high grade dysplasia or carcinoma compared to SSA. About 1 in 5 associated with advanced neoplasia (19%).
Are rare, large (mean size 16 mm)
mostly located in the sigmoid or rectum (71%) in older men and women (mean age 64 with equal male to female ratio).
A clinicopathological and molecular analysis of 200 traditional serrated adenomas.
THE GOOD NEWS: SUSTAINED AND NOTABLE DOWNWARD TREND IN
COLON CANCER AND DEATHS FROM COLON CANCER ( P E R 1 0 0 , 0 0 0 )
1975
1977
1979
1981
1983
1985
1987
1989
1991
1993
1995
1997
1999
2001
2003
2005
2007
2009
2011
0
10
20
30
40
50
60
70
Number of new cases Number of deaths
CASE
91
60 year old man with juvenile polyposis and family history of the same presents for endoscopy.
CASE
92
94
ARE THERE ANY ENDOSCOPIC
OPTIONS FOR THE ADVANCED JP
STOAMCH?
95
JP is caused by mutations in the SMAD4 and BMPR1A genes. Patients with mutations in the last portion SMAD4 have HHT features as well.
JP OVERLAP WITH HHT
96
97
33 year old man with juvenile polyposis and family history of the same presents for endoscopy.
CASE
98
How many polyps is too many?
“Approx 25 6 to 15 mm polyps in the ascending colon and in the cecum. Resected and retrieved.”
Colon
HOW MANY POLYPS UNTIL SURGERY?
99
AGITATED SALINE INJECTION INTO A PERIPHERAL VEIN WILL NORMALY ONLY BE SEEN IN RIGHT HEART UNLESS THERE IS A
SHUNT
Right Atrium
Small pulmonary AVMs in a patient with JP/HHT (SMAD4 mutation)
CASE