Familial Polyposis and Lynch syndrome review March 2014

SCAN AND FOLLOW BARCODE TO LINK OF UPDATED PRESENTATION.

GENETIC COLON CANCER SYNDROMES:

ANSWERS TO FREQUENT QUESTIONS REGARDING FAMILIAL A. POLYPOSIS AND

LYNCH SYNDROME

DOUGLAS R IEGERT- JOHNSON, MD

MAYO CL IN IC FLORIDA

RIEGERT [email protected]

DISCLOSURES None.

OFF LABEL DRUG USE. Lovaza fish oil and celecoxib for familial adenomatous polyposis.

FAMILI

AL

ADENOMATO

US POLY

POSIS

A CL IN

ICAL D

IAG

NO

S IS

FAP TERMINOLOGY

FAP

Gardner FAP + CHRPE

aFAP <100 polyps

FAP

Gardner

aFAP

APC MUTY

H mutatio

n

Attenuated FAP (aFAP)= FAP with less than 100 adenomas in an adult. There is a tendency to rectal sparing.

Gardner sydrome = FAP or aFAP + extracolonic manifestations such as osteomas, skin cysts, extra teeth (odontogenic cysts), desmoid tumors, and congenital hypertrophy of the retinal pigmented epithelium (CHRPE).

Scenario: 18 yo with 1000 adeno. polyps and 4 generation family history of the same with osteomas, but does not have an APC mutation. Does he still have FAP? Answer: Yes!

A gene mutation is not need for the diagnosis. For many reasons, not all patients have a detectable APC or MUTYH mutation (could have polymerase proofreading associated polyposis POLE, POLD1). Patients with aFAP have a 50% chance or less of having a detectable APC mutation.

WW

W.

POLY

PPOLY

P.CO

MA WEB BASED TOOL FOR DOCUMENTING FAP PAT IENT V IS ITS .

DOES NOT STORE OR COLLECT ANY PAT IENT INFORMATION.

NO COMMERCIAL INTERESTS INVOLVED.

RECOMMEND GOOGLE CHROME AS BROWSER .

Select text from template to add to note

Review note (plan is repeated at top)

Copy to Clipboard and paste to EMR

NSGC.ORG Hyperlink

EPA FOR CHEMOPREVENTION OF POLYPS IN THE RETAINED RECTUM OF FAP PATIENTS

55 FAP patients28 EPA 1000 mg bid

27 Placebo

6 months

West N J et al. Gut 2010;59:918-925. 20348368.

West N J et al. Gut 2010;59:918-925. 20348368.

FAP CHEMOPREVENTION STUDIES MONITOR A TATTOOED SECTION OF THE RETAINED RECTUM

22 % NET REDUCTION WITH 1 GM EPA BID. TO DECREASE FROM 5 TO 4 POLYPS IN OBSERVED AREA

EPA CHEMOPREVENTION EFFECT SIMILAR TO CELECOXIB

Guidance in blue.

Spigelman score

determines EGD follow up

VIEW OF THE PAPILLA USING AN ENDOSCOPIC CAP

BIOPSY OF PAPILLA NOT REQUESTED ROUTINELY (YIELD IS LOW, RISK OF PANCREATITIS, SEE SUPPLEMENTAL SLIDES)

CAP ASSISTED ENDOSCOPY OF THE PAPILLA

Choi J et al. World J Gastroenterology 2013;19: 2037-43. 23599622.

Endoscopic transparent cap. A: Short transparent cap (Olympus distal attachment D-201-10704, outer diameter: 11.35 mm, length from distal end of endoscope: 4 mm; Olympus Tokyo, Japan); B: Long transparent cap (Olympus distal attachment MH-593, outer diameter: 12.9 mm, length from distal end of endoscope: 11 mm; Olympus);

ConventionalShort cap

Long cap

0%20%40%60%80%

100% 0.81 0.981

Percentage of patients were papilla was seen n =120

LYNCH

SYNDROM

E

HEREDITARY NON POLYPOSIS COLON CANCER WA S P R E V I O U S LY U S E D , H O W E V E R N O LO N G E R A S I T B E C A M E A P PA R E N T T H AT T H E R E W E R E C A N C E R R I S K S O U T S I D E O F T H E C O LO N ( E N D O M E T R I A L , B I L I A RY, PA N C R E AT I C , A N D O T H E R S ) F O R LY N C H S Y N D R O M E

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 infiltration.

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.

B. Tumor testing for microsatellite instability. (Senstive for LS)

C. Examination for peri oral pigmentation. (PJS)

D. Sequencing of the MSH2 gene. (Will miss MLH1 + ..)

Clues for LS

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.” (Micro satellite term replaced by short tandem repeat ,STR).

Example:

Big A tract 26 (BAT 26) AAAAAAAAAAAAAAAAAAAAAAAAAA

How are they unstable?“Instability” refers to the change of micro satillete 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 satilletes to

develop DNA profiles for

law enforcement.

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

TESTING FOR LYNCH S., OR DIAGNOSING LYNCH S. BASED ON CLINICAL CRITERIA IS INSENSITIVE (MISSES CASES).TA R G E T E D T E S T I N G

( R E V I S E D B E T H E S D A ( B E L O W )

O R A M S T E R D A M )

Test if any criteria meet,

• Diagnosed with colorectal cancer 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 first-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 MSS TUMOR TEST ING

(OR CLOSE TO IT )A) Micro satellite

instability testing on all colon cancers

OR

B) Micro satellite instability testing on most colon cancers

All CRC cases less than 70Any patient regardless of age who has any Bethesda criteria. (95% sensitive and requires 35% fewer tests) Moreira and others. JAMA 2012. 23073952

NOW

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.

THE N

EW

DEVELOPM

EN

TTH

E NEXT G

ENERAT IO

N.

NEXT GENERATION SEQUENCINGGeneric term for parallel testing of numerous genes relatively quickly and

inexpensively in panels. Current MC panel has 14 genes. Was >$14,000 -> Now $3,500 with NextGen.

APC

EPCAMMSH

6MSH

2

MLH1MUTYH

PMS2

STK11

TP53

PTEN

CDH1 SMAD4AXIN2

CHEK2

MLH3 GREM1

BMPR1A

SUMMARYFor familial polyposis,FAP is a clinical dx. Many patient will not have a APC or MUTYH mutation. Testing for new described genes not yet available (eg polymerase proofreading associated polyposis PPAP).

Consider chemoprevention with Lovaza (EPA fish oil).

Fundic gland polyps dysplasia not clinically significant.

Lower endoscopy fu for most FAP patients is q 6 months.

For Lynch syndrome,The emerging standard of care is programatic micro satellite instability testing on all or a large subset of colon caners.

The continued development and implementation of Next Generation Sequencing will make DNA diagnostics accessible (FINALLY!).

END

SUPPLE

MENTAL

IRON AND B12 DEFICIENCY COMMON IN FAP AND LS PATIENTS.About 1/3 of patients will have hypoferritinemia or

hypovitaminosis B12.

All patients have ferritin and vitamin B12 measured annually.

THYROID, ADRENAL AND DESMOID TUMORThyroidAbout 3% lifetime risk for papillary thyroid cancer.

Mostly female [89% female (96 F: 11 M)] Mostly young [mean age dx 29.2 (+/− 10.3) years.]

Seth Septer and others. Hereditary Cancer in Clin Practice 2013;11:13. 24093640.

BENEFIT AND RISK OF AMPULLARY BX

What is the reason for the biopsy?

To prevent ampullary cancer by detecting premalignant precursors.

What is the benefit?

Normal ampulla: Information yield low in normal appearing ampulla, 75% of patients have histologic ampullary adenoma .

Abnormal ampulla: Unlikely to progress. 1 of 69 patients with untreated histologically proven adenoma progressed to CA. Interval for that patient was 39 months.

What is the risk?

Pancreatitis. (St Mark’s halted routine ampullary bx in 1992.)

CONSIDER: Enlarged ampulla >10 mm refer to ERCP for evaluation for ampullary bx and or ampullary bx. (Assumption cancer risk associated with size).

Carol Burke and others. Gastrointestinal Endoscopy 1999. 10049420.T Matsumoto and others. Am J Gastroenterology 2000. 10894596.KP Nugent and others. Gut 1999. 8406166.CJ Groves and others. Gut 2002. 11950808.Bleau and others. Clinical J Gastroenterology 1996. 8724267.

RETROFLEXED VIEW OF THE ANUS IN FAP PT S/P PROCOTOCOLECTOMY/J POUCH

Subtotal Colectomy(Ileal Rectal Anastamosis,

IRA)• 3 BM/day Mean• 4% night time incontinence• 5% need a pad for continence• Laproscopic and no impact on fertility•Followup every 6 mo flexible sigmoidoscopy required. If advanced neoplasia interval decreases to every 3 months•Rectal loss rate quoted as 10%, decreasing with improved follow up.

BACKGROUND: SUBTOTAL COLECTOMY IS THE SURGICAL TREATMENT FOR MOST PATIENTS WITH FAP (80%)

A. Sinha, Britsh Journal of Surgery, 2010.

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. The patient underwent right colon resection. Pathology was reported adenocarcinoma with lymphocytic tumor infiltration.

The patient’s mother had a hysterectomy in her 50s for bleeding. Otherwise she has no history of cancer. Father (73), brother (45) and sister (41) are alive and well.

Which test is the most appropriate?

A. Sequencing and testing for large deletions of APC.

B. Tumor testing for microsatellite instability

C. Examination for peri oral pigmentation.

D. Test for the common MUTYH mutations.

Micro satellite Status of Tumor

Normal Tumor

Stable AAAA AAAA

Unstable AAAA AAAAAAA

HNPCC Tumor Tissue

MLH1 MLH1

Inactivation

MLH1

HNPCC Normal Tissues

MLH1

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

NormalTumor

Unstable micro satellite

Protein

DNA

“Downstream” MutationsMicro Satellites – small repetitive DNA sequences

Normal

MLH1MLH1

100%

50%

0%

100%

50%

0%

IHC IHCFXN FXN

100%

50%

0%

IHCFXN