Mary McCullum RN MSN CONC Nurse Educator Hereditary Cancer Program BC Cancer Agency September 22 2017 Objectives Identify hereditary polyposis syndromes Review hereditary cancerpolyposis referral process ID: 909116
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Slide1
Hereditary Polyposis:When do polyps run in the family?
Mary McCullum, RN, MSN, CON(C)Nurse Educator, Hereditary Cancer ProgramBC Cancer AgencySeptember 22, 2017
Slide2ObjectivesIdentify hereditary polyposis syndromes
Review hereditary cancer/polyposis referral processDescribe some implications of hereditary polyposis genetic testing
Slide3Slide4Sporadic, Familial & Hereditary Cancer
60-75%20-25%5-10%
Slide5Adapted from Burt RW, Peterson GM.
Prevention and Early Detection of Colorectal Cancer: WB Saunders; 1996: 171-194.
Slide6When to consider hereditary cancer?
Family history may include: Same cancer, 2 or more close relatives (same side of family)
Multiple generations affected
Earlier age at diagnosis
Multiple primary
tumours
Rare cancers
Constellation of
tumours
consistent with specific cancer syndrome (e.g. colorectal and endometrial; breast and ovarian;
polyposis
)
Personal
history:
Pathology
featuresSee specific syndromes
Slide7Lynch Syndrome (MLH1, MSH2, MSH6, PMS1, EPCAM)
Hereditary Breast/Ovarian Cancer Syndrome (BRCA1, BRCA2, others)less common: Familial
adenomatous polyposis (
APC
) and other
polyposis
syndromes
Hereditary diffuse gastric cancer (
CDH1
)
Li
Fraumeni
Syndrome (
p53
)Cowden syndrome (PTEN)Hereditary paraganglioma/pheochromocytoma (
SDHB, SDHC,
SDHD, others)von Hippel LindauMultiple endocrine neoplasia – type 1 and 2 And others …
Hereditary Cancer Syndromes (
genes
)
Slide81. Hereditary Polyposis Syndromes
Slide9Majority
of colorectal cancers evolve from adenomatous polypsBUT:
not
all adenomas develop into
cancer
not
all polyps are adenomas
Colorectal carcinogenesis
Slide10High Risk PolypsVillous featuresHigh grade dysplasiaSize > 10 mm (at time of excision)
Sessile serrated adenoma/polyps > 10 mm or with cytologic dysplasiaTraditional serrated adenoma3 or more low risk polypshttp://www.bccancer.bc.ca/screening/Documents/COLON_GuidelinesManual-PathologyStandardsBooklet.pdf
Slide11“Other” polypshyperplastichamartomaJuvenile (retention) polypPeutz-Jeghers
polypinflammatorymesenchymallipoma, leiomyoma, ganglioneuroma, GIST, etc.neuroendocrine tumourmixedother
Slide12>10 adenomatous polyps
are seen in colon
< 5 adenomas
Hamartomatous polyps
FAP:
Familial Adenomatous Polyposis
MAP:
MUTYH-Associated Polyposis
Peutz-Jegher’s (PJS)
Juvenile Polyposis (JP)
PTEN syndrome (CS)
Lynch Syndrome
(H
NP
CC)
Hereditary CRC syndromes
12
Slide13Slide14Adenomatous polyps
Hamartomatous polyps
Serrated polyps
FAP/AFAP
MAP
Peutz-Jeghers
(PJS
)
Hereditary
Polyposis/Colorectal Cancer
S
yndromes
Tubular
adenoma
Tubulovillous
adenoma
Villous
adenoma
Traditional Serrated Adenoma
Hyperplastic
Sessile Serrated Adenoma
Hereditary
Sporadic
POLE
POLD1
Lynch syndrome
Juvenile
Polyposis (JP
)
PTEN
syndrome (CS)
inflammatory
Hereditary Mixed Polyposis (HMPS)
*lots of diff types (juvenile, PJ polyp)
ganglioneuroma
Serrated
Polyposis
(SP)
Slide15Adenomatous polyps
Hamartomatous polyps
Serrated polyps
FAP/AFAP
MAP
Peutz-Jeghers
(PJS
)
Hereditary
Polyposis/Colorectal Cancer
S
yndromes
Tubular
adenoma
Tubulovillous
adenoma
Villous
adenoma
Traditional Serrated Adenoma
Hyperplastic
Sessile Serrated Adenoma
Hereditary
Sporadic
POLE
POLD1
Lynch syndrome
Juvenile
Polyposis (JP
)
PTEN
syndrome (CS)
inflammatory
Hereditary Mixed Polyposis (HMPS)
*lots of diff types (juvenile, PJ polyp)
ganglioneuroma
Serrated
Polyposis
(SP)
Slide16Familial Adenomatous Polyposis (FAP/AFAP)Autosomal dominantMost common polyposis syndrome (1/8000
)Accounts for < 1% of all CRCConsider if: >10 synchronous adenomas or > 15 non-synchronous adenomasGermline mutation in APC gene (30% de novo) Clinical diagnosis: early onset of 100+ polyps, other clinical features (desmoid tumours, CHRPE)
Lifetime cancer risk almost 100% by age 50
Risk of other
cancers – upper GI, brain, thyroid
Slide17MUTYH-Associated Polyposis (MAP)Autosomal recessiveConsider if polyposis seen only in siblings
Implications of “carrier” statusUsually < 100 adenomas, later onset than FAPMay also see hyperplastic polyps, SSPs, TSAsIncreased risk for duodenal cancer as well as colorectal cancer
Slide18FAP/AFAP vs MAP
# AdenomasAPC mutationMUTYH mutation> 1000
80%
2%
100-999
56%
7%
20-99
10%
7%
10-19
5%
4%
Grover et al., JAMA 2012; 308: 485-492
Slide19POLE/POLD1Autosomal dominantAssociated with oligopolyposis (5-20 adenomas) and colorectal cancer or
endometrial cancer (POLD1)Frequency of germline mutations is uncertainIdentified in some patients after other genes excluded (e.g. APC, MUTYH, Lynch)
Slide20Adenomatous polyps
Hamartomatous polyps
Serrated polyps
FAP/AFAP
MAP
Peutz-Jeghers
(PJS
)
Hereditary
Polyposis/Colorectal Cancer
S
yndromes
Tubular
adenoma
Tubulovillous
adenoma
Villous
adenoma
Traditional Serrated Adenoma
Hyperplastic
Sessile Serrated Adenoma
Hereditary
Sporadic
POLE
POLD1
Lynch syndrome
Juvenile
Polyposis (JP
)
PTEN
syndrome (CS)
inflammatory
Hereditary Mixed Polyposis (HMPS)
*lots of diff types (juvenile, PJ polyp)
ganglioneuroma
Serrated
Polyposis
(SP)
Slide21Serrated Polyposis SyndromePreviously known as Hyperplastic PolyposisClinical diagnosis (WHO criteria):
> 5 serrated polyps proximal to sigmoid colon, at least 2 > 10 mm> 1 serrated polyp proximal to sigmoid colon + first degree relative with SPS> 20 serrated polyps throughout the colonNo gene identified to dateSerrated polyps can be see with MAP
Slide22Adenomatous polyps
Hamartomatous polyps
Serrated polyps
FAP/AFAP
MAP
Peutz-Jeghers
(PJS
)
Hereditary
Polyposis/Colorectal Cancer
S
yndromes
Tubular
adenoma
Tubulovillous
adenoma
Villous
adenoma
Traditional Serrated Adenoma
Hyperplastic
Sessile Serrated Adenoma
Hereditary
Sporadic
POLE
POLD1
Lynch syndrome
Juvenile
Polyposis (JP
)
PTEN
syndrome (CS)
inflammatory
Hereditary Mixed Polyposis (HMPS)
*lots of diff types (juvenile, PJ polyp)
ganglioneuroma
Serrated
Polyposis
(SP)
Slide23Peutz-Jeghers SyndromeAutosomal dominantClinical diagnosis = at least 2 of: >
2 PJS-polyps of small intestine Characteristic (blue/black) pigmentation of perioral and perianal areas, fingers/toesFamily history of PJSSTK11 (LKB1) gene mutation in about 50%Increased risk for CRC, breast, pancreas, ovary, gallbladder
Slide24Juvenile Polyposis SyndromeAutosomal dominantClinical diagnosis:> 3-5 juvenile polyps in colon ORMultiple
juvenile polyps thru GI tract OR> 1 polyp + family history of JPSMutation in BMPR1A or SMAD4 genesIncreased cancer risks: colon, upper GI, pancreas
Slide25Cowden Syndrome (PTEN Hamartoma Tumour Syndrome)Autosomal dominant
Germline PTEN gene mutation Clinical features include: Hamartomatous GI polyps MacrocephalySpecific mucocutaneous lesions Breast, thyroid, endometrial, renal cell cancersPTEN mutation probability risk calculator http
://www.lerner.ccf.org/gmi/ccscore
/
Slide26Hereditary Mixed Polyposis Syndrome (HMPS)
No clinical criteria -
polyps
with multiple and mixed morphologies:
adenoma
atypical
juvenile
hyperplastic/serrated
inflammatory
Genes:
GREM1
and
BMPR1A
emerging data
Colon cancer risk not defined
Slide27Adenomatous polyps
Hamartomatous polyps
Serrated polyps
FAP/AFAP
MAP
Peutz-Jeghers
(PJS
)
Hereditary
Polyposis/Colorectal Cancer
S
yndromes
Tubular
adenoma
Tubulovillous
adenoma
Villous
adenoma
Traditional Serrated Adenoma
Hyperplastic
Sessile Serrated Adenoma
Hereditary
Sporadic
POLE
POLD1
Lynch syndrome
Juvenile
Polyposis (JP
)
PTEN
syndrome (CS)
inflammatory
Hereditary Mixed Polyposis (HMPS)
*lots of diff types (juvenile, PJ polyp)
ganglioneuroma
Serrated
Polyposis
(SP)
Slide282. Hereditary Cancer/Polyposis Referrals
Slide29Permanent Clinics
Vancouver Abbotsford
Outreach Clinics
Vancouver Island
Surrey
Videoconference/
Telehealth
most BC/Yukon communities
Hereditary Cancer Program
BC Cancer Agency
Provincial Clinical Service
Slide30Hereditary Cancer AssessmentReduce the morbidity & mortality from hereditary cancer syndromesIdentify people with hereditary cancer syndromes
Provide risk management adviceAssist with cancer treatment decisionsIdentify resources and supports
Slide31Slide32Referral ProcessReferral form/Criteriawww.bccancer.bc.ca/screening/health-professionals/hereditary
Medical records to providePathology reportsOperative reportsConsult lettersWhat to expectpatient provider
Slide33Personal
medical history & review of family history
Education
Review of genes, chromosomes & inheritance
Discussion of sporadic, familial, hereditary cancer
Empiric risk and likelihood of specific cancer syndrome
Associated cancer probabilities
Strategies for cancer screening & risk reduction
Genetic testing
Eligibility, potential harms & benefits, limitations
Psychosocial issues, resources
Communication with family
members
Documentation to referring provider and patient
Cancer Genetic
Counselling
Session
Slide34Genetic Non-Discrimination Actbecame Canadian law in May 2017 illegal to require disclosure of genetic test results or uptake of genetic testing as condition of a contractprotections added to:
Canadian Human Rights Act Canada Federal Labour Code
Slide35Current waiting listUp to 12-18 months for regular 1
st GC apptApprox 3 months to discuss carrier testingExpedited appointments as needed for medical urgency
Strategies to address waiting list
Timeline for appointments (BC)
Slide363. Implications of Genetic Testing
Slide37Germline Genetic TestingIndex test:
1st genetic test in familytrying to identify a specific gene mutationusually affected individual (relevant cancer dx)usually blood test; sometimes begin with tumour tissue
Carrier
(
cascade)
test
:
f
or specific mutation known in the family
Slide38Why consider genetic testing? Confirm clinical diagnosis for patientInform clinical managementOffer carrier testing to family membersClarify clinical management
Children Adults
Slide39Potential Harms/Limitationsimpact on family dynamics/relationshipsincreased cancer worry – self, others
privacy concerns – family pressure “survivor guilt”false sense of security uncertain significance of some results
Slide40Stomach
Problems
d. 60
d.85
d. 20s
during
childbirth
d.45
Colon cancer
d.75
Colon removed
in 20s
100s of adenomatous
colon polyps at
age 25
Case #1
Slide4116 tubular adenomas
APC
Slide4265-75%
10-15%
15-20%
What are the possible index results?
Slide43APC+ Clinical ManagementAnnual colonoscopy after polyps detected (until colectomy)Upper endoscopy at age 25 and every 1-3 years depending on results
Annual physical exam (abdomen, thyroid)
Slide44Genetic testing for children?Usual approach is to offer only if: Genetic test result can be adequately interpretedChildhood onset of diseaseEffective
interventionsRelevant for: APC, JPS (SMAD4), others
Slide45APC and childrensignificant risk for hepatoblastoma
consider physical exam, abdominal ultrasound and AFP q3-6 months until age 5flexible sigmoidoscopy or colonoscopy every 1-2 years starting at age 10-12
Slide46Additional genetic testing? If initial (single gene) test does not identify a mutation: sporadic?“familial“?
missed mutation?
Slide47Shift from testing single gene(s) to multi-gene panels
Current approach to genetic testing
Slide4848
Benefits
Increased
mutation detection
rate (comprehensive test)
Cost-effective
Less testing fatigue
“Unexpected” findings
Multi Gene Panels
Drawbacks
Information overload
Uncertainty if poorly understood genes are
analyzed
VUS rate
“Unexpected” findings
Slide49BCCA Hereditary Cancer (17) Gene Panel
Gene(s)
Syndrome
BRCA1, BRCA2
Hereditary breast and ovarian cancer syndrome
PALB2
Hereditary breast and pancreatic cancer
TP53
Li Fraumeni syndrome
PTEN
PTEN Hamartoma Tumour (Cowden) syndrome
CDH1
Hereditary diffuse gastric and lobular breast cancer
MLH1, MSH2, MSH6, PMS2
Lynch syndrome
MUTYH
MutYH-associated Polyposis (MAP)
APC
Familial Adenomatous Polyposis (FAP)
POLE
Hereditary colorectal cancer and colonic polyposis
POLD1
Hereditary colorectal & uterine cancer; colonic polyposis
STK11
Peutz-Jeghers syndrome
SMAD4, BMPR1A
Juvenile polyposis syndrome
Slide50SporadicFamilial
Missed a mutation
APC
BMPR1A
CDH1
CHEK2
EPCAM
MLH1
MSH2
MSH6
MUTYH
PMS2
POLD1
POLE
PTEN
SMAD4STK11ATM AXIN1BARD1BRCA1BRCA2BRIP1CDK4CDKN2A
FANCC
NBNPALB2RAD51CRAD51DSCG5/GREM1TP53VHLXRCC2
Slide51More = Better?
Slide52Case #2
46 year old woman referred by GP with a copy of pathology report confirming 1 hamartomatous polyp with “Peutz–Jeghers features”
Referral notes some family history of breast and colon cancers
Slide53Peutz-Jeghers SyndromeAutosomal dominantClinical diagnosis = at least 2 of: >
2 PJS-polyps of small intestine Mucocutaneous pigmentation of mouth, lips, nose, eyes, genitalia, fingers/toesFamily history of PJSSTK11 (LKB1) gene mutation in about 50%Increased risk for CRC, breast, pancreas, ovary, gallbladder
Slide54Case #2
Slide55Cowden Syndrome (PTEN Hamartoma Tumour Syndrome)Autosomal dominant
Germline PTEN gene mutation Clinical features include: Hamartomatous GI polyps MacrocephalySpecific mucocutaneous lesions Breast, thyroid, endometrial, renal cell cancersPTEN mutation probability risk calculator http
://www.lerner.ccf.org/gmi/ccscore
/
Slide56Case #2Family history meets BRCA1/2 criteria (hereditary breast/ovarian cancer)
Suggestive of other syndromes but criteria not strictly metPanel test offeredGenetic test results:No STK11 mutation (Peutz-Jeghers syndrome)No PTEN mutation (Cowden syndromePMS2 pathogenic mutation (Lynch syndrome)BAP1 c.479G>A (VUS)
Slide57Slide58Clinical Implications
Slide59Case #3
57 year old man referred after first colonoscopy 12 polyps removed (operative report)
Pathology report confirms:
TA x 6 (ascending and transverse colon)
TVA x 1 (sigmoid)
SSA x 1 (transverse)
HP x 2 (sigmoid)
2 polyps reported as normal tissue
No family history of cancer
Slide60Adenomatous polyps
Hamartomatous polyps
Serrated polyps
FAP/AFAP
MAP
Peutz-Jeghers
(PJS
)
Hereditary
Polyposis/Colorectal Cancer
S
yndromes
Tubular
adenoma
Tubulovillous
adenoma
Villous
adenoma
Traditional Serrated Adenoma
Hyperplastic
Sessile Serrated Adenoma
Hereditary
Sporadic
POLE
POLD1
Lynch syndrome
Juvenile
Polyposis (JP
)
PTEN
syndrome (CS)
inflammatory
Hereditary Mixed Polyposis (HMPS)
*lots of diff types (juvenile, PJ polyp)
ganglioneuroma
Serrated
Polyposis
(SP)
Slide61Hereditary Cancer Program (BC)
www.bccancer.bc.ca/screening/health-professionals/hereditaryCanadian Association of Genetic Counsellors – find a clinic:
www.cagc-accg.ca
National Comprehensive Cancer Network (USA)
www.nccn.org/professionals/physician_gls/f_guidelines.asp#detection
Gene
Reviews
www.genetests.org/resources
eviQ
Cancer Treatments Online (Australia)
www.eviq.org.au/cancer-genetics
Hereditary Colon Cancer Foundation (USA)
http://
www.hcctakesguts.org
Selected Resources
Slide62Hereditary cancer is rare (<10%).
Most hereditary polyposis/cancer syndromes are inherited in an autosomal dominant
manner, but not all
.
Not everyone with hereditary risk will develop cancer.
Options for risk reduction and/or early detection are available.
Hereditary risk can come from either the maternal or paternal side.
Genetic
testing usually starts with an affected family
member.
If your patient’s personal or family history is suspicious, refer and we will assess!
Key Points to Remember
Slide63Questions?
Mary McCullum, RN, MSN, CON(C)Nurse Educator, Hereditary Cancer ProgramBC Cancer Agency
Telephone: 604-877-6000, local 672325
Email:
mmccullum@bccancer.bc.ca