Inherited Colon Cancer Syndromes

15th Annual West Coast Colorectal Cancer Symposium Oct. 27, 2017

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Inherited Colon Cancer Syndromes

Cathy Goetsch, ARNP, AOCNP, AGN-BCHereditary Cancer Risk Specialist


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© 2015 Virginia Mason Medical Center

Colorectal Cancer Incidence

• In US about 140,000 new cases of colorectal cancer are diagnosed each year.


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Why Do Genetic Testing

• To have better outcomes for patients and/or their families.

• Care would be changed for patient or family

– Treatment

– Screening


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Benefits of genetic testing

• Gain knowledge of one’s risk status -- most patients feel better

• Increased surveillance may be available and justifiable to insurance with positive results.

• Enhanced surveillance can be avoided if result is negative in a family with a known mutation.

• More informed decision-making: regarding prevention and treatment.

• May be able to identify pre-symptomatic risk in close relatives.

• May guide treatment decisions for specific medication choices.


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Management of Risk

• Early initiation of surveillance

• Increased frequency of surveillance

• Surveillance for other malignancies

• Consideration of prophylactic surgery

• Chemoprevention may be an option

• Notification of family members at risk


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Limitations of genetic testing

• Positive Results – Harmful mutation found

– Can’t fix inherited mutation.

– Not everyone with risk mutations develops cancer.

– Psychosocial impact in patient and families.

– Exact risks may not be known

– Increased cost of surveillance/interventions

– Not all cancers have effective screening or prevention methods

• Negative Results – No clinically significant mutation found

– May not mean there isn’t inherited risk, just that we can’t find it

– Population risk for cancer in those with true negative result still exists

• Variants of Uncertain Significance – Not clinically actionable

– Does not help to guide care

– Unsettling

– Requires a system for keeping track of reclassifications and contacting patients with updated results


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Genes Associated with Inherited Colon Cancer Risk(testing available and data about effect of mutations available)

• Lynch Syndrome (HNPCC): MLH1, MSH2, MSH6, PMS2, EPCAM

• Familial Adenomatous Polyposis (FAP & attenuated FAP): APC

• MUTYH-associated Polyposis (biallelic errors) & MUTYH (monoallelic error)

• CHEK2

• PTEN

• TP53

• STK11

• CDH1

• BMPRIA

• SMAD4

• POLD1, POLE, GREM1


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Lynch Syndrome

• Cancer risk--inherited in an autosomal dominant pattern

• Approximately 3 to 5 percent of these colon cancers are probably related to Lynch syndrome.

• Increases risk for other cancers: uterus, ovaries, stomach, small bowel, pancreas & bile duct, kidneys & ureters, brain, thyroid, and sebaceous skin neoplasms.


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Genes Associated With Lynch syndrome

• MLH1,

• MSH2,

• MSH6,

• PMS2,

• EPCAM


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Proportion of Lynch Syndrome Attributed to Pathogenic Variants in Each Gene

GENE PERCENT

MLH1 50%

MSH2 40%

MSH6 7%-10%

PMS2 <5%

EPCAM

(TACSTD1)~1%-3%


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Lynch Syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM Inherited Errors Cause Loss of Function

• Normal gene function: repair of DNA errors occur during replication in preparation for cell division.

• Mutations prevent the proper repair of DNA replication mistakes.

• As the abnormal cells continue to divide, the accumulated mistakes can lead to uncontrolled cell growth/cancer.

• EPCAM gene lies next to the MSH2 gene on chromosome 2, certain EPCAM gene mutations cause the MSH2 gene to be turned off.


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Clinical Features of Classic Lynch Syndrome

• Multiple cancers in the same individual

• Earlier onset cancers are seen (but average age of CRC in Lynch is >60)

• Colorectal, association with R-sided may be diminishing as screening increases

• Endometrial & ovarian cancer in women

• Other Lynch Syndrome-associated cancers

– stomach, small intestines, pancreato-biliary tract

– ureter, kidney (usu. transitional cell, rarely renal cell)

– brain tumors (usu. glioblastoma): Turcot Syndrome

– skin tumors (e.g.: keratoacanthomas, sebaceous adenomas & adenocarcinomas) Muir-Torre Syndrome

• Early onset polyps but not polyposis have been reported

• Prognosis may be better than for same stage sporadic cases


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Risk Variance by Gene with Mutation

Cancer TypeUS Average Pop.

Risk to Age 70

MLH 1 , MSH2, &

EPCAM

MSH6 PMS2

Colorectal Male 2.2% 52-80% 22-69% 15-20%

Colorectal Female 1.7% 40-70% 10-30% 15-20%

Endometrial 1.6% 25-60% 16-71% 15% early onset (49)

Gastric 0.3% 6-13% Elevated ~1%

Ovarian 0.7% 4-12% Elevated ElevatedEarly onset (42)

Sebaceous Neoplasm <1% 1-9% Elevated Not reported

Small Bowel 0.1% 3-6% Elevated ~1%

Ureter/Renal Pelvis 0.1% 1-4% Elevated ~1%

Hepatobiliary 0.4% 1.4-4% Elevated Not reported

Pancreatic 0.5% 1-6% Elevated Not reported

Brain/CNS 0.4% 1-3% Elevated ~1%Early onset (45)


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Amsterdam Criteria

Must meet all

• At least 3 relatives have colorectal cancer (or another cancer linked with Lynch syndrome).

• One is a first-degree relative (parent, sibling, or child) of the other 2 relatives.

• At least 2 successive generations are involved.

• At least 1 diagnosed at age 50 or younger


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Limitations of Amsterdam Criteria

• Many families with Lynch syndrome do not meet the Amsterdam criteria.

• Only about half of families who meet the Amsterdam criteria have Lynch syndrome.

• Individuals meeting criteria, but without molecular diagnosis of Lynch syndrome, still have colorectal cancer risk about twice as high as average.


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Revised Bethesda guidelines

• Used to identify who should have MSI or IHC tumor testing done.


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Revised Bethesda criteria

• Colorectal carcinoma (CRC) diagnosed in a patient who is less than 50 years old;

• Presence of synchronous or metachronous CRC or other Lynch syndrome-associated tumors, regardless of age;

• CRC with high microsatellite instability histology or IHC MMR LOF diagnosed in a patient less than 60 years old

• CRC diagnosed in one or more first-degree relatives with a Lynch syndrome-associated tumor, with one of the cancers being diagnosed at less than 50 years of age;

• CRC diagnosed in two or more first-degree or second-degree relatives with Lynch syndrome-associated tumors, regardless of age.

https://en.wikipedia.org/wiki/Microsatellite_instability

https://en.wikipedia.org/wiki/Histology


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Limitations of only Testing Those Who Meet Amsterdam and Bethesda Criteria

2016 ASCO Abstract

Yurgelun , et al; JCO 2017 Jan 30:

• Reported on a single institution series of 1059 consecutive CRC cases unscreened for family history

• Tested with a 25 gene NGS panel for inherited cancer risk mutations


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Findings:

• 9.9 % of CRC patients had cancer susceptibility gene mutations found

• 14 % of those with mutations had no personal or family hxsuggesting inherited risk

• 52% were high-penetrance gene mutations

• 31 % were Lynch syndrome (96% also detected by MSI / MMR IHC testing)

• 8 % with adenomatous polyposis syndromes (APC or biallelicMUTYH mutations)


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Unexpected findings:

• 4% had other high-penetrance mutations (PALB2, CDKN2A, TP53)

• 33% with moderate-penetrance gene mutations linked to CRC risk (Monoallelic MUTYH, APC*I1307K, and CHEK2)

• 15% had moderate-penetrance gene mutations not linked to CRC risk

• 10% with BRCA1/2 mutations (Estimated 0.2-0.3% prevalence in general population) -- only 27% met NCCN criteria for BRCA1/2 testing


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Multigene panels find more harmful mutations than expected by expert opinion or prediction models

Idols, et al, ASCO poster 2017

N=2000 25 gene panel

Patients seen in inherited risk clinics (with or without cancer dx)

Inclusion criteria: Had 2.5% or greater risk estimated of having a inherited cancer risk mutation found.

34% of mutations found were not in the pretest differential diagnosis.


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Familial Adenomatous Polyposis (FAP)

• Causes excessive incidence of polyps.

• Classic FAP onset in late childhood with hundreds of polyps

• 100% chance of colon cancer if no screening or preventative actions are taken.


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Familial Adenomatous Polyposis (FAP & AFAP)

• Caused by inherited mutations in the APC (adenomatous polyposis coli) gene– located on chromosome 5 (at 5q21)

– autosomal dominant pattern of inheritance

• Diagnosis – By phenotype:

– Classic FAP

– presence of >100 colon polyps on initial colon screening, may occur as early as 10 years old.

– AFAP (attenuated FAP)

– Colon polyps continue to accumulate over time, sometimes accelerating in rate of formation

– Most insurances recognize an accumulation of more than 10 polyps as medical necessity for genetic testing

– By genotype: mutation located on APC gene

• Incidence: 1/6000 to 1/13,000 US gen. Pop.– I1307K mutation 6% carrier frequency in Ashkenasi Jewish heritage--increases colon ca

risk by factor of 2, but not at younger age


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CHRPE

• congenital hypertrophy or hyperplasia of the retinal pigment epithelium

• Associated with FAP if

– Occurs before age 30

– Multiple lesions

• Seldom associated with malignant transformation


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MUTYH (aka MYH)

• Normal function:

– involved in oxidative DNA damage repair

• MUTYH-Associated Polyposis (autosomal recessive:

– homozygous, or compound heterozygous—

– 2 copy errors

– MYTYH-heterozygous elevated risk of colon cancer

• (single copy error)


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MUTYH Biallelic mutations (homozygous or compound heterozygous)

Cause MUTYH-Associated Polyposis (MAP)

• Lifetime risk of CRC : 43% to almost 100% in the absence of timely surveillance.

• Ten to a few hundred colonic adenomatous polyps by age 50

• Serrated adenomas, hyperplastic/sessile serrated polyps, and mixed polyps (hyperplastic and adenomatous) can also occur.

• CRC has been seen in the absence of polyposis.

• Duodenal adenomas found in 17%-25%

• Lifetime risk of duodenal cancer ~4%.

• Slight increased risk for malignancies of the ovary, bladder, and skin (not early onset)

• Some evidence for increased risk for breast and endometrial cancer.

• Also reported: sebaceous gland tumors, thyroid abnormalities (multinodular goiter, single nodules, and papillary thyroid cancer)


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MUTYH Monoallelic mutations (heterozygous, single copy error)

• Two- threefold increase in their risk for colorectal cancer at an age similar to that in the general population.

• No standard guidelines for screening, but

• Are expected to benefit from population screening measures and could be offered average moderate-risk colorectal screening similar to people with family history of colon cancer.


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PTEN Hamartoma Tumor Syndromes(PHTS)

• Include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRB), and PTEN-related Proteus syndrome (PS).

– Inheritance is autosomal dominant.

• Cowden Syndrome is characterized by multiple hamartomatous polyps in the GI tract

• CS has increased risks for breast, thyroid, uterine, colon, and renal cancers.

• BRRS is a disorder characterized by GI polyposis, macrocephaly, lipomas of the skin, and pigmented macules of the glans penis.

• PS has variable expressivity, – often involving hamartomatous overgrowth of tissues, connective tissue nevi, epidermal nevi, and

hyperostoses.

• Diagnosis is by molecular testing.

• There are criteria for operational diagnosis


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PTENHamartoma Tumor Syndrome

Major Criteria

Breast cancer

Endometrial cancer (epithelial)

Thyroid cancer (follicular)

Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps; ≥3)

Lhermitte-Duclos disease (adult)

Macrocephaly (≥97 percentile: 58cm for females, 60cm for males)

Macular pigmentation of the glans penis

Multiple mucocutaneous lesions (any of the following):

Multiple trichilemmomas (≥3, at least one biopsy proven)

Acral keratoses (≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)

Mucocutaneous neuromas (≥3)

Oral papillomas (particularly on tongue and gingiva), multiple (≥3) OR biopsy proven OR dermatologist diagnosed

Minor criteria

Autism spectrum disorder

Colon cancer

Esophageal glycogenic acanthosis (≥3)

Lipomas (≥ 3)

Mental retardation (ie, IQ ≤ 75)

Renal cell carcinoma

Testicular lipomatosis

Thyroid cancer (papillary or follicular variant of papillary)

Operational diagnosis in an individual (either of the following):

1. Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or gi hamartomas; or

2. Two major and three minor criteria.

Operational diagnosis in a family where one individual meets revised PTEN hamartoma tumor syndrome clinical diagnostic criteria or has a PTEN mutation:

1. Any two major criteria with or without minor criteria; or

2. One major and two minor criteria; or

3. Three minor criteria.

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Peutz-Jeghers Syndrome (PJS)

• Increased risk for colon, gastric, breast, lung, pancreas, and sex organ cancers.

• GI hamartomatous polyps, most often in the small bowel.

• Mucocutaneous pigmentation.

– dark brown to dark blue spots that often fade with age.

• A heterozygous pathogenic variant in STK11 can be detected in up to 94% of individuals with PJS

• Inheritance is autosomal dominant.


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Hereditary Mixed Polyposis Syndrome (HMPS)

• Rare condition described in only a few families worldwide.

• Increased risk for adenomatous polyps, juvenile polyps, hyperplastic polyps, and polyps containing mixed histology.

• Increased risk for colon malignancy

• Associated with a heterozygous pathogenic variant in BMPR1A gene

. Appears to be inherited in an autosomal dominant manner.


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Serrated polyposis syndrome (SPS),

• Previously referred to as hyperplastic polyposis syndrome

• Characterized by sessile serrated polyps, serrated adenomas or hyperplastic polyps of the GI tract

• Increased risk of CRC.

• Criteria established by the WHO International Classification of Tumor Definition: presence of 20 serrated (or hyperplastic) polyps distributed throughout the colon.

• Although the exact basis of SPS is not known.


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Juvenile Polyposis Syndrome (JPS)

• The term juvenile reflects the histology of the polyps rather than the age of onset.

• JPS is characterized by hamartomatous polyps of the GI tract.

• ~20% of individuals with JPS have a pathogenic variant in BMPR1A;

• ~20% have a pathogenic variant in SMAD4.

• Inheritance is autosomal dominant.

• Individuals with a SMAD4 germline pathogenic variant are also at increased risk for hereditary hemorrhagic telangiectasia.

https://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/pathogenic-variant/

https://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/

https://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/germline/

https://www.ncbi.nlm.nih.gov/books/n/gene/hht/


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JPS: Clinical diagnosis

– Presence of more than five juvenile type polyps of the colon, multiple juvenile polyps throughout the GI tract,

– Any number of juvenile polyps and a family history of juvenile polyps.

– Juvenile polyps are benign, but malignancies can occur.

– Risk for GI cancers in families with JPS ranges from 9% to 50%.

– Most of this increased risk is for colon cancer,

– Cancers of the stomach, upper GI tract, and pancreas have also been reported.


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Helpful Websites

• To construct a family tree– https://familyhistory.hhs.gov/fhh-web/home.action

• Look for genes to explain unusual findings– http://www.ncbi.nlm.nih.gov/omim

• General information about cancer genetics– http://www.cancer.gov/cancertopics/prevention-genetics-causes

• In-depth information about a syndrome– http://www.ncbi.nlm.nih.gov/books/NBK1116/

• Find a testing lab– http://www.ncbi.nlm.nih.gov/sites/GeneTests/

https://familyhistory.hhs.gov/fhh-web/home.action

http://www.ncbi.nlm.nih.gov/omim

http://www.cancer.gov/cancertopics/prevention-genetics-causes

http://www.ncbi.nlm.nih.gov/books/NBK1116/

http://www.ncbi.nlm.nih.gov/sites/GeneTests/


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Case 1

• Patient is 17 yo male with colon cancer

• No family history except a small bowel cancer in his maternal grandfather in his 60s. Mother and her 4 sibs all in their 40s and 50s without cancers.

• At 21, pt tests positive for HNPCC associated mutation on MLH1

• Mother age 51 tested positive for the same mutation. Sent for initial gyn eval with endometrial cancer found. Diagnosed and dies from breast cancer at 54.

• One maternal uncle and patients two sisters have tested negative


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Case 2

• Patient: 35 yo female with early colon cancer. Treated with partial colectomy.

• Father with 3 separate colon cancer sites, ages 37 & 57

• Patient continues screening has second colon cancer at age 50.

• In the interim sister had endometrial cancer at age 47, and father has a 3rd colon cancer at age 70

• Pt has genetic testing w/ MSH2 mutation found 2007.

• Her 2 sons and three brothers come in for group counseling and testing. Neither sister comes.

• One son is positive, begins screening at 25, no cancer so far

• Sister with uterine cancer is presumptive positive.

• Her son did not have genetic testing. 2015 stage 4 small bowel cancer diagnosed at age 21

Documents

Inherited Colon Cancer Syndromes