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Transcript
GENETIC COUNSELING AND
TESTING FOR CANCER
Kayla York, MS, LCGC
Licensed Genetic Counselor
Avera Cancer Institute
Outline





Genetic Counseling
Cancer Genetics
Breast/Ovarian Cancer
Colon/Endometrial Cancer
Summary
Genetic Counseling
Genetic Counseling


Genetic counselors are health professionals with specialized
graduate degrees and experience in the areas of medical genetics
and counseling.
Genetic counseling is the process of helping people understand and
adapt to the medical, psychological and familial implications of
genetic contributions to disease. This process integrates:




Interpretation of family and medical histories to assess the chance of
disease occurrence or recurrence.
Education about inheritance, testing, management, prevention, resources
and research.
Counseling to promote informed choices and adaptation to the risk or
condition.
National Society of Genetic Counselors, 2005
Genetic Counseling

Cancer Genetic Counseling
 Educate
patients and their families as well as provide
emotional support:
 Cancer
risks
 Options for genetic testing
 Options for cancer screening
Genetic Counseling

Initial Visit
Personal History
 Family History (both mother’s and father’s side)
 Risk Assessment
 Discussion of genetics and specific genes
 Discussion of possible test results
 Discussion of impact of genetic testing
 Insurance/GINA
 Arrange testing as needed



Result Disclosure
Follow-up visits as needed
Cancer Genetics
Cancer Genetics
Cancer Genetics
Cancer Genetics
Cancer Genetics
High Risk
Genes
Low Risk
Genes
Sporadic
Lifestyle and
Environment
Lifestyle and
Environment
Lifestyle and
Environment
Genetics
Genetics
Cancer Genetics






Cluster of specific types of cancers/ same cancer
Young ages at diagnosis
Individuals with multiple or bilateral cancers
Rare cancers
Pattern of inheritance in the family
Certain ethnic groups have higher frequencies of
specific genetic disorders
Cancer Genetics

BRCA1/BRCA2: Breast and Ovarian

Lynch Syndrome: Colorectal, Endometrial, GI

Other Syndromes

Familial Adenomatous Polyposis (FAP): Colon polyps, Colorectal, Stomach and Pancreatic

MEN1: Parathyroid, pituitary, pancreas

MEN2: Medullary thyroid Cancer

Li Fraumeni Syndrome (Tp53): soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors,
adrenocortical carcinoma

RET: Medullary thyroid, pheochromocytomas, parathyroid adenomas

Cowden Syndrome (PTEN): Breast cancer, uterine cancer, thyroid cancer, benign findings (colon
polyps, thyroid nodules, macrocephaly, etc)

Peutz Jeghers Syndrome (STK11): Colon polyps, breast cancer, pancreatic cancer, colon cancer,
ovarian cancer, germ cell cancers

Hereditary Diffuse Gastric Cancer and Lobular breast cancer (CDH1): Gastric cancer and lobular
breast cancer

MYH- Associated Polyposis: Colon polyps, Colorectal cancer
Breast and Ovarian Cancers
Breast Cancer





Most common cancer in women
1 in 8 women will develop breast cancer in their
lifetime
1 in 1000 men will develop breast cancer in their
lifetime
5-10% of all women with breast cancer carry an
inherited genetic predisposition
15-20% of all men with breast cancer carry an
inherited genetic predisposition
Ovarian Cancer



Ovarian cancer is the 5th most common cancer for
women
1 in 72 women will develop ovarian cancer in their
lifetime
Approximately 10- 20% of women with ovarian
cancer have an inherited gene predisposition
Breast and Ovarian Cancers

Risk Factors- Both
 Age
 Parity
 Menarche
(≤ 11)
 Menopause (≥55)
 Alcohol
 Weight
 Physical Activity
 Family History

Risk Factors- Breast
 Previous
chest radiation
 Hormone Therapy
 Breast Conditions
 Atypia/Hyperplasia
 LCIS
Breast Cancer

Only a fraction of
breast cancers are
caused by an inherited
gene mutation
Breast Cancer
High Risk
Genes
Low Risk
Genes
Sporadic
Lifestyle and
Environment
Lifestyle and
Environment
Lifestyle and
Environment
Genetics
Genetics
Hereditary Breast Cancer Predisposition
Syndromes
Family #1
Ovarian 40
Breast 42
Triple Neg
Breast 40
Ovarian 50
Breast 38
Cancer Genetics






Cluster of specific types of cancers/ same cancer
Young ages at diagnosis
Individuals with multiple or bilateral cancers
Rare cancers
Pattern of inheritance in the family
Certain ethnic groups have higher frequencies of
specific genetic disorders
Family #1
German
BRCA1 mutation
Norwegian
German
Ashkenazi Jewish
Breast 38
Ovarian 48
Breast 42
Triple Neg
Breast 40
Ovarian 50
Breast 38
BRCA1 and BRCA2



BRCA1 and BRCA2 are the most common genes that
predispose to breast and ovarian cancer when a
mutation is present.
Approximately 2-3% of women with breast cancer
carry a mutation in BRCA1 or BRCA2
Approximately 10% of women with ovarian cancer
carry a mutation in BRCA1 or BRCA2
BRCA1 and BRCA2
BRCA1

Lifetime risk for breast cancer
56%-80%




More commonly triple negative
breast cancer
Lifetime risk for ovarian cancer
up to 44%



Lifetime risk for male breast
cancer 2%
Lifetime risk for prostate cancer
20%
For Men and Women

Lifetime risk for Pancreatic cancer
2-4%


Lifetime risk for breast cancer
56%-80%
Lifetime risk for ovarian cancer
11-27%
For Men:

For Men:


BRCA2
Lifetime risk for male breast
cancer 8%
Lifetime risk for prostate cancer
32%
For Men and Women:


Lifetime risk for pancreatic
cancer: 5-8%
Lifetime risk for melanoma: 5%
Hereditary Breast Cancer Syndromes

Management: BRCA1/BRCA2

Women: Breast Cancer






Breast Awareness starting at age 18
Clinical Breast Exam starting at age 25 every 6-12 months
Annual Breast MRI starting at age 25 or individualized based on
family history
Annual Mammogram starting at age 30 or individualized based on
family history
Discuss prophylactic bilateral mastectomies
Women: Ovarian Cancer


Recommend salpingo-oophorectomy, ideally between the ages of 3540 or individualized based on family history and when child bearing
is complete
Data is limited but Providers can consider concurrent transvaginal
ultrasound + CA-125 every 6 months starting at age 30 or based on
family history
NCCN guidelines 2.2016
Hereditary Breast Cancer Predisposition
Syndromes
High Risk Genes


Cowden syndrome: PTEN
Hamartoma Syndrome


Breast, Uterine, and
Thyroid cancers
Macrocephaly and benign
findings ( ex: thyroid
disorders, colon polyps,
and dermatological
findings)
Li Fraumeni Syndrome:
Tp53 gene



Breast, sarcoma, brain
tumors, adrenocortical
carcinoma, leukemia, lung
bronchoalveolar cancers
Multiple primaries
Diffuse Gastric cancer and
Lobular breast cancer:
CDH1 gene

Diffuse gastric cancer and
lobular breast cancer
Hereditary Breast Cancer Predisposition Syndromes

Moderate Risk Genes:





PALB2
CHEK2
ATM
These genes are well studied with lifetime risks for breast cancer of
20%-56%. They have also been shown to increase the risks for other
cancers
NCCN Guidelines (2.2016)



Annual Mammogram and Breast MRI starting at age 30 or
individualized based on family history
Prophylactic mastectomy is an option with mutations in PALB2
Discussion of prophylactic bilateral mastectomies for mutations in ATM or
CHEK2 is controversial and is based on family history and personal
history
Hereditary Breast Cancer Predisposition Syndromes

Newer Genes:
 RAD51D
 BRIP1
 RAD51C
 BARD1
 RAD50
 FANCC
 NBN
 MRE11A
These genes are known to have an association with an increased risk for breast and
other cancers but they are not as well studied and data is based on a small number of
patients. The precise lifetime risks for cancers have not been determined nor have the
spectrum of cancers associated with mutations in these genes.
Hereditary Breast Cancer Predisposition
Syndromes
Family #2
d. 80s
Colon 60s
Polyps
83
Breast 40s
Breast 44
Breast 53
d. 60s
Breast 47
Endometrial 41
Endometrial
70s
Family #2
d. 80s
Colon 60s
Polyps
83
d. 60s
Breast 44
Breast 47
Breast 40s
Breast 53
Endometrial 41
BRCA1/2 NEG
HC: 59cm; thyroid nodules and goiter
PTEN mut
Endometrial
70s
Cowden Syndrome: PTEN

PTEN gene
 Tumor
suppressor gene located on Chromosome 10
 Responsible for control of cell division as well as other
functions
 The exact prevalance of PTEN/Cowden syndrome is
unknown
 Lifetime risk for breast cancer = 85%
 Also associated with uterine cancer, thyroid cancer,
kidney and colon cancers as well as thyroid nodules,
colon polyps, trichilemmomas, and macrocephaly
Family #3
Prostate 55
Breast 50
Pancreatic 60
Breast 58
Breast 47
Family #3
Prostate 55
Breast 50
Pancreatic 60
Breast 58
Breast 47
BRCA2
Family #4
Breast 40
Breast 55
Breast 50
Breast 35
Family #4
Breast 40
Breast 55
Breast 50
Breast 35
BRCA1/2; TP53; PTEN; STK11; and CDH1 = NEG
Family #5
Family #5
RAD51C
RAD51C



RAD51C is a newer gene that has been mostly
associated with ovarian cancer risk
Estimated to confer a 10-15% lifetime risk for
ovarian cancer
NCCN guidelines (2.2016) recommend
consideration of risk reducing salpingooophorectomy
Colon Cancer
Colon Cancer



3rd most common cancer
1 in 20 individuals will develop colon cancer in their
lifetime
Slightly higher incidence in men than women
Colon Cancer

Risk Factors

Risk Factors
 Age
 Smoking
 Phx
 Alcohol
of colon polyps
 Phx of Inflammatory
Bowel Disease
 Type 2 diabetes
 Diet high in red meats and
processed meats
 Weight
 Physical
Activity
 Family History
Hereditary Colon Cancer Predisposition
Syndromes
Family #1
Col 40
Panc 60
Endo 35
Col 45
Col 40, 50
Breast 55
2 Adenomas
Col 50
Endo 40
2 adenomas
Family #2
Col 80
83
Col 60
2 Adenomas
1 Adenoma
Colon 60
Family #3
Colectomy 40
100+ polyps
#
Colon 45
20 adenomas
#
No information
Family #4
Dx 70s
Dx 80 Dx 57
Dx 60
Dx 75 Dx 54
Dx 70
Colon 45
Colorectal
Endometrial
Bladder
Dx 71
3
Dx 60
Dx 40 Dx 67
Dx 50
Dx 40s Dx 40s
Pancreatic
Breast
Prostate
Hereditary Colon Cancer Predisposition
Syndromes





Pt meets Bethesda criteria
Pt meets Amsterdam criteria
>10 adenomas in same individual
Individual with multiple GI hamartomatous polyps,
Juvenile polyps or serrated polyposis syndrome
Individual with a desmoid tumor
NCCN Guidelines 4.2013
Hereditary Colon Cancer
Predisposition Syndromes

Polyposis Syndromes
 Generally
>20 colon
polyps in a lifetime

Non-Polyposis Syndromes
 Generally
<20 colon polyps in
a lifetime
There can be overlap between the two- especially with
attenuated forms of polyposis syndromes
Hereditary Colon Cancer Predisposition
Syndromes

Amsterdam II Criteria
 At
least 3 relatives must have a cancer associated with
HNPCC/Lynch Syndrome and all of the following criteria
should be present:
 One
must be a first degree relative of the other two
 At least 2 successive generations affected
 At least one of the relatives with cancer associated with
HNPCC should be diagnosed before age 50
 FAP should be excluded in the colorectal cancer cases
 Tumors should be verified whenever possible
Hereditary Colon Cancer Predisposition
Syndromes

Bethesda Criteria
 Tumors
from individuals should be tested for MSI in the
following situations:
 Colorectal
cancer diagnosed less than 50 years of age
 Presence of synchronous, or metachronous colorectal or other
LS- associated tumors, regardless of age
 Colorectal cancer with histology suggestive of MSI-H in a
patient less than 60 (tumor infiltrating lymphocytes, Crohn’s
like lymphocytic reaction, mucinous/signet-ring
differentiation, or medullary growth pattern)
 Colorectal cancer in a patient with ≥ 2 first or second
degree relatives with a Lynch syndrome related cancers
regardless of age
Hereditary Colon Cancer Predisposition
Syndromes
•
•
Sjursen et al [2010] found the sensitivity of the
Amsterdam II criteria to be 87% (MLH1), 62%
(MSH2), 38% (PMS2), and 48% (MSH6) for
identifying individuals with a germline mutation.
Hampel et al [2005] also reported that in a
population-based study of persons with colon
cancer, only three of 23 persons with a germline
mutation in an MMR gene met the Amsterdam
criteria.
Hereditary Colon Cancer Predisposition
Syndromes

IHC-MMR Tumor Testing
 Screens
the tumor for Lynch syndrome
 Analyzes presence or absence of 4 proteins
 MLH1,
 95%
MSH2, MSH6, PMS2
of individuals with Lynch syndrome will have
absence of at least 1 protein on IHC-MMR
 Absence of staining could indicate a germline mutation
 At Avera- done on all colon cancer resections and
endometrial cancers at time of surgery
Hereditary Colon Cancer Predisposition
Syndromes
Lynch Syndrome
Hereditary Colon Cancer Predisposition
Syndromes

FAP/Attenuated FAP
Caused by mutations in the APC gene
 Classic FAP is associated with 100s-1000s of polyps in the
teens-30s
 The risk for colon cancer for untreated individuals is ~87%
by age 45 and 93% by age 50
 Attenuated FAP is associated with <100 polyps and older
age at onset. The risk for colon cancer is ~70% to age 80


MYH-Associated Polyposis
Autosomal Recessive polyposis disorder caused by mutations
in the MYH gene
 10s-100s of polyps
 Lifetime risk for colon cancer 43%-100%

Hereditary Colon Cancer Predisposition
Syndromes

Peutz Jeghers Syndrome
 STK11
gene
 Breast, Ovarian (often sex cord tumors), pancreatic,
and colon cancers
 Colon polyps and oral freckling (mouth and lips)

Juvenile Polyposis Syndrome
 SMAD4
and BMPR1A genes
 Juvenile polyps of the colon
 Colon cancer
Hereditary Colon Cancer Predisposition
Syndromes
Family #1
Col 40
Panc 60
Endo 35
Col 45
Col 40, 50
MSH2
Breast 55
2 Adenomas
Col 50
Endo 40
2 adenomas
Family #2
Col 80
83
Col 60
PMS2 absent IHC
PMS2 mut
2 Adenomas
1 Adenoma
Colon 60
Family #3
APC +
Colectomy 40
100+ polyps
APC +
#
Colon 45
20 adenomas
22yo
10 polyps
20yo
20 polyps
15yo
#
No information
12yo
Family #4
Dx 70s
Dx 80 Dx 57
Dx 60
Dx 75 Dx 54
Dx 70
Dx 45
Normal IHC
25 gene panel = MSH6 VUS
Colorectal
Endometrial
Bladder
Dx 71
3
Dx 60
Dx 40 Dx 67
Dx 50
Dx 40s Dx 40s
Pancreatic
Breast
Prostate
Variant of Uncertain Significance

VUS: A variant of uncertain or unknown significance
is a change in the DNA sequence of the gene where
it is unknown if it damages the gene or not.
DNA Change Classification
Deleterious Mutation
Positive Result= Damaging change to the gene
VUS- Suspected Deleterious
Evidence points to most likely damaging/positive
Variant of Uncertain/Unknown
Significance
Unknown if damaging or benign change
VUS- Likely Benign
Evidence points to most likely negative/benign
Benign Polymorphism
Negative Result- does not affect gene function
Family #4
Dx 70s
Dx 80 Dx 57
ATM VUS
Dx 60
No Answer
Dx 75 Dx 54
Dx 70
Dx 45
Normal IHC
25 gene panel = MSH6 VUS
Dx 71
3
Dx 60
Dx 40 Dx 67
Dx 50
Dx 40s Dx 40s
ATM VUS- likely benign
Colorectal
Endometrial
Bladder
Pancreatic
Breast
Prostate
Hereditary Colon Cancer Predisposition

Management:
 Lynch
Syndrome- Depends on the gene involved
 Colonoscopies
1-2 years starting at age 20-25 or
individualized based on family history
 Consider EGD every 3-5 years starting at age 30-35
(MLH1/MSH2)
 Prophylactic TAH/BSO when childbearing is complete
 Consider annual urinalysis starting at age 30-35
 Consider annual physical/neurological exam
Hereditary Colon Cancer Predisposition

Management

Classic FAP
Annual Colonoscopy starting at age 10-15
 Proctocolectomy or Colectomy: Age at surgery depends on polyp
load and severity of family history


Attenuated FAP


Colonoscopy every 1-2 years with consideration of colectomy
depending of polyp burden
Extracolonic surveillance:




Upper Endoscopy starting at age 20-25- earlier if colectomy prior
to age 20
Annual Physical exam
Annual abdominal exam with consideration of CT or MRI
Annual thyroid exam
Summary
Summary



Approximately 5-10% of all cancers are caused by
a hereditary gene mutation
Family history is an important tool for identifying
these families
Management guidelines and recurrence risks may
differ significantly if a patient has a hereditary
cancer syndrome
Questions?