Download Breast Cancer 6 - Tennesse Department Of Health

Breast Cancer Risk
Assessment and Genetic
Testing
Susan W. Caro, RNC, MSN, APNG
Director, Family Cancer Risk Service
Vanderbilt-Ingram Cancer Center
Objectives:
1. Appreciate the complex and emerging
information about the impact of genetics on
breast cancer risk.
2. Identify resources available for assessing
genetic risk.
3. Articulate when risk counseling and
assessment is recommended.
4. Know the TN resources for genetic risk
assessment.
In 1990, the National
Institutes of Health and
the Dept. of Energy
launched the Human
Genome Project, an
international effort to
map, sequence, and
characterize the human
genome. Working draft
completed in June
2000, published in
Science and Nature in
February 2001.
Why?
• Hereditary cancer syndromes are being more clearly defined
with increasingly clear recommendations for management.
• Clinical genetics tests for hereditary cancer syndromes are
available and in some markets are being marketed directly to
the consumer.
• Recognizing hereditary cancer syndromes provides the
opportunity to identify those at significantly increased risk
and offer options to identify cancers earlier or prevent cancer
in these individuals.
• Potential for medico-legal implications of not recognizing
hereditary cancer syndromes.
Lynch HT, Paulson JD, Severen M, et al. Failure to Diagnose Hereditary Colorectal Cancer and Its Medicolegal
Implications. Dis. Colon Rectum January 1999;42:31-35.
Hereditary Cancer Burden in
Tennessee?
Breast Cancer
3,720 new diagnoses
920 deaths
Colorectal Cancer
3,290 new diagnoses
1130 deaths
If ~10% hereditary cancer – 372 new cases of hereditary
breast cancer (392 CRC) this year.
Could some of these have been foreseen,
even prevented?
*Excludes carcinoma in situ (CIS, non-invasive cancer) of any site except urinary bladder.
Does not include basal and squamous cell skin cancers (of which there are 1.3 million per year).
American Cancer Society, 2008
Prevention (medical)
• In medicine, prevention is any activity which reduces the
burden of mortality or morbidity from disease. This takes
place at primary, secondary and tertiary prevention
levels.
• Primary prevention avoids the development of a disease.
Most population-based health promotion activities are
primary preventive measures.
• Secondary prevention activities are aimed at early
disease detection, thereby increasing opportunities for
interventions to prevent progression of the disease and
emergence of symptoms.
• Tertiary prevention reduces the negative impact of an
already established disease by restoring function and
reducing disease-related complications.
Wikipedia
All cancer is genetic,
not all cancer is
hereditary.
Breast Cancer Genes Found
Clip
• BRCA1 (for BReast
CAncer gene 1) was
described in 1990 on
chromosome 17,
isolated in 1994
• BRCA2 was isolated
on chromosome 13 in
late 1994
• BRCA3?
The Development of
Hereditary Cancer
2 normal genes
1 damaged gene
1 normal gene
Tumor
develops
2 damaged genes
In hereditary cancer, one damaged gene is inherited.
1 damaged gene
1 normal gene
2 damaged genes
Tumor
develops
Myriad Genetics, Inc.
© 2006 Myriad Genetic Laboratories, Inc.
American Society of Clinical Oncology
Guidelines for Genetic Testing
• Personal or family history features
suggestive of hereditary cancer risk
• Test can be adequately interpreted
• Test result will aid in diagnosis or
influence medical management of the
patient and/or family
J Clin Oncol 2003;21:2397-406
Cancer Syndromes
• Hereditary Breast Cancer Syndromes
– BRCA1, BRCA2, Cowden, CHEK2, Li-Fraumeni
• Hereditary Colorectal Cancer Syndromes
– HNPCC
– FAP
• Endocrine Syndromes – VHL, MEN1, MEN2,
FMTC
• Other – Li Fraumeni, Peutz-Jeghers
• DNA Banking
Ask – out loud
• Ask the question: Do you have a family
history of cancer?
• Clarify - maternal AND paternal family history
• Ask the question again more specifically:
Does anyone in your family have a history of
breast, ovarian, colon cancer, colon polyps,
or other cancers?
• Ask the question again at follow up visits, as
family histories change over time.
FCRS
Listen when your patients voice a
concern:
• In many health care encounters today, we are
focused on the problem at hand and it is difficult to go
beyond this.
• Not suggesting that every health care provider have
an expert knowledge of the complex issues
surrounding all of the hereditary cancer syndromes rather that continual exposure to this information will
prompt recognition and referral for more thorough
evaluation of the family.
• A significant number of our patients seek consultation
independently. Their health care providers do not
always recognize the significance of family history.
Refer
• Refer for comprehensive risk assessment and
consideration of genetic testing.
• Genetic testing is only one aspect of this. There is
a great deal to be learned from gathering and
documenting the family history and the educational
component of the counseling process.
• Many patients are concerned as a result of things
they have read or been told about insurance
discrimination. This is addressed in the counseling
session (before any decision for genetic testing is
made).
Family Cancer Risk Consultation
Should include:
• Education about cancer risk in families
• Cancer/genetic risk assessment
• Discussion of possible risks and
benefits of genetic testing
• Psychological support, guidance about
medical options, and referral for medical
or surgical means of early detection or
Offit, 1998, p. 3
prevention of cancer
Comprehensive Risk Assessment
/ Consultation
•
•
•
•
•
•
•
•
•
•
Assess patient’s view of their risk, experience with cancer in the family
Review what is known and not known about cancer risk
Medical history, current surveillance activity
Review family history and draw pedigree
Document cancers in history (medical record and pathology review)
Provide risk assessment - Risks associated with hereditary cancer syndromes
under consideration, risks if no recognizable syndrome
Education - Cancers, risks factors, surveillance, basic genetics, cancer
genetics
Testing? Benefits, limitations, risks, costs, insurance, process
Recommendations for surveillance or possible preventive measures, discuss
implications to others in family.
Interpretation of test results, including psychological, social, and family
implications of test results
Management Options / Counseling
• Review options for increased screening or
measures to decrease risk
• Discuss efficacy (or lack of efficacy/ or lack of
data to support efficacy) of surveillance,
prophylactic / risk reducing, or
chemopreventive measures
• Increasing understanding of utility and
consequences of surveillance and
intervention options – a moving target.
How Much Breast and
Ovarian Cancer Is Hereditary?
15% 20
%
5%–10%
Breast Cancer
5%–10%
Ovarian Cancer
Sporadic
Family clusters
Hereditary
ASCO
Contribution of BRCA1/2 to hereditary breast /ovarian cancer families:
Other
16%
Hereditary
Cancer
10%
BRCA1
52%
BRCA2
32%
Breast Cancer Families
Others
90%
BRCA2
14%
Breast and ovarian
cancers
Other
5%
BRCA1
81%
Breast and Ovarian
Cancer Families
King, Rowell, Love, 1993; Ford, Easton, Stratton, et al, 1998
BRCA Mutations and
Ashkenazi Jews
• 185delAG mutation noted in
1% of 850 samples of
Ashkenazi Jewish individuals
unselected for family history of
cancer (studied stored
samples from Tay-Sachs
research)
• Carrier rate 3 X that expected
in general population
• May account for 16% of
breast and 39% of ovarian
cancer in AJ women <50
• 2 other “founder mutations”
Male Breast Cancer and BRCA2
Studies of BRCA2 in population- and clinic-based series of male breast cancer
patients from the United States and Europe have found carrier frequencies of
BRCA2 mutations of 4% - 40%
The percentage of male breast cancer cases that are associated with a BRCA2
mutation varies depending on the population. Figures from various studies (some
small):
4% in U.S.;
21% in Sweden;
40% in Iceland.
One study showed that among men with breast cancer and a first-degree relative
(e.g., mother or sister) with breast cancer approximately 11% were carriers of a
BRCA2 mutation.
For male BRCA2 alteration carriers:
• Estimated cumulative risk of male breast cancer is ~6% by age 70
• Age of onset not as early as female breast cancer in BRCA2 carriers
•BRCA1 may account for more cases of male breast cancer than initially
estimated.
(Couch et al. 1996, Thorlacius et al. 1996, Friedman et al. 1997, Csokay et al. 1999)
Cumulative Risk of Breast and Ovarian Cancer in
BRCA1 and BRCA2 Mutation Carriers
From Rebbeck,T; J Clin Oncol
18:100s-103s 2000
Risks of Breast Cancer with
BRCA1 or BRCA2 Mutation
Breast cancer
risk by age
(women)
BRCA1
BRCA2
40
50
60
70
19%
50%
64%
85%
12%
28%
48%
84%
Ashkenazi
women w/
BRCA1/2
General
population US
33%
2%
56%
7%
Easton DF, Ford D, Bishop T, and the Breast Cancer Linkage Consortium, 1995. Am J Hum Gen 56:265-271.
Easton DF, et al., and the Breast Cancer Linkage Consortium, 1999. JNCI 91:1310-1319.
Ford D, Easton DF, Stratton M, Narod S, et al., 1998, Am J Hum Genetics 62:676-689.
Struewing JP, Harge P, Wacholder W, et al. NEJM, 1997. 336(20):1401-1408.
Ford D, Easton DG, Bishop T, Narod S, 1994. Lancet 343:692-695.
Contralateral Breast Cancer Risk
BRCA1/2 Mutation Carriers
Risk of new
breast ca dx by
age 70
BRCA1
BRCA2
BRCA1 or
BRCA2
Women w/ prior
hx breast cancer
60%
52%
3%/year
<1% per year
Recognition: the first step in
management of familial cancer risk
The hope is that increased surveillance
and/or interventions may identify
cancers early or reduce the risk of
cancers.
Risk assessment may also identify
those not at increased risk.
Cancer Clusters
• Cancer can happen in a family just by chance
• Cancer can cluster in families because of shared
environmental exposures (diet, lifestyle,
“environment”, work related exposures)
• Cancers may be due to inheritance of a single
genetic alteration that poses very high risk of
cancer
• Cancers may be due to inheritance of less
penetrant genetic alterations
Sporadic/Familial/Hereditary
Sporadic cancers
Age appropriate
Common cancers
Familial Cancer
Occurring in or affecting more
members of a family than would
be expected by chance”
Generally, two or more family
members with the same type of
Hereditary Cancer
-Multiple affected family members cancer, age appropriate
-Several cases of the same type of cancer or cancers known to be part of an
hereditary cancer syndrome (e.g. breast & ovarian, colon & endometrial,
sarcoma & breast).
-Younger than expected ages of onset - such as breast < 40, colon < 50
-Rare cancers in the family such as males with breast cancer
-Individuals with multiple primary cancers or multifocal or bilateral cancers
-Family history consistent with generation to generation transmission
Tools for risk assessment:
Breast cancer risk assessment models Claus, Gail, BRCAPRO, Frank/Myriad
models
Models for other cancers from the literature
Computer/Internet resources
Gene tests, OMIM, NCI website
Ongoing education
Models used to calculate breast
cancer risks
• Claus Model - Age specific risk estimates for breast cancer,
considers maternal and paternal history, age at onset, first and
second degree relatives (excludes some relatives).
• Gail Model - Estimates the chance that a woman of specific age
would develop breast cancer, includes age at menarche, childbirth, #
of prior biopsies, and first degree relatives. Excludes paternal
relatives, non-first degree relatives. Adapted to consider atypical
hyperplasias.
• Tyrer-Cusick Model – (2004) Uses personal risk factors for breast
cancer, and likelihood of BRCA gene mutation and a low penetrance
gene to assess breast cancer risk.
Claus EB, Risch N, Thompson WD, 1990;1991;1994;
Gail MH, Brinton LA, Byar EP, et al, 1989; Tyrer J, Duffy SW, Cuzick J. Stat Med 2004; 23: 1111-1130
FCRS
Models used to calculate likelihood of
BRCA1 or BRCA2 mutation:
• BRCAPRO - computer model, uses pedigree to
calculate risk based on several different models.
• Frank or Myriad Model/Tables - use family history and
personal history to estimate risk of mutation in BRCA1 or
BRCA2.
• BOADICEA (Breast and Ovarian Analysis of Disease
Incidence and Carrier Estimation Algorithm) – University
of Cambridge computer model to assess risk of
BRCA1/2 mutation.
Euhus D, Berry D, Parmigiani G, Iverson E, 1998; Frank TS, Manley SA, Olopade OI, et al, 1997,
1998. Antoniou AC, Hardy R, Walker L, Evans DG, Shenton A, Eeles R, Shanley S, Pichert G, Izatt
L, Rose S, Douglas F, Eccles D, Morrison PJ, Scott J, Zimmern RL, Easton DF, Pharoah PD.
J Med Genet. 2008 Jul;45(7):425-31. Epub 2008 Apr 15.
Characteristics of those families appropriate for
consideration for BRCA1 or BRCA2 testing
(including patient’s personal history)





several breast cancers or breast and ovarian cancer
two or more ovarian cancers in one family
presence of bilateral cancers of the breast or ovary
cancers diagnosed at younger than expected ages
multiple affected relatives, demonstrating an autosomal
dominant pattern of inheritance
 presence of individuals diagnosed with more than one cancer,
e.g. breast and ovarian
 breast and/or ovarian cancer and Ashkenazi (Eastern European)
Jewish heritage
 male breast cancer
Cindy’s Story
Alice
D. 50?
? stomach
Rick
Colon dx 31
D. 33
Susan
30 yo
James
5 yo
X3
No CA
Renee
65 yo
Ov dx 46
Br dx 52
John
66 yo
Janice
61 yo
FCRS
Bessie
D.91
Br Dx 91
Katherine
3 yo
John Jr.
6 yo
Kate
61 yo
Cindy
Jason
34 yo
31 yo
+ BRCA2
mutation
Caroline
2 yo
Jane
28 yo
Cindy’s Risk Assessment
Gail Model
Race - Caucasian
Age - 34
Age Menarche - 13
Age 1st live birth - 28
# Mother, Sister, Daughter with
Breast Cancer - 1
# previous biopsy - 0
5 year risk = 0.5%
lifetime risk = 19.2%
Claus Model
Using Table of One First
Degree Relative
Predicted cumulative
probability of breast
cancer by age:
39 = .8%
49 = 2.3%
59 = 4.9%
69 = 8.2%
79 = 11%
Benichou J, Gail M, Mulvihill J. 1996. JCO 14:103-10
Claus EB, Risch N, Thompson WD, 1994. CANCER
73:643-51.
FCRS
Hereditary Breast/Ovarian Cancer Syndrome
Br ca
44
Ov ca
52
d. 79
d. Br ca 42
L br ca 42
R br ca 55
Oophorectomy (BSO) 53
+ BRCA2
70-80
No cancer
3
75
3
5
2
+BRCA2
Bil mastectomy
Bil Salingooophorectomy
36
5
d. 94 ht dz
3
30-50
No cancer
- Risk Perception Everyone’s is Unique
• Individual’s view of “high risk”, “common”, “rare”, “unlikely”
is colored by their experience and psychological make-up.
• Half-full vs. half-empty
• Experience with statistics (“I will be the <1% who develops
….”)
• Personal experience with cancer or cancer scares, caring
for others with cancer (especially if repeatedly or recently)
• Relationships and age influence reaction - parent’s cancer
and child or adolescent vs. adult, siblings with cancer,
friends with cancer.
Page DL, Caro SW, Dupont SD, 1998.
Testing Process
•
•
•
•
Counsel/Education
Gather pedigree and documentation
Test affected individual for mutation
If family + for mutation, then can test
unaffected individuals
• If + mutation in family, - mutation in individual,
individual risk is close to population risk
• If no identified mutation in family, risk is
estimated based on history and empiric data
Outcome of process
• Clarify risks of cancer
• Identify individuals who may not be aware of
increased risk
• Identify individuals who may not be at
increased risk
• Identify those appropriate for increased
cancer surveillance, or measures to decrease
risk (prophylactic surgery, chemoprevention),
or those appropriate for research on
surveillance or chemoprevention
Options for Women at Risk
Increased Surveillance
Risk-reducing Surgery
Medical Intervention
FCRS
Increased Surveillance
Breast Cancer
• Clinical examination
every 6 months
• Mammogram yearly
beginning age 25-35
• MRI (ACS 2007)
• Monthly BSE
• Prompt evaluation of
abnormal findings
Ovarian Cancer
• Ca-125
• Pelvic color-doppler
ultrasound every 612 months
• Pelvic examination
every 6-12 months
ACS Recommendations for Breast MRI Screening as an
Adjunct to Mammography 2007
Recommend Annual MRI Screening (Based on Evidence*)
BRCA mutation
First-degree relative of BRCA carrier, but untested
Lifetime risk 20–25% or greater, as defined by BRCAPRO or other models that are largely dependent on
family history
Recommend Annual MRI Screening (Based on Expert Consensus Opinion )
Radiation to chest between age 10 and 30 years
Li-Fraumeni syndrome and first-degree relatives
Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives
Insufficient Evidence to Recommend for or Against MRI Screening
Lifetime risk 15–20%, as defined by BRCAPRO or other models that are largely dependent on family
history
Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)
Atypical ductal hyperplasia (ADH)
Heterogeneously or extremely dense breast on mammography
Women with a personal history of breast cancer, including ductal carcinoma in situ (DCIS)
Recommend Against MRI Screening (Based on Expert Consensus Opinion)
Women at <15% lifetime risk
* Evidence from nonrandomized screening trials and observational studies.
Based on evidence of lifetime risk for breast cancer.
Payment should not be a barrier. Screening decisions should be made on a case-by-case basis, as there may be particular factors to support MRI. More
data on these groups is expected to be published soon.
CA Cancer J Clin 2007; 57:75-89
Risk-Reducing Surgery
Oophorectomy
Mastectomy
Unfortunately not 100% effective in
eliminating ovarian cancer risk, as
intraabdominal carcinomatosis has
occurred (2-4%)
Questions - hysterectomy?
HRT?, do we screen after BSO
Bilateral oophorectomy reduced risk of
breast cancer in BRCA1 mutation
carriers. (RR=0.53). HRT did not
negate reduction in risk.
Total mastectomy vs..
subcutaneous
mastectomy?
Not 100% effective, true
risk reduction unclear,
>90%.
Hugely personal
Rebbeck TR, Levin AM, Eisen A, et al. JNCI 91(17):1475, Stuewing JP, Watson P,
decisions.
Easton DF, et al JNCI Monographs 1995. 17:330; Eisen A, Rebbeck TR, Wood
WC,Weber BL. JCO 18(9)”1980; May 2000. Hartmann LC, Daniel JS, Woods JE, et al.
NEJM 340(2):77-84, Jan 14, 1999;
Medical Interventions
Breast Cancer
Ovarian Cancer
• Oral contraceptives have
• Risk reducing
been shown to decrease the
medications should
risk of ovarian cancer in the
be discussed based
general population.
on current
• In women with mutations in
understanding.
BRCA1 or BRCA2 that risk
reduction was also
documented, with 60%
reduction (RR=0.4) with use
of 6 years or more.
Narod SA, Risch H, Moslehi R, et al. NEJM 1998, Aug 13;339(7):469-71.
Fisher B, Costantino JP, Wickerman DL, et al. JNCI, 1998; 90(18):1371-1388.
Misconceptions about genetic testing:
1.
Testing is not covered by insurance. In most instances insurance
covers the cost of testing like any other medical expense.
2.
Testing is complicated. True and false – choosing the appropriate test
is not always simple, there are significant opportunities for
misinterpretation. Seek consultation with a health care provider (nurse
practitioner, genetic counselor, MD) specializing in hereditary cancer.
3.
Testing will cause you to lose your insurance. Concerns exist about
genetic discrimination, but after nearly 15 years of clinical testing, no
significant problems have been seen. Members of group health
insurance plans have protection under Federal Law (HIPPA, 1996).
GINA signed into law May 2008, extends protections from discrimination
based on genetic information to those with private health insurance
“Walking with
the Ghosts of
My
Grandmothers”
a painting by
Hollis Sigler
on the cover of
the journal
Science
October, 1994
Hereditary Diffuse Gastric
Cancer Syndrome
Autosomal dominant inheritance
Germline mutations in CDH1/E-Cadherin Gene
(described in hereditary gastric families in
1998)
Initially found in Maori families, since described
in families from many ethnic groups.
Penetrance thought to be 70%,
Also increased risk of colon cancer and breast
cancer
Cowden syndrome
•An autosomal dominantly inherited hamartoma syndrome with an incidence of
at least 1/200,000 (probably an underestimate)
(hamartomas are benign, disorganized growths)
•characterized by multiple hamartomas that can occur
in any organ of the body
•pathognomonic cutaneous feature is the trichilemmoma,
a benign tumor derived from outer-root sheath epithelium of a hair follicle
•Carries a high risk of breast, thyroid, and endometrial cancers
•Variable expression
•Highly penetrant:
•Usually presents by the late teens to the late 20’s
•90% of individuals with CS have symptoms by age 20
•By the 3rd decade, 99% of affected individuals would
have developed mucocutaneous lesions
•Age-dependent penetrance: only 10% exhibit symptoms by age 10
Cowden syndrome
•Associated with inherited alterations in the gene, PTEN
(‘phosphatase and tensin homolog deleted on chromosome ten’),
also sometimes called MMAC1 (‘mutated in multiple advanced
cancer’) which was isolated in 1997
•PTEN is located on chromosome 10q23
•Function of PTEN:
•Tumor suppressor
•Controls pathway for regulation of cell proliferation and
cell survival
•Alterations in PTEN also associated with
Bannayan-Riley-Ruvalcaba (BRR) syndrome and a small
percentage
of cases of juvenile polyposis syndrome (JPS).
Cowden Syndrome
Cancer Risks Associated with Cowden Syndrome:
Female Breast Cancer 25%-50% lifetime risk (vs ~11% in general pop.)
Average age of diagnosis may be around age 38-46
Thyroid Carcinoma 3%-10% lifetime risk
(vs 1% in general population)
Non-medullary
Usually follicular, but can be papillary
Endometrial Cancer 5-10%
Other cancers may be associated with Cowden syndrome:
Genitourinary Mucocutaneous Male Breast Gastrointestinal
Central Nervous System medulloblastomas are more common
Other, e.g. liposarcoma
Li-Fraumeni Syndrome
• Initially described by Frederick Li and Joseph Fraumeni
(1969) as syndrome associated with sarcomas and other
diverse tumors.
• Associated cancer include soft-tissue sarcoma,
osteosarcoma, early-onset breast cancer, brain tumors,
adrenocortical carcinoma, and leukemias, primarily acute
leukemia. (Was also called SBLA for Sarcoma,
Breast/Brain, Leukemia, and Adrenal)
• Inherited in an autosomal dominant manner.
• Other reports have associated other cancers - including
melanoma, cancers of the stomach, pancreas, colon,
and esophagus, and gonadal germ cell tumors.
• Gene mutations TP53 (1990) on 17p13, possibly others
DNA BANKING
If genetic testing is not possible or
not informative, DNA banking is a
relatively inexpensive and simple
procedure that can save a sample
of the affected person’s DNA for
future testing.
Resources to find cancer genetics
professionals in your area:
• http://www.cancer.gov/search/genetics_
services/
• genetests.org
• http://www.nsgc.org/resourcelink.cfm
Disparities….
Family Cancer Risk Service
of the Vanderbilt-Ingram Cancer Center is
made possible by support from:
Vanderbilt-Ingram Cancer Center
Tennessee Breast Cancer Coalition
Susan G. Komen Foundation, Greater
Nashville Affiliate (past)
Our physician consultants:
Mark Kelley, Ingrid Meszoely,
Marta Crispens, John Phay, Paul Wise
And the individuals and families who seek
counsel
From Generation to Generation © 1998
Jay M. Rotberg, artist and sculptor
Family Cancer Risk Service
of the Vanderbilt-Ingram Cancer
Center
Susan Caro, RNC, MSN, APNG
Director
Kate McReynolds, MSc, RN
Telephone:
(615) 343-0738
or TOLL FREE:
1-877-688-7555
From Generation to Generation ©
1998
Jay M. Rotberg, artist and sculptor
Selected Hereditary Cancer Syndromes
Hereditary Breast/ovarian cancer
BRCA1, BRCA2, CHEK2
Other?
Breast, ovarian prostate, pancreatic r (BRCA2), ? Colon
and other cancers
Site specific breast cancer
BRCA1, BRCA2
Breast
Site specific ovarian cancer
BRCA1, BRCA2
Ovarian
Li-Fraumeni Syndrome
TP53, CHEK2
Breast, sarcomas, adrenocortical carcinoma, leukemia,
brain tumors
Cowden
PTEN
Breast, thyroid, benign lesions of skin, breast, thyroid;
renal cell carcinoma
Peutz-Jegher Syndrome
STK11
Breast cancer, benign ovarian tumors, testicular tumors,
pancreatic cancer, polyps (ureter, bladder, GI tract, renal
pelvis, characteristic skin lesions (melanin spots, lips,
buccal mucosa
Familial adenomatous polyposis
APC, MYH
Polyposis, colorectal cancer, thyroid gastric cancer,
periampullary carcinoma, hepatoblastoma
Variant of FAP - Attenuated FAP
APC
<100 colorectal polyps, later age onset CRC, gastric,
duodenal adenomas or cancer
Variant of FAP - Gardner’s Syndrome
APC
Osteomas of skull and mandible, CHRPE, dental
anomalies, lymphangiomas, lipomas, desmoids
HNPCC (Lynch Syndrome)
MLH1, MSH2, MSH6
, PMS1, PMS2,
Colorectal cancer (often right sided and multifocal),
endometrial ca, ovarian ca, small bowel, stomach,
pancreas, ureter, renal pelvis
Turcot’s Syndrome
APC, MMR genes
Colorectal adenomas, CRC, primary brain tumors
(mudulloblastoma APC, glioblastoma MMR)
OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4):191-208, April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York.
Selected Hereditary Cancer Syndromes (cont’d)
MEN
MEN1, RET
Multiple endocrine cancers
Retinoblastoma
RB1
Retinoblastoma, often bilateral and
< 1 year of age, also associated
increased risk of sarcoma,
melanoma, brain tumors
Von Hippel-Lindau
VHL
Renal cell carcinoma, retinal
angioma, cerebellar
hemangioblastoma,
pheochromocytoma, pancreatic
cysts, islet cell tumor
Prostate cancer
HPC1, BRCA1, p53
Earlier age onset prostate cancer,
maybe part of other syndromes
Pancreatic cancer
BRCA2, MADH4, TP53,
CDKN2A, ARMET, +++
Other syndromes, HNPCC, HBOC,
Li-Fraumeni, VHL, melanoma,
hereditary pancreatitis, site specific
pancreatic ca
Melanoma
P16, CDK4, others
Melanoma, dysplastic nevi,
pancreatic ca
OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4):191-208, April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York
Stigmata of Selected Syndromes Associated with Susceptibility to Cancer
Syndrome
Major Cancer Risks
Selected physical findings
Cowden Syndrome
Breast cancer
Facial papules, oral “cobblestone”
papules, macrocephaly
Down Syndrome
Acute leukemia
Characteristic facies, round head,
congenital heart disease
Fancomi Anemia
Acute leukemia
Upper extremity malformations,
increased skin pigmentation
FAP (Gardner’s subtype)
Colon cancer
Retinal pigmentation, sebaceous cysts,
osteomas, impacted teeth, exostoses, ,
desmoids, florid polyposis
Muir-Torre syndrome
Colon cancer, skin tumors
Sebaceous adenomata,
keratocanthomata, basal cell carinomas,
Multiple Endocrine
Neoplasia type 2b
Medullary thyroid
carcinoma,
pheochromocytoma,
Enlarged and nodular lips, Marfanoid
habitus
Peutz-Jegher syndrome
Breast, colon cancers
Dark spots on lips, perioral areas,
buccal mucosa and extremeties
Turcot syndrome
Colon cancer, brain tumors
Polyps, café-au-lait spots, sebaceous
cysts on skin
“WAGR” syndrome (Wilm’s
tumor, aniridia, genitourinary
abnormalities and mental
retardation)
Wilm’s tumor
Aniridia, genitourinary malformations
Offit, K. Clinical Cancer Genetics, Risk Counseling & Management, Wiley-Liss, New York, 1998.
RED FLAGS – Think about hereditary
susceptibility when you see:
• Breast Cancer at age less than 50
• Ashkenazi Jewish heritage and breast or ovarian
• More than one ovarian cancer in a family, or breast and
ovarian cancer
• Men with breast cancer
• More than one pancreatic cancer in a family
• Colorectal cancer less than 50 years of age
• Polyposis
• Pheochromocytoma
• Medullary thyroid cancer