Download Heredity Cancer Syndromes: Implications for Improved Medical Management and Cancer Prevention

Hereditary Cancer Syndromes:
Implications for Improved Medical
Management and Cancer Prevention
Objectives

Recognize who to refer

Review hereditary cancer syndromes

Discuss genetic testing available for pediatric and
adult cancer as well as genetic research opportunities

Provide the latest medical management
recommendations for cancer prevention and early
detection in carriers of a genetic predisposition for
cancer
Debbie Pencarinha, M.S., C.G.C.
Li
Licensed
d Genetic
G ti Counselor
C
l
Kingsport Hematology and Oncology
15th Annual Primary Care Conference
March 30, 2011
Audience Demographics
1. Family practice
2. Internal medicine
3 Ob/
3.
Ob/gyn
4. Pediatrics
5. Specialist
6. Other
Personal Identification with
Cancer
1. Personal history of cancer
2. Personal and family history
3. One 1st or 2nd degree relative
4. 2 or more 1st or 2nd degree relatives
5. Distant or no family history of
cancer
Hereditary cancer genes can lead
to cancer risks as high as 100%!
BRCA1 or BRCA2 = 85%
MLH1/MSH2 = 80%
APC = 100%!!!
P53 90 %
Percentage of Cancer that is Hereditary
Are cancer genes REALLY rare?
1. 1-2%
Tri-Cities population > 500,000
2. 5-10%
1
3. 15-20%
4. 25-30%
in 400 carry BRCA = 1,250
 1 in 1000 carry Lynch syndrome = 500
 1 in 20,000 carry Li Fraumeni = 25
(previously thought 400 worldwide!)
All cancer is genetic …
but not all cancer is hereditary!
“An ounce of prevention
is worth a pound of cure”
Germline mutations
Parent
All cells
affected in
offspring
Mutation in
egg or
sperm



Somatic mutations
Child
Present in egg or sperm
Are heritable
Cause cancer family syndromes
Somatic mutation
(eg,
(eg breast)


Occur in nongermline tissues
Are nonheritable
ASCO
Hereditary Breast and Ovarian
Cancer (HBOC)
Mutations in Specific Genes are
Responsible for Hereditary Cancer Risk
•~
MYH
180,510 new cases in 2007
• ~10,614 due to a BRCA mutation
MSH2
MSH6
MLH1
• ~22,430 new cases in 2007
• ~2,243 due to a BRCA mutation
VHL
APC
15%
15%
20%
PMS2
CDKN2A
RET
PTEN
BRCA2
RB1
CDH1
PALB2
ATM
TP53
BRCA1
5%–
5%
–10%
5%–
5%
–10%
TP53
MLH1
Breast Cancer
Ovarian Cancer
Sporadic
Family clusters
Hereditary
STK11
Cancer Statistics, 2007, American Cancer Society
ASCO
Cancer Susceptibility Genes and DNA Repair
BRCA1
Endogenous DNA
damage
 hydrolysis
Exogenous DNA
damage
 ROS, RNS
 UV rad.
 ionizing rad.
 chemicals
4
Avg cell repairs 10 SSB
each day
Exon 2






17q12 (22 exons)
Tumor suppressor
Dominant Inheritance
Up to 87% risk for BC
Up to 44% risk for OC
Tumors tend to be
ER-, PR-, HER2-
185delAG
Low penetrance
Med. onset br=55y
br=55y
Exon 11
Exon 13
4184delTCAA
Duplication
British mutation
Med. onset
br=41y
br=
41y
Med. onset br=47y
br=47y
Refer women diagnosed <50 with triple negative breast cancer…
Venkitaraman A. NEJM
2003;348:1917-1919
Chen Y, Lee WH et al., J Cell Physiol. 1999;181:385-92.
Family with Hereditary Risk of
Breast and Ovarian Cancer
BRCA Mutation: Other Cancer Risks
BRCA1
BRCA2
Increased
6%
16-30%
19-34%
Cancer
Male Breast Cancer
Prostate
Pancreas
2 to 3-fold increase
Melanoma
GI cancers:
Stomach, colon
Breast ca d.49
5%
ovarian ca
dx 49; d. 52
< 5%
2-fold increase
57
60
No increase
breast ca
dx 38
Liede A, Karlan B, Narod S. JCO 2004;22(4):735-742
At risk?
36
45
43
28
35
39
Hereditary Breast and Ovarian Cancer
Syndrome
After Mutation is Identified, Risk of Individual Family
Members is Clarified

Cancer
Breast ca d.49
Red-flags (Individuals at increased risk for hereditary cancer)

High risk


Population risk
ovarian ca
dx 49; d. 52
57

60



breast ca
dx 38
36
45
43
28
35
As more of these features are present in the family, the chance of
a BRCA1 or BRCA2 mutation increases
39
NCCN Guidelines: High Risk Screening
And Hereditary Breast/Ovarian

Women




BSE: Begin at age 18
CBE: Every 6 months
b i att age 25
begin
Annual mammogram
& breast MRI: begin
age 25 (or individualized)
Consider
chemoprevention

Breast cancer before age 50
Ovarian cancer at any age
Bilateral breast cancer
Both breast cancer and ovarian cancer diagnosed in the same
individual
Male breast cancer
Ashkenazi Jewish ancestry
Men



BSE education,
monthly BSE
CBE semiannually
CBE,
i
ll
Baseline mammogram
• Annual if gynecomastia or
parenchymal/glandular
breast density on baseline
study

Strict adherence to
prostate cancer
screening
Sensitivity of Screenings





Mammography: detects 36% of cancers
Ultrasound: detects 33% of cancers
MRI: detects 77% of cancers
Sensitivity
i i i up to 95% with
i h Mammography,
h
Ultrasound, MRI and clinical breast exam.
Sensitivity and specificity: dependent upon
radiologic experience and follow-up capabilities
Warner, et al, 2004. JAMA, 292(11):1317-1325.
Prophylactic Mastectomy

Total Mastectomy


Risk Reducing SalpingoSalpingo-Oophorectomy

95-99% removal of breast
tissue

S b
Subcutaneous
or nipple
i l
sparing mastectomy


 risk of GYN and
breast cancer
Pathologic evaluation
of specimen after
BSO

Thin skin flaps
2-3mm thick nipple-areolar
flap


Awareness of
spectrum of lesions
Metcalfe KA et al., Lancet Oncol 2005; 6:431-4; Fatouros M. et al., Annals of Surg Oncol
2007;15(1)21-33
Kauff et al., Atlas Of Cancer, 2008; Weber et al., Zaloudek et al, Am J Surg Pathol 2009;33(8)1125-36
Tamoxifen
Impact on Mortality?
BRCA1
53%
BRCA2
71%
Absolute Survival Gain
BRCA1
Absolute Survival Gain
BRCA2
Mammo + MRI only
6%
4%
PM at age 25y
13%
8%
PM at 25y & PO at 40y
26%
12%
PM at age 40y
11%
7%
PO at age 40y
15%
6%
With no intervention survival
to age 70 =





First drug approved by FDA to reduce the risk of developing a cancer.
20 mg day for 5 years
Estimated that 2 million women in US could benefit from Tamoxifen
Risk reduction of up to 49% (NSABP P-1)
Common side effects:







Overall survival to age 70 in the general US population = 84%
Survival Analysis of Cancer Risk Reduction Strategies for BRCA1/2 Mutation Carriers . Plevritis SK, et
al., JCO 2010;28(2):222-31.
2-10% BRCA carriers
have occult cancers
2-3mm interval
sections

Hot flashes
Vaginal discharge or vaginal dryness
Fluid retention
Fracture risk reduction
Lowering of cholesterol levels
Reduced incidence of benign breast disease and fewer biopsies
Rare: endometrial cancer, thromboembolic events, cataracts
Contraindications: history of DVT, PE, stroke, TIA, pregnancy
Fisher, et al, 1998. Journal of the National Cancer Institute, 90(18):1371-1388.
PARP Inhibitors Hinder Alternative DNA Repair in BRCA Deficient Cells
Leading to Cell Death
Effects of delaying prevention on survival
6
Survival benefit inyears
5
4
3
Tamoxifen
2
Oophorectomy
1
Tamoxifen and
oophorectomy
0
30
35
40
45
50
55
Age at initiating preventive measure
© The Author
2010. Published by Oxford University Press on behalf
of the European Society for Medical Oncology.
Underhill C et al. Ann Oncol 2010;annonc.mdq322
Case I -- 32 yo female is diagnosed with
breast cancer after stereotactic biopsy. She
had a prior history of adrenocortical
carcinoma at age 2

Lumpectomy and radiation vs.
mastectomy if genetic test was positive

“No other history of breast or ovarian
cancer but there are lots of relatives with cancer”

Patient did not want chemotherapy, strongly desired to
have a child with her new partner
Olufunmilayo I. Olopade, M.B.,B.S.
University of Chicago Medical Center
60
Mastectomy
Mastectomy and
oophorectomy
LFS Cancer Risks
Li--Fraumeni Syndrome:
Li
Incidence—
Incidence
—1 / 20,000








Breast cancer (early-onset 25.5%)
Soft tissue sarcoma (14.3%)
Adrenocortical carcinoma (13.1%)
(13 1%)
Brain tumor (11.9%)
Osteosarcoma (11.0%)
Hematological (3.4%)
Other: melanoma, colon, pancreatic, lung, stomach,
ovarian, head and neck, renal


Petitjean, et al (2007) Hum Mutat
Radiation exposure and cancer risk in
LFS patients has been documented:
Available surveillance guidelines for LFS:
are these sufficient?
• Recommended
surveillance for children
– Annual physical examination, CBC, urinalysis
– Annual abdominal ultrasound
– Additional organ based screening depending on family history
• Recommended
surveillance for adults
– Annual physical examination (with skin and neuro evaluation)
– Annual CBC, urinalysis
– For women: clinical breast exam q6 months at 20-25 yrs
– For women: annual mammogram at 20-25 yrs
– Consideration of annual rapid full body MRI or PET scan—NEW
(found ca in 20% of asymptomatic carriers when screening--soon to be
published by Schiffman et. al.)
Slide Courtesy of Kowalski --CHOP
http://www.nccn.org http://www.genetests.org
Cancer risk by age:
 50% by age 30 (vs. 1% pop risk)
 90% by age 70
Age-specific cancer risk:
 42% from 0-16 years
 38% from 17-45 years
 63% after age 45
Lifetime risk of cancer:
 90%- 100% for women
 70% for men

Heyn R, et al. J Clin Oncol 1993
 Several cases of soft tissue sarcoma occurred in
previous radiotherapy fields

Hisada M, et al. J Natl Cancer Instit. 1998
 Radiotherapy led to 8 subsequent solid tumors in six
patients and one patient with acute leukemia

Salmon A, et al. Clinical Oncology 2007.
 Case report of a LFS patient who developed a second
and third primary in the irradiation field.
Clinical Features of Lynch Syndrome
(Hereditary Nonpolyposis Colorectal Cancer)
Case Report II


A 58-year old male is diagnosed with three
separate primary colon cancers.

He has a partial colectomy.
colectomy

He is referred to genetics for testing despite a
negative family history.

He tests positive for Lynch syndrome.

Early but variable age at CRC diagnosis (~45 years)years)- ~ 80%
Lifetime risk for cancer: 90% ---males,
males, 70%
70%--females

Tumor site in proximal colon predominates

Extracolonic cancers:

endometrium - Up to 60% risk

ovary – 9-12% risk

stomach – 11
11--19% risk

urinary tract – 4-5% risk

small bowel – 1-4%

bile ducts – 2-7%

brain/CNS – 1-3%
Colonoscopy Improves Survival of GeneticallyGeneticallyConfirmed Lynch Syndrome
Surveillance
No surveillance
Survival
100
92.2%
80
73.9%
60
40
0
5
10
15
Follow--up time (years)
Follow
Gastroenterology 2000;118:829
2000;118:829--34
NCCN guidelines for management of
1.2011--10/4/10)
10/4/10)
Lynch Syndrome (version 1.2011--
NCCN guidelines (cont.)

Colonoscopy beginning at 20-25, every 1-2 years

Consider EGD with extended duodenoscopy and polypectomy
every 2-3 yrs. at age 30-35.

Consider prophylactic TAH-BSO after childbearing

Preliminary data suggests baseline gastric biopsies

Educate re: prompt response to endometrial ca
symptoms

Consider capsule endoscopy for small bowel cancer every 2-3 yrs
beginning at 30-35.

Consider annual urinalysis.

Annual endometrial sampling may be appropriate in
select patients

Annual physical exam with a high index of suspicion for
associated cancers.

Transvaginal u/s may be considered
Accumulating evidence for “anticipation” in Lynch syndrome families…
Clinical Characteristics of Classic
Familial Adenomatous Polyposis (FAP)
Hereditary Susceptibility to CRC

Clinically defined as:
• at least 100 adenomatous polyps
• often thousands of polyps
• present throughout the colon
• with early age of onset
~16 yrs, range 8-34 yrs

autosomal dominant
near 100% penetrance
20-30% de novo mutation rate1
(eg., no prior family history)
Sporadic
(65%–
(65%
–85%)
Familial
(10%–
(10%
–30%)
Rare CRC
syndromes
(<0.1%)
Lynch Syndrome (aka
Hereditary nonpolyposis
colorectal cancer) (5%)

Familial adenomatous polyposis
(FAP) (1%)
Adapted from Burt RW et al. Prevention and Early Detection of CRC,
CRC, 1996
Pediatric Management of FAP

Endoscopic Surveillance or Management

Infancy to 5 years (for known mutation carriers)
• Twice yearly physical exam & serum AFP
• Annual abdominal ultrasound (hepatoblastoma)

Childhood
• Evaluation of GI symptoms (changes in stool
number/consistency, mucous or blood, abdominal/back
pain) (?early indicators of CRC)

10-12 Years
• Genetic counseling
• First screening colonoscopy (adenoma development)

1Bisgaard,
ASCO
Other Cancer Risks and Management for
Older Individuals with FAP
•UpperGI malignancies --duodenal ampullary carcinomas, gastric ca
Screening: EGD every 1-3 years
•Non-intestinal cancers = HB (1-2%), desmoid tumors (10-20%),
pancreatic ca (2%), thyroid ca (1-2%), medulloblastoma (1-2%),
benign adrenal adenomas or other adrenal masses (7-13%)
Screening: periodic EUS (no data), annual thyroid exam
• Colorectal
polyps and cancer
Screening: Sigmoidoscopy or colonoscopy q 1-2 years, starting at 10 12 yrs or 10 years before earliest cancer diagnosis in the family
• Total
Vasen HF, et al. GUT 2008, Aretz S, Dtsch Arztebl Int 2010, www.NCCN.org V.I.2010
Hum Mutation 1994; 3:1213:121-125
Colectomy after initial polyps are identified
EJ Groen et al. Annals of Surgical Oncology 2008; 15(9):2439-2450
Attenuated FAP (AFAP)
Colorectal Cancer in FAP
is Inevitable without Intervention
Fewer polyps than classic FAP



~20-100 colon polyps
Polyps generally begin at an older age (~44)
generally
ll right-sided
i ht id d colon
l polyps
l

Cancer risk approaches 80-100%

Extra-intestinal manifestations may be present

later colorectal cancer onset (~50 yr)
Probability of cancer (%)
100

FAP
HNPCC
Population Risk
30
Age (Years)
Risk Factors for Renal Cancer


Male:Female (2:1)
Non--hereditary factors
Non






smoking
end stage renal disease (30X)
cystic diseases of the kidney
hypertension
analgesic use
Hereditary (~4(~4-5% of all cases)



Multiple tumors
Bilateral disease
Young age at onset
50
70
Bussey, Familial Polyposis Coli 1975
Petersen, Gastroenterology 1991; 100:1658
Hereditary Renal Cancer Syndromes
Syndrome
Gene / Locus
von Hippel-Lindau (VHL)
VHL / 3p26-p25
Familial Non-VHL clear cell RCC
H dit P
Hereditary
Papillary
ill R
Renall C
Carcinoma
i
(HPRCC)
Chromosome 3
translocations-all different
c-MET
MET / 7q31.1-34
7 31 1 34
Birt Hogg Dube (BHD)
FLCN / 17p11.2
Hereditary Leiomyomatosis & Renal Cell
Carcinoma (HLRCC)
? Familial Renal Oncocytoma (FRO)
FH / 1q42.1
? Low Penetrant susceptibility genes
VHL Clinical Manifestations & Incidence
Retinal 45-60%
Angioma
Endolymphatic
sac tumor 10%
Pancreatic
cysts 90%;
islet cell
tumors;
cystadenomas
Epididymal
cystadenomas
20-26%
VHL: CNS Hemangioblastoma
(benign)
Cerebellar HB
65%
Spine HB
13-60%
Pheochromocytoma
15%
Clear cell renal
cancer 35% - 45%
Cysts 60-80%
Broad Ligament
cystadenomas
Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI
Birt‐‐Hogg
Birt
Hogg‐‐Dube (BHD): Fibrofolliculomas
 Benign tumor hair follicle
 Frequency Frequency ~84%
84%  Distribution primarily face & neck
Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI
Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI
BHD: Pulmonary Cysts
 84% one or more pulmonary cyst
 38% history of pneumothorax
 Can be recurrent
 Bilateral Slide from Lindsay Middelton, RN, CGC; Urology Oncology Branch, NCI
Preventative Measures for
Mutation Carriers–
Carriers– MEN2A, 2B

Screen for pheochromocytoma first!

Totall Thyroidectomy
h id


< 6 yo for MEN2A
At birth for MEN2B
The Genetic Influence on
Prostate Cancer Risk
Genome-wide Association Studies
Genomeand Prostate Cancer
 Prostate
cancer has the largest number of susceptibility
loci identified of any cancer to date
 At
l
least
25 SNPs (single
( i l nucleotide
l id polymorphisms)
l
hi
) are
commercially available
Limitations of SNP testing
Hereditary Prostate Cancer

Panel applies only to Caucasians

Other risk factors not included in calculation
(Hopkins Criteria)

Does not account for HPC or other genetic risk
• Potential for false reassurance
At least one of the following:
1.
Three or more first degree relatives

New technology
• Validity, clinical utility
2.
Three successive generations on one side of the family

There are no standard SNP panels
3.
At least two relatives affected at age 55 or younger

No consensus guidelines for medical management
(Carter –1993 J. Urol.)
Finasteride
Putative HPC Genes







HPC1/RNASEL (1q24-p25)
 Associated with younger and more aggressive HPC (inconsistent results)
HPC2/ELAC2 (17p11)
 2 missense mutations identified (linkage not replicated elsewhere)
MSR1 (8p22-p23)
 Associated with later onset HPC (confirmed in some but not all studies)
PCAP (1q42.2-q43)
 Linked to early onset PC (not confirmed by most studies)
HPCX (Xq27-q28)
 X-linked HPC (conflicting data)
HPC20 (20q13)
 Associated with PC in men over 65; less than 5 affected men/family, no male to male
transmission (conflicting data)
CAPB (1p36)
 Linked to prostate and brain cancer in 12 families (inconsistent results)

New guidelines:



Healthy men with PSA of 3.0 or lower should consider taking a 5-alpha
reductase inhibitor (Finasteride) to prevent prostate cancer





American Urological Association
American Society of Clinical Oncologists
Applies to men who plan to get yearly PSA or regular prostate cancer screenings and
h
have
no signs
i
off prostate
t t cancer
Prostate Cancer Prevention Trial found an overall 25% relative risk
reduction for prostate cancer in men who took Finasteride for 1-7 years
Reduction of about 50% in PSA by 12 months expected
Decision aid tool: www.asco.org/guidelines
Patient guide: www.cancer.net
Kramer, et al. (2009). (http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.16.9599)
X Germ cell & trophoblastic
tumors & neoplasms of
gonads
3%
XI Other malignant
epithelial neoplasms and
melanomas
4%
XII Other and unspecified
malignant neoplasms
0%
Pediatric Cancers
Ages 0-14
Not classified by ICCC
0%
IX Soft tissue and other
extraosseous sarcomas
7%
Leukemia
(includes MDS)
31%
VIII Malignant bone tumors
4%
VII Hepatic tumors
2%
VI Renal tumors
5%




V Retinoblastoma
3%
IV Neuroblastoma and
other peripheral nervous
cell tumor
6%
III CNS and misc
intracranial and intraspinal
neoplasms (2004+ only)
25%
Pediatric Cancers that Merit
Genetics Referral
Lymphomas and
reticuloendothelial
neoplasms
10%
Age-Adjusted and Age-Specific SEER Cancer Incidence
Rates, 2003-2007




Retinoblastoma (RB1)
Bilateral Wilms Tumor (WT1)
Adrenocortical carcinoma (p53)
Choroid Plexus Tumor (p53)
Rhabdomyosarcoma < 3 yo (p53)
Osteosarcoma < 10 yo (p53)
Medullary thyroid cancer (RET)
Hepatoblastoma (APC)
Pediatric Cancers
for Genetics Referral (cont.)
Pheochromocytoma / paraganglioma (VHL, NF1,
RET,SDHB, SDHC, SDHD)
 Retinal/cerebellar hemangioblastoma (VHL)
 Endolymphatic sac tumors (VHL)
 Optic pathway tumor (NF1)
 Acoustic or vestibular schwannomas (NF2)
 Atypical teratoid and malignant rhabdoid tumor
(INI1/SNF5)

Cancer risk and screening in
hereditary retinoblastoma (RB)
• 40%
of RB patients have hereditary disease
• RB1 gene (13q14)
p intracranial tumors
• 0.5 - 15% develop
• Increased life-long risk of 2nd cancers
– Bone, soft tissue sarcomas
– Brain, nasal cavity cancer
– Melanoma, lung, GI, bladder
– Commonly in irradiated sites
C-L Yu et al. JNCI 2009; 101:581-591.
C Eng et al. JNCI
1993; 85:1121-1128.
R Kleinerman et al. JCO 2005; 23:2272-2279.
Idiopathic hemihypertrophy (Beckwith
Beckwith-Wiedemann syndrome) and associated cancer risks
Leukemias/Lymphomas
•Overgrowth syndromes most commonly due to defects
in methylation of genes at 11p15

•7-14% risk of developing embryonal tumors


Wilms tumor, hepatoblastoma (2:1 ratio)
Adrenocortical carcinoma
Case reports of neuroblastoma, rhabdomyosarcoma
• Screening:
Abd U/S q 3 months until age 4 yrs
Serum AFP q 6-12 weeks until 4 yrs
At 4 yrs, renal U/S until age 8-10 yrs

Not typically hereditary
Risk for 1st and 2nd degree relatives (1.5-4.5%)
RARE families have a hematologic malignancy
syndrome
Higher risk for leukemia can be seen with other
genetic syndromes
Genetics Challenge #1
Genetics Challenge #2
Which patient does NOT need a genetics referral?
A patient tells you that her mother carries a BRCA
mutation. She has not been tested. What is her
approximate risk for breast cancer?
1. Male with breast cancer diagnosed at age 55
2. Twenty-year-old with medullary thyroid carcinoma
3. Sixty-year-old female with a sister diagnosed with
breast cancer at age 55. No other family history.
1.
2.
3.
4.
4. Fifty-year-old male diagnosed with colon cancer with
no family history
Last Challenge
Choose the FALSE statement:
1.
Skin lesions are as important as cancer in making
some genetic diagnoses
2.
BRCA mutations can be associated with Fanconi
anemia
3.
Breast cancer is not inherited from the father
4.
Do genetic testing on the person with cancer first
50%
50% x 87% = 45%
100%
25% x 87% = 22%
HOW DO WE IDENTIFY INDIVIDUALS
AT RISK?

Early diagnosis of cancer

Bilateral or multiple primaries of the same type

Two different, associated p
primary
y cancers (breast and
ovarian, colon and endometrial, medullary thyroid and
pheochromocytoma)

FAMILY HISTORY

Rare cancer—male breast ca, sarcoma, ACC

Polyposis
Genetic Information NonNon-discrimination Act
(GINA)
BOTTOM LINE
Signed May 21, 2008
KNOWLEDGE IS POWER

Many have concerns about
potential adverse effects to
employability
p y
y and health
insurability
GENETIC DIAGNOSIS ALLOWS FOR:




Protects individuals from genetic
information discrimination in
health insurance and employment




Earlier, more frequent, most appropriate screening for cancer
Surgical options for cancer prevention
Chemoprevention
Avoidance of risk factors (ie. radiation)
Research opportunities
Information for family members
Avoidance of unnecessary screening and anxiety
Genetic Testing is here to stay
Where should you go for information?
www.genetests.org
NCCN Guidelines™ &
Clinical Resources
http://www.nccn.org/index.asp
Genetics Home Reference
http://ghr.nlm.nih.gov/
Thank You!
Debbie Pencarinha, M.S., CGC
Genetic Counselor
Kingsport Hematology and Oncology
423--224
423
224--3736