Hereditary Cancer Syndromes

Presenter:
Dr.Vineetha Boban
Moderator:
Dr.S.M.Choukimath
 OUTLINE
 Genetic terminology and concepts
 Hereditary cancers
• When to consider
• Genetics assessment
• Surveillance
 AUTOSOMAL DOMINANT CANCER SYNDROMES:
 Hereditary breast & ovarian cancer syndromes
 Li-Fraumeni Syndrome
 Cowden syndrome
 Lynch syndrome
 FAP
 PJ syndrome
 MEN 1,MEN2
 Neurofibromatosis 1&2
 VHL
 Birt-Hogg-Dube Syndrome
 Carney complex
 AUTOSOMAL RECESSIVE CANCER SYNDROMES:
 Ataxia telangiectasia
 Bloom Syndrome
 Fanconi Anemia
 Xeroderma pigmentosum
 Genetic testing
 Genetic counseling
 Cancer is a genetic disease.

• Random replication errors

• Exposure to carcinogens

• Faulty DNA repair processes

 Hereditary cancer syndromes
• Hereditary cancer syndromes are caused by
mutations in certain genes passed from parents to
children.
• In a hereditary cancer syndrome, certain patterns
of cancer may be seen within families.
• These patterns include having several close family
members (such as a mother, daughter, and sister)
with the same type of cancer, developing cancer at
an early age, or having two or more types of
cancer develop in the same person. 
Penetrance and
expressivity
Incomplete Penetrance
 Variable Expressivity
• Not all individuals with a mutation will develop
the same manifestations
– E.g. BRCA1 patient
• Mom has ovarian cancer
• Daughter has breast cancer
– Von Hippel Lindau
• Variety of systemic manifestations
• Not all patients will have same organ
involvement
 When to suspect hereditary cancer
syndromes ?
 Cancer in >2 relatives (on same side)
 Early age at diagnosis
 Multiple primary tumors
 Bilateral or multiple rare cancers
 Constellation of tumors consistent with specific
cancer syndromes.
 Evidence of autosomal dominant transmission.
 Ancestry
Spectrum of hereditary
cancer syndromes
 Hereditary Breast and Ovarian Cancer(HBOC)

• Mc type of inherited cancers.

• mutations in the BRCA1 and BRCA2 genes.
 Risk Factors
•Breast cancer diagnosed at age 50 or younger

•Ovarian cancer at any age

•Two primary breast cancers

•Male breast cancer

•Triple Negative Breast Cancer

•Pancreatic cancer with a breast or ovarian

cancer
• Ashkenazi Jewish ancestry with an HBOC-
associated cancer
• Two or more relatives with breast cancer, one
under age 50
• Three or more relatives with breast cancer at any
age
• A previously identified BRCA mutation in the
family
 BRCA-1

• BRCA-1 related tumors typically occur in:

• younger women
• Have more aggressive features:
 histologic grade
 high proliferative rate
 aneuploidy
 absence of ER,PR and HER2
 BRCA-2
• 40-70% Breast cancer
• 10-20% Ovarian cancer
• 30-40% Prostate cancer
• 6% Male breast cancer
• 3% Melanoma
• 5% Pancreatic
CONSEQUENCES OF HAVING A
BRCA MUTATION:
• Mutation in a gene called TP53
•  1 in 5,000 to 1 in 20,000.
• 25-fold greater chance of developing a malignant
tumor by age 50.
• Classic LFS is diagnosed when a person has all of
the following criteria:
 A sarcoma diagnosed before age 45
 A first-degree relative, with any cancer before age
45
 A first-degree relative or second-degree relative,
with any cancer before age 45 or a sarcoma at any
age
 Screening Protocol
• Whole body magnetic resonance imaging (MRI),
• Brain MRI
• Abdominal ultrasound,
• Colonoscopy/Upper endoscopy (performed every 1-2
years)
• Biochemical markers of adrenal cortical function
• Complete urine analysis every 3-4 months
• Blood work every 4 months (ESR,LDH,AFP)
• Monthly breast self examination
• Biannual clinical breast examination
• aka multiple hamartoma syndrome

• Multisystem genetic disorder

• Early twenties.

• Multiple hamartomatous polyps in GIT,

mucocutaneous lesions such as oral mucosal
papillomas,palmoplantar
keratosis,trichilemmomas.
Thyroid cancer in cowden syndrome
 LYNCH SYNDROME
• Aka Hereditary Non-Polyposis Colon Cancer(HNPCC)

• 2-3% of total colon cancer cases.

• Incidence:1 in 400

• DNA mismatch repair defect.

• germline mutations in one of the 6 genes:

MLH1,MSH2,MSH3,MSH6,PMS1 ,PMS2
 Types of lynch syndrome
• Lynch syndrome I
site specific CRC(more in right colon)

• Lynch syndrome II
CRC,Endometrial,Ovarian,Gastric,small
bowel,pancreatic,breast,hepatobiliary,CNS,
sebaceous gland Ca.
 Bethesda Guidelines
Screening for Lynch syndrome

• Colorectal cancer
Under age 50
• With a synchronous or metachronous Lynch
(HNPCC) tumor.
• Under age 60 with histology consistent with Lynch
(HNPCC) syndrome.
Tumor infiltrating lymphocytes, Crohn-like
reaction, mucinous/ signet ring differentiation,
medullary growth pattern
• With a first-degree relative who has an HNPCC
tumor
 Muir-Torre Syndrome
• Variant of Lynch syndrome.
 Turcot syndrome
• Colonic polyps
• Glioblastoma
multiforme
• Medulloblastoma
• Congenital
hypertrophy of the
retinal pigmented
epithelium.
 Familial adenomatous polyposis
• Highly penetrant
• AD disorder
• Germline mutation in the adenomatous
polyposis coli(APC) gene on chromosome
5q.
 Clinical features
• Hallmark – presence of atleast 100
adenomatous polyps in the colon/rectum

• Cancer risk for FAP patients is virtually

100% by age 40 years.
 Genetic suceptibility
• Positive genotype and significant polyp burden if
present- prophylactic colectomy
• Elevated risk for upper GI tract neoplasms
• Other phenotypes observed in FAP patients
include:
 congenital hypertrophy of the retinal pigment
epitheilum,
 dental anomalies,
 epidermoid cysts,
 osteomas,desmoid tumors,mesenteric fibrosis.
 Therapeutic intervention
• Routine monitoring for complications.
• Annual examinations
• Surgery, Chemotherapy and radiotherapy
for cancerous tumors.
• Genetic testing .
• Autosomal dominant
• Gene Locus on chromosome 3p25
• 1 in 35000 live births
 SCREENING PROTOCOL
• Annual physical examination
• Annual comprehensive fundus examination
• MRI of Brain & Spinal cord every 3 years
to age 50 and every 5 year thereafter
• Annual retinal USG with CT scan every 3
year
• Annual 24hr urine collection for VMA.
•Autosomal
dominant disorder

•Mutation in the
FLCN gene
DIAGNOSTIC CRITERIA
 Clinical features
• Short stature
• Sun sensitive skin changes on face,hands
• High pitched voice
• Distinctive facial features including :
 long narrow face
 small lower jaw
 large nose
 prominent ears
 Diagnosis and screening
• DEB test (diepoxybutane analysis)
• MMC test
• Usually found at a very young age (1-2years)
• 1 in 1 lakh individuals.
• Mutation of nucleotide excision repair enzymes.
 Diagnosis

• Amniocentesis
• Chorionic villous sampling
• Severe sunburn after first exposure to sunlight.
• Development of typical symptoms
 The American Society of Oncology has
recommended that three conditions should be met
before an individual is tested for hereditary cancer
predisposition:
 There should be a reasonably high likelihood of a
positive test.
 The physician should be able to interpret the
result
 Result should be intended to influence the medical
management.
 THE FUTURE!!
• Genetic information can be used to create effective
clinical and diagnostic tools.
• Future research will allow for the continued
development of the rational therapies directed
specifically to individuals with hereditary cancer
syndromes.
 REFERENCES
1.Robbins and Cotran Pathologic Basis of disease,9th Edition
2.Harrison’s principles of Internal Medicine,19th Edition.
3.Devita, Hellman, and Rosenberg’s cancer: principles and
practice of oncology 11th edition
4.Rahner N, Steinke V. Hereditary cancer syndromes. Dtsch
Arztebl Int. 2008;105(41):706–714.
doi:10.3238/arztebl.2008.0706
5.Steinke, Verena, et al. "Hereditary nonpolyposis colorectal
cancer (HNPCC)/Lynch syndrome." Deutsches Ärzteblatt
International 110.3 (2013): 32.
6.Other internet sources