2. OBJECTIVES
Review the role of genetic susceptibility in
various cancer types
Discuss the genetic syndromes and testing
options of various cancer types
3. GENETICS IN CANCER
5-10% of all malignancies are due to highly
penetrant hereditary cancer predisposition
syndromes [Ballinger, 2012]
Over 400 cancer-related genes have been identified
May account for many familial cancers
Caution! Current clinical testing may
include some of these genes of lower-risk
4. BREAST CANCER
•
•
•
•
Most prevalent type of cancer in women
2nd leading cause of cancer death in the US
New cases in 2012: 229,060 (estimated)
Deaths in 2012: 39,920 (estimated)
15%−20%
5%–10%
Sporadic
Family clusters
Hereditary
5. OVARIAN CANCER
•
•
•
•
22,000 newly diagnosed in the US annually
1.4% lifetime risk
~45% 5-year survival rate
4.6x RR if mother had ovarian cancer and 1.6x RR
is sister [Ziogas et al., 2009]
5%–10%
Sporadic
Hereditary
6. ENDOMETRIAL CANCER
• 47,130 newly diagnosed in 2012 (estimated)
• Lifetime risk is estimated to be 2.5%
• 8,010 estimated deaths in 2012
• Most common heritable form is Lynch syndrome
(a.k.a. hereditary non-polyposis coli) which
represents 2-3% of all cases
• May also be related to Cowden (PTEN Hamartoma
Tumor syndrome) and Peutz-Jeghers
7. COLORECTAL CANCER
•
•
•
•
•
4th most common cancer diagnosis in US
1 in 20 Americans will develop CRC
In 2012, expected number of new cases: 143,460
Expected deaths due to CRC: 51,690
Death rate is declining – early detection and
prevention
5%
General population
15%-20%
Personal h/o CRC
15%–40%
Inflammatory bowel disease
HNPCC mutation
70%–80%
FAP
>95%
0
20
40 60 80 100
Lifetime risk (%)
8. GASTRIC CANCER
•
Estimated 21,320 new diagnoses in the US (2012)
•
Estimated 10,540 deaths in the US (2012)
•
4th leading cause of cancer deaths worldwide
•
5 year survival of 20%
•
3-10% are hereditary
– Hereditary diffuse gastric cancer
– Hereditary breast/ovarian cancer
– Lynch syndrome
– Li-Fraumeni syndrome
– Familial Adenomatous Polyposis
– Juvenile polyposis
– Peutz-Jeghers
9. PANCREATIC CANCER
•
Estimated 43,920 new diagnoses in the US (2012)
•
4th leading cause of cancer-related deaths in the US
– Estimated deaths 37,390 in 2012
•
5-10% are hereditary
– Associated with familial forms of pancreatitis
– Breast-ovarian cancer syndrome (BRCA2 and PALB2)
– Familial multiple melanoma with 0.6-31% lifetime risk
•
Higher risk if first-degree relative with pancreatic ca.
– Lynch syndrome 0.4-4% lifetime risk
– Peutz-Jeghers 8-36% risk
10. MELANOMA
•
•
76,250 new cases in the US in 2012 (estimated)
9,180 estimated attributable deaths in 2012
•
~10% hereditary
– Familial atypical mole-melanoma syndrome
• Accounts 5-7% of all melanoma
– May be associated with HBOCS (BRCA2)
11. PROSTATE CANCER
• Most frequently diagnosed cancer in US men
- 36% of all cancers
• Lifetime risk for men in US: 15-20%
• 241,000 new cases diagnosed in 2012
(estimated)
• 5-10% is heritable
– ~40% under 55y
– Higher in families with
breast/ovarian cancer
5-10%
13. GENETIC SYNDROMES
•
There are those with dysmorphic or characteristic features that also have a
tumor predisposition
–
–
–
–
–
–
–
–
–
–
Beckwith-Wiedemann syndrome
Bloom syndrome
Diamond-Blackfan
Down syndrome
Fanconi anemia
Neurofibromatosis type I and II
Gorlin syndrome (basal cell nevus syndrome)
Rothmund-Thomson syndrome
Tuberous sclerosis
Werner syndrome
14. HEREDITARY BREAST CANCER SYNDROMES
•
Hereditary breast-ovarian cancer (5% of all breast cancer)
•
Li-Fraumeni (~1%)
•
PTEN hamartoma (<1%)
•
Peutz-Jeghers (<1%)
•
Hereditary diffuse gastric cancer syndrome
•
Also:
– Autoimmune lymphoproliferative (ALPS)
– Ataxia telangiectasia
– Bloom syndrome
– Familial melanoma
– Werner syndrome
– Xeroderma pigmentosa
15. HERITABLE OVARIAN
CANCER
• Lifetime risk varies from 12-60%
• Often earlier than those of the general population
• 6-15% breast/ovarian cancer syndrome
• Also includes:
– Lynch syndrome
– Peutz-Jeghers syndrome
16. BREAST/OVARIAN CANCER
SYNDROME
• Primarily BRCA1 and BRCA2
• Frequency of carriers 1 in 300 (BRCA1) to 1 in 800 (BRCA2)
– Ashkenazi Jewish (1 in 40)
• Accounts for >90% of families with breast and ovarian cancers
17. BREAST-OVARIAN CANCER
SYNDROME
•
Of those with BRCA1 mutations:
– 50-80% risk of invasive breast carcinoma-females
• ~1% risk for males
– Up to 60% risk of serous ovarian carcinoma
– Up to 30% risk of prostate cancer
– 1-3% risk of pancreatic
•
Of those with BRCA2 mutations:
– 40-85% risk of invasive breast carcinoma-females
• 6-7% risk for males
– Up to 35% risk of serous ovarian carcinoma
– Up to 39% risk of prostate cancer
– 2-7% risk of pancreatic
18. HBOCS- TUMOR
CHARACTERISTICS
• Breast tumor often originates from breast
epithelia cells
– Basal keratin positive
• More commonly a/w with invasive lobular
and ductal carcinoma as well as DCIS
• More likely to be high-grade malignancies
and lymph node positive
– Estrogen receptor negative
– Progesterone receptor negative
– Her2/neu negative
• >90% ovarian serous adenocarcinoma
19. HEREDITARY CRC
SYNDROMES
•
Accounts for 5-10% of all CRC cases
•
Polyposis types:
– Adenomatous
• Familial adenomatous polyposis (<1%)
• MYH-associated polyposis (<1%)
– Hamartomatous
• Juvenile polyposis (<1%)
• Peutz-Jeghers
• Cowden (PTEN)
•
Lynch syndrome (2-3%)
– Often not polyps but can have and still increased cancer risk
•
Seldom in:
– Bloom, hereditary diffuse gastric cancer syndrome, and Li-Fraumeni
20. LI-FRAUMENI SYNDROME
•
Prevalence: Up to 1 in 20,000
•
Inheritance: Autosomal dominant
•
Gene: TP53
•
Lifetime risk of cancer:
– 50% by age 30-35y
– 90% by 60y
– Female lifetime risk is 90%
– Male lifetime risk is 70%
– 57% risk of a second primary
21. LFS- DIAGNOSTIC CRITERIA
•
Proband with sarcoma <45yoa
•
First-degree relative with any cancer <45yoa
•
First- or second-degree relative with any cancer <45yoa or sarcoma at any age
•
LFS-related cancers include:
– Breast cancer
• Most common LFS-related cancer
• Lifetime risk 49%
• <1% overall of total breast cancers; however, more likely with diagnosis <30yoa (up
to 7%)
• More likely to be triple positive
– Soft tissue and bone sarcomas
– Brain tumors Choroid plexus tumors
– Adrenocortical carcinoma
– Leukemia
– Bronchoalveolar cancer
LFS accounts for 80% of childhood ACC
22. PTEN HAMARTOMA SYNDROME
• Prevalence: 1 in 200-250,000
• Inheritance: Autosomal dominant
• Gene: PTEN
Planchon S M et al. J Cell Sci 2008;121:249-253
23. PTEN HAMARTOMATOUS
SYNDROME
•
25-85% lifetime risk of breast cancer
– <1% overall of all breast cancer
– Average age of diagnosis 38-46y
•
5-28% lifetime risk of endometrial cancer
•
3-35% lifetime risk of non-medullary thyroid (follicular) cancer
•
40-93% lifetime risk of polyps (hamartomatous)
– 9% lifetime risk of CRC
– Ganglioneuroma
– 13% of PTEN mutation-associated Cowden
syndrome patients developed CRC <50yoa
•
Strongly a/w Lhermitte-Duclos (dysplastic gangliocytoma)
•
May also be associated with renal cancer and melanoma
25. BREAST CANCER- WHEN TO
REFER
•
•
Breast cancer <50yoa
Triple negative breast cancer
– 11-28% have BRCA1 mutations
•
Two breast cancer primaries in a single individual
– ~30% risk of second primary in 10 years for
BRCA1/2
•
•
Breast or ovarian cancer at any age in those of Ashkenazi Jewish
ancestry
Breast cancer at any age and…
– ≥1 close relative* with breast cancer <50yoa
– ≥1 close relative* with epithelial ovarian cancer at
any age
– ≥2 close relatives* with breast cancer and/or
pancreatic cancer at any age
26. ( WHEN TO REFER (2
•
A combination of breast cancer with one or more of the following in close relatives:
– Thyroid cancer
– Sarcoma
– Endometrial cancer
– Pancreatic cancer
– Brain tumors
– Diffuse gastric cancer
– Dermatologic manifestations and/or macrocephaly
– Leukemia/lymphoma
•
Ovarian cancer with a family history of breast and/or ovarian cancer
•
Male breast cancer
– 4-14% due to BRCA2
27. LYNCH SYNDROME
•
A.k.a. hereditary nonpolyposis colorectal cancer; includes Muir-Torre
(sebaceous adenomas)
•
Incidence: 1 in 440
•
Accounts for:
MSH6
– 2-10% of all CRC
MSH2
– 2% of ovarian cancers
– 2-5% of endometrial
• 9-20% of those <50y
•
Autosomal dominant
•
Multiple genes (MLH1, MSH2, MSH6,
PMS1
MSH3, PMS1, PMS2, TACS (EPCAM), TD1)
Chr 2
28. LYNCH SYNDROME- CANCER
RISKS
•
22-92% lifetime risk of CRC
– Mean age of 44yo (MLH1 or MSH2)
•
6-19% lifetime risk of gastric cancer
– More common in Japan
•
20-70% risk of endometrial cancer
– MSI-IHC testing recommended
•
•
•
•
4-12% risk of ovarian cancer
18% hepatobiliary
5-10% urinary tract cancers
May also develop:
– Small bowel, pancreatic cancer
– Skin: (sebaceous carcinomas, keratocanthomas,
and epitheliomas)
– Brain tumors, especially glioblastoma
29. LYNCH SYNDROME- AMSTERDAM
II
• Amsterdam II criteria (all have to be
met):
– ≥3 family members, one of whom is a firstdegree relative of the other two, with
HNPCC-related
cancers
(CRC,
endometrial, stomach, small bowel,
hepatobiliary, renal pelvic, or ureteral
cancer)
– Two successive generations
– One or more HNPCC-related
diagnosed before 50yoa
cancer
30. LYNCH SYNDROME- BETHESDA
• Modified Bethesda
following):
criteria
(any
of
the
– CRC diagnosed <50yoa
– Presence of synchronous or metachronus CRC, or
other HNPCC-related tumors (CRC, endometrial,
gastric, ovarian, pancreatic, ureteral, biliary tract and
brain tumor) regardless of age
– CRC with microsatellite instability-high <60yoa
– CRC in ≥1 first-degree relatives with HNPCC-related
tumor with one cancer <50yoa
– CRC in ≥2 first- or second-degree relatives at any age
31. LYNCH SYNDROME- MSI
• Microsatellite instability
– Microsatellites are highly-repetitive DNA
sequence
– Susceptible to dynamic changes if not for
the mismatch repair genes
• MSI-high= instability >30% of cells
• MSI-low= instability <30% of cells
• MSI stable= no evidence of MSI
32. LYNCH- MSI CAVEATS
• 90% of inherited tumors are MSI-high
• MSI-high can be caused by many somatic (not
inherited)
events,
most
notably
BRAF
methylation/mutation
• Some Lynch syndrome patients will have MSI-low or
MSI-stable testing
• Immunohistochemistry for mismatch repair proteins
(MLH1, MSH2, MSH6, PMS1, PMS2) recommended
as adjunctive analysis
33. LYNCH- GENETIC
TESTING
• If met Amsterdam II criteria, recommend genetic
testing
• If met Bethesda, testing of the tumor sample by
MSI/IHC recommended initially with consideration of
genetic testing
• If MSI-high and IHC positive (i.e. absence of one of
the proteins) the probability of Lynch is high therefore
genetic testing recommended
34. FAMILIAL ADENOMATOUS
POLYPOSIS
•
A.k.a Turcot or Gardner syndromes
•
1 in 6-20,000 live births
•
Due to genetic defect in APC
– If negative, consider MYH
testing
•
Accounts for <1% of all CRC
•
Hallmark is the adenomatous polyposis
– 20-100% penetrance in the
duodenum
•
100% lifetime risk of CRC with average
age of cancer diagnosis of 39y
35. FAP: AGE AND DEVELOPMENT
OF ADENOMAS AND CRC
100
% of patients
with neoplasia
FAP
Adenomas
80
CRC
60
40
General population
20
0
20
40
Age
60
80
36. FAP- ASSOCIATED RISKS
•
4-12% lifetime risk of other intestinal cancers
– 0.5-2% gastric
– 5% duodenal
•
1-2% risk of pancreatic and non-medullary thyroid
•
0.6% risk of hepatoblastoma before 6yoa with 1-2% lifetime
•
10-30% lifetime risk of desmoid tumors
•
Also a/w medulloblastoma as well as gliomas and ependymoma
•
CHRPE- congenital hypertrophy of the retinal pigmented epithelium
37. PEUTZ-JEGHERS SYNDROME
•
•
•
•
•
Prevalence: 1 in 25-280,000
Inheritance: Autosomal dominant
Gene: STK11
Hamartomatous and adenomatous polyposis especially
of the small intestine
37-93% lifetime risk of cancer
– 38-66% risk of gastrointestinal
•
•
29% gastric
•
–
–
–
–
2-39% CRC
11-36% pancreatic
30-54% risk of breast cancer
Lifetime uterine cancer risk is 9-21%
Lung 15% lifetime risk
Includes ovarian and sex cord tumors
Labial and oral mucosal
hyperpigmentation- may
fade with time