Genetics Flashcards
Describe the prevalence of cancers
Sporadic : 75-85%
Familial : 10-20%
Hereditary : 5-10%
Describe Lynch Syndrome
Genes: MLH1, MSH2, MSH6, PMS2, EPCAM
Colon, Endometrial, ovarian, gastric, urinary tract, small bowel, sebaceous tumors (CO-GUESS)
Prevalence of 1/400
1/35 colon cancer cases and 1/43 endometrial cancer cases
Increases risk of 2nd cancers
- about 10 fold
- 30% within 10 years of first cancer Dx, and 50% within 15 years of first cancer diagnosis
IF no Gene is identified, then it is HNPCC
(Hereditary non-Polyposis colon Cancer)
Describe Li Fraumeni
Gene: TP53
Childhood cancers, Sarcoma, Leukemia, Brain tumors, Breast cancer, Colon Cancer
Describe FAP
What is attenuated FAP
FAP = Familial Adenomatous Polyposis
Gene: APC
30-1000s of adenomas Early onset of colon CA Thyroid CA, Osteomas Soft Tissue tumors Desmoid Tumors Benign cutaneous lesions Gastric and small bowel polyps CHRPE (Congenital Hypertrophy of the Retinal Pigment Epithelium) Hepatoma stomp Dental anomalies Medulloblastoma Adrenal/bile duct/pancreatic AdenoCA
2 types of FAP: Classic and attenuated
Describe MAP and Colon CA
MAP = MYH-Associated Polyposis
Gene : MYH Gene (MUTYH gene)
AR condition, 10-100s of adenomas
Colon Cancer
Thyroid cancer
Screening options:
Colono once every 1-2 years, from 18-20yo
Yearly colono once polyps develop, with the goal of removing all large polyps, KIV surgery if numerous
OGD once 25-30 yo or once colorectal polyps develop
US thyroid to be considered once 25-30 yo
Describe Peutz-Jeghers
Gene = STK11
AD
- 50% de novo
Mucocutaneous melanin spots - dark blue to brown macules around mouth, eyes and nostrils, fingers (fade over time) GI harmartomatous polyps Breast GI Pancreatic Ovarian tumors Sex cord tumor (SCTAT)
May cause obstruction, intussusception
Describe Cowden
AD
Gene = PTEN
PTEN multiple hamartoma syndrome
Multiple harmatomas Mucocutaneous growths Breast - Benign and malignant tumors - 25%-50% lifetime risk of breast cancer Renal Thyroid (usually follicular CA, rarely papillary) - 10% lifetime risk of thyroid CA Endometrial cancer - 5-10% lifetime risk Benign overgrowths of the: - skin (Trichilemmomas) - Oral cavity (oral papillomas) - GI Tract (ganglioneuromas) - Acral Keratoses
Features:
- Macrocephaly
- Trichilemmomas and papilloma tours papules (usu by late 20s)
- Lhermitte-Duclose Disease (Cerebellar days plastic Gangliocytoma)
» Rare benign brain tumor, usu presenting as hydrocephalus 30-40yo
Describe Juvenile Polyposis Syndrome
Gene = BMPR1A, SMAD4
4-100s of harmatomatous polyps in upper and lower GIT
Colon cancer
Some with SMAD4 have HHT (hereditary hemorrhagic telangiectasia)
What are the Colon Cancer associated syndromes?
FAP = Familial Adenomatous Polyposis (APC Gene) MAP = MYH- associated Polyposis (MAP Gene) Cowden = PTEN Gene Peutz-Jeghers = STK11 JPS = Juvenile Polyposis syndrome (BMPR1A, SMAD4) Li-Fraumeni = TP53 Lynch = MLH1, MSH2, MSH6, PMS2, EPCAM
What are the colon cancers syndromes associated with thyroid cancers?
FAP = Familial Adenomatous Polyposis (APC Gene) MAP = MYH-Associated Polyposis (MYH Gene) Cowden = PTEN Gene
What are the other APC-associated Polyposis syndromes
Gardner Syndrome
Turcot syndrome
Attenuated FAP
Describe Turcot Syndrome
It is an AFP-associated Polyposis syndrome
Lesser number of colonic polyps, about 30
A/w CNS tumors (usually medulloblastoma)
Significant risk of CLR CA at later age of diagnosis of 50-55yo
Describe the Lynch syndrome genes
MLH1 and MSH2:
- 90% with detectable mutations have MLH1/MSH2 mutations
MSH6: may have 30% less risk for colon cancer
- more frequent in families with endometrial cancer
PMS2:
- low penetrance/no increased cancer risk in heterozygous
- Homozygous PMS2 deficiency (recessive) leads to severe phenotype
» very early onset CLR CA
» Duodenal Cancer
» Leukemia/Lymphoma
» Childhood brain tumors (astrocytoma/glioblastomas/PNET)
» Cafe au lait spots
What is the Amsterdam II Criteria?
1) 3 relatives with Lynch-associated cancer
- one of whom is a 1st-degree relative of the other 2
- Lynch-associated cancer: Colon, endometrium, small bowel, renal pelvis, ureter
2) 2 successive generations involved
3) One or more of the cancers is diagnosed
How do we test for Lynch syndrome?
1) Tumor screening via micro satellite instability (MSI) and/or immunohistochemistry
- This detects 90% of Lynch syndrome colorectal CA and endometrial cancer
2) Follow-up with Germline (blood) Testing of MMR Gene in question
What do the following mean?
1) Lack of PMS2 alone
2) Lack of MLH1/PMS2
3) Lack of MSH2 +/- MSH6
1) likely due to Lynch syndrome
2) Lynch syndrome OR Somatic hypermethylation of the MLH1 promoter
3) Almost always due to Lynch syndrome
How would you surveil a patient with Lynch syndrome?
1) Colonoscopy - Every 2 years from 20 yo. Every year after 40yo
2) OGD - Every 3 years from 25yo
3) Trans-vaginal US + CA 125 - every year from 30yo
4) TAHBSO - Consider after 35yo or upon completion of childbearing
5) Urinalysis - Every year from 35yo. US for patients with MSH2 mutation or family history
6) Capsule endoscopy - Every 3 years, from 30 yo for those with family hx of small bowel cancer
7) Dermatology exam - yearly
What is the diagnostic criteria for Peutz-Jeghers syndrome?
John Hopkins criteria
1) Histo-verified hamartomatous polyps with 2 or more of the following:
- Small-bowel location for Polyposis
- muco-cutaneous melanotic pigmentation
- FHx of Peutz-Jegher syndrome
How would you surveil Cowden Syndrome in its related cancers?
Breast - start at 30yo, annual mammogram. KIV MRI for dense breasts
- Lifetime risk of 85%
Thyroid - Annual US
- Lifetime risk of 35%
Renal Cell - From 40yo, renal imaging every 2 years
- Life time risk of 34%
Endometrial - From 30yo, annual endometrial biopsy or transvaginal US
- lifetime risk 28%
Colon - from 35yo, colonoscopy every 2 years
- lifetime risk of 10%
Melanoma - annual dermatological examination
- lifetime risk of 5%
Which chromosomes are BRCA genes found on?
BRCA1 = Chromosome 17,
BRCA2 = Chromosome 13
What are the functions of BRCA1 and BRCA2?
DNA repair Cell Cycle checkpoint control Ubiquitylation - tagging proteins for degradation by the proteasome Transcriptional degradation
What is the mutation risk like in BRCA patients?
2% risk of breast cancer by 50 yo in general population.
30-50% chance in BRCA 1/2 patient
How can you prevent breast cancer?
1) Tamoxifen
2) Raloxifene
3) Letrozole
- WISE Trial (letrozole vs placebo)
4) Exemestane
- GOSS trial (Exemestane vs placebo)
Describe the GOSS trial
Aim: To reduce in the incidence of invasive breast cancer
Incl criteria: At least one of the following:
- 60 yo or older
- Gail 5-year risk score >1.66% (Chances in 100 of invasive breast cancer developing within 5 yrs)
- prior atypical ductal or lobular hyperplasia
- prior lobular CIS
- Prior DCIS with mastectomy
N=4600
med f/u 3 years
-HR 0.35 = 65% Relative reduction in annual incidence of invasive breast cancer
» 0.35% vs 0.77%
Same risk of adverse events
Conclusion: Exemestane significantly reduced invasive breast cancers in post-menopausal women who were at moderately increased risk for breast cancer
Describe the IBIS-I Trial
Aim: To find out if Tamoxifen reduces the risk of invasive ER+ breast cancer
N=7000+
2 arms: Tamoxifen daily or placebo; total 5 years
F/u of 8 years (Updated):Risk ratio of 0.73
Side-effects lower after active period
2 arms did not differ in risk of ER- invasive tumors, but risk of ER+ beast cancer was 34% lower in Tamoxifen arm. RR 0.66
Describe the STAR P-2 trial
Vogel et al, JAMA 2006
Aim: To compare the effects and safety of Raloxifene and Tamoxifen in the risk of developing invasive breast cancer and o/r disease outcomes
N=20 000 post-menopausal women, with increased 5-yr breast cancer risk
2 arms:
- Tamoxifen (20mg/day) or Raloxifene (60mg/d) x 5 years
Conclusion:
- Raloxifene is as effective as Tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts.
- Also has a non-statistically significant higher risk of non-invasive breast cancer.
- 38% (RR0.62) reduction of uterine cancer with Raloxifene
Describe Fanconi Anemia
BRCA2 is a Fanconi Anemia Gene
- BRCA2 = FANCD1
Rare, recessive childhood disease
Mutations in FA genes lead to chromosomal instability
Affected individuals are compound heterozygous
A/w:
- short stature
- skeletal and developmental abnormalities
» Radial Ray anomalies are common
- Increased risk of:
» Leukemia
» Other hematological and solid cancers
- primary diagnostic test: Assessment of the response of cells to diepoxy butane
Describe BRCA 2
Causes Germline mutations in tumor suppressor genes Confers increased risk for (B.O.P.P): - Breast CA - Ovarian CA - Pancreatic CA - Prostate CA
AD inheritance Regulates RAD51 (necessary for repair of dsDNA breaks)
Germline mutations have loss of 1 of 2 of their wt alleles–> genomic instability
Subsequent somatic mutations or LOH leads to tumorigenesis
Describe Hereditary Diffuse Gastric Cancer
Caused by mutations in CDH1 Gene (e-Cadherin protein)
Diffuse gastric cancer
Women with 40% risk for lobular breast cancer
Average age of onset of gastric CA is 38yo
Cumulative risk of gastric cancer by 80yo is 70% for men, 80% for women
Options for intense screening or prophylactic gastrectomy
Describe Li-Fraumeni Syndrome
AD mutations in TP53 on chr 17
Lifetime risk of cancer:
- 90% for women, average age 29yo
- 70% for men, average 40yo
- 50% risk of cancer by 35yo
A/w increased risk of (SBLA syndrome):
- Sarcomas
- Brain
- Breast
- Leukemia/Lymphoma
- Lung
- Adrenocortical
- Additional (Melanoma, Colon, Stomach, Ovary, Kidney)
Lifetime risk of cancer in Li-Fraumeni?
90% for women
70% for men
50% by 35yo
What is the Gail Model ?
It calculates the 5-year and lifetime risk (up to 90yo) of breast cancer based on multiple criteria.
Limitations: Following not included
- age of onset
- 2nd degree relatives
- paternal history
- ovarian CA
- Ethnicity
Describe the Claus Model
It calculates the risk of breast CA to age 80yo.
It is based on:
- age of onset of breast cancer in 1st and 2nd degree relatives (including paternal)
Limitations:
- may underestimate risk in families with 3 or more affected members
- Does not include ethnicity
What is the Myriad Risk Tables?
It identities the chance of detecting a BRCA1 or BRCA2 mutation in women with a FHx of early-onset breast +/- breast&ovarian CA
Limitations:
- Breast CA >50yo not included
- clinical data not validated
- does not capture other breast cancer syndromes
What are the 3Ps in MEN1?
Pituitary Tumors
Pancreatic tumors
Parathyroid tumors
- 90% of individuals 20-25yo
Describe MEN1
MEN1 = Multiple Endocrine Neoplasia Type 1
MEN1 Gene, AD, 10% de novo
Combination of >20 endocrine and non-endocrine tumors
Endocrine tumors:
- Parathyroid tumors (90% of individuals at 20-25yo)
- Pituitary Tumors
- Well-diff endocrine tumors of the Gastro-enters-pancreatic tract (GEP)
- Carcinoid tumors
- Adrenocortical Tumors
Non-endocrine tumors:
- Facial angiofibromas
- Collagenomas
- Lipomas
- Meningiomas
- Ependymomas
- Leiomyomas
Describe MEN2
Due to RET Mutations
3 groups:
- MEN2A 60-90%
- MEN2B 5%
- FMTC 5-35%
MEN2A 60-90%
- Medullary Thyroid CA 90%
- Benign Adrenal 50%
- Parathyroid tumors 15-30%
- Genetic Testing Rate 95%
MEN2B 5%
- Medullary Thyroid CA 100% early childhood
- Marfanoid habitus
- No Parathyroid tumors
- Benign Adrenals (50%), lip, tongue, eyelid, GI Tumors
- Genetic Testing Rate 95%
FMTC 5-35%
- Medullary thyroid cancer
- Genetic Testing Rate 88%
What are the other Pheochromocytoma Syndrome?
Von Hippel Lindau Syndrome
Hereditary Paraganglioma-Phaeochromocytoma Syndromes I
Describe Von Hippel Lindau Syndrome
VHL Gene, AD, 20%
1:36000 live births
- CNS hemangioblastomas - retinal hemangioblastomas (angiomas) Often initial feature
- cc RCC (40%)
- Pheochromocytoma
- Pancreatic endocrine tumors
- Endolymphatic sac tumors
- Renal, pancreatic, and epididymal cysts
Describe Hereditary Paraganglioma-Pheochromocytoma Syndromes
SDHD, SDHC and SDHB genes
AD, with parent of origin effect
Paragangliomas
Pheochromocytomas
Multi focal, bilateral, younger age, recurrent disease
What are the features of Cowden Syndrome
Macrocephaly
Lhermitte-Duclose Syndrome = Cerebellar displastic Gangliocytoma
- rare benign brain tumor, usually presenting as hydrocephalus 30-40yo
Trichilemmomas and papilloma tours papules
What are the PTEN multiple hamartoma syndrome ?
1) Cowden Syndrome
2) Bannayan-Riley-Ruvacalba
3) Proteus syndrome
Describe the Bannayan-Riley-Ruvacalba?
A PTEN Hamartoma Syndrome
Macrocephaly
Hamartomatous intestinal polyposis
Pigmented macules of the glans penis (Speckled penis)
Describe the Proteus Syndrome
A PTEN Multiple Harmatomatous Syndromes
Caused by a mosaic alteration, or mutation in AKT1 Gene
Connective tissue nevi Disproportionate overgrowth (limbs, hands, feet, skull, vertebrae) Lipomas or absence of fat Vascular malformation Facial Phenotype Cerebriform connective tissue nevus
Overgrowth becomes apparent between 6-18months and gets more severe with age
Describe the Brit Hogg Dube Disease
Defective gene us FLCN
Spontaneous Pneumothorax
Chromophobe and oncocytoma RCC
Fibrofolliculoma
What is the GINA?
GINA = Genetic Information Non-Discrimination Act
Prevents health insurers from:
- Denying coverage
- adjusting premiums
- discriminating on basis of genetic information
Applies to group and self-insured policies
Insurers may not request that an individual undergo a genetic test
Employers cannot use genetic information to make hiring/firing/compensation/promotion decisions
Limits a health insurer’s or employer’s right to request/require/purchase someone’s genetic information
Explain Variant of uncertain Significance (VUS)
Unknown if Gene change increases risk for cancer
Reclassified, can get updated information
Other family members should not be tested for variant, except on research basis
Describe Gorlin Syndrome
= Nevoid Basal Cell Carcinoma Syndrome
Mutations in the PTCH 1 Gene
AD
A protein called Sonic Hedgehog is the ligand for patched-1 receptor
Patched-1 blocks cell Roth and proliferation until Sonic Hedgehog is attached
PTCH1 Gene is a tumor suppressor gene.
Mutations of this Gene prevents the production of patched-1 or lead to the production of an abnormal version of the receptor
An altered/missing patched-1 receptor cannot effectively suppress cell growth and division, and cells hence proliferate uncontrollably to form the tumors characteristic of Gorlin syndrome
A/w chr 9 q22.3 deletion
Affects many areas of the body and increases the risk of developing various cancerous and non-cancerous tumors
Most common cancer is BCC - usually during adolescence/early adulthood Keratocystic odontogenic tumors - non-cancerous tumors of the jaw Medulloblastoma Fibroma Macrocephaly with a prominent forehead Small depressions in the skin of the palms of hands/soles of feet
What is the constitutional mismatch repair deficiency syndrome? CMMRD syndrome
Rare, recessive syndrome
Both partners are a carrier of a mutation/s in the same MMR Gene or EPCAM
Eg. Both partners carry a mutation in the PMS2 Gene, then the offspring have a risk for CMMRD syndrome
What is the Bethesda criteria for?
Intended to help identify CRC patients whose tumors should be tested for MMR defects, thereby identifying patients with a greater chance of having LS
- By MSI and/or IHC
More sensitive than the Amsterdam criteria
Up to 50% of LS patients still fail to meet even the revised Bethesda Guidelines
Describe the IHC of MMR genes in CRC
IHC refers to staining of the tumor tissue for protein expression of the 4 MMR genes known to be mutated in LS
- MLH1, MSH2, MSH6, PMS2
Normal IHC test = all 4 MMR proteins are normally expressed. Unlikely for MMR Gene mutation to be present.
Abnormal IHC Test = at least one of the proteins not expressed and an inherited mutation may be present in the related Gene.
Loss of protein expression by IHC guides genetic testing (mutation detection) to the Gene(s) where protein expression is not observed or to the corresponding protein dimmer.
ABnormal MLH1 IHC should be followed by tumor testing for presence of BRAF V600E mutation or with IHC for BRAF or hypermethylation of the MLH1 promoter.
- A/w sporadic colorectal tumors
- if Geraldine mutation = LS patients
5-10% false negative rate with IHC testing
What is the Bethesda Guidelines?
- Ca in a family that fulfills the Amsterdam Criteria
- Dev of 2 HNPCC-related (extra-colonic) cancers in one individual (I.e. Endometrial, small intestine, ovarian, gastric)
- Dev of CLR Ca in an individual with a 1st-Deg relative with CLR Ca and/or HNPCC-related extra colonic cancer and/or colorectal adenoma, with one of the cancers Dx before 45yo and the adenoma Dx before 40yo
- CLR ca or Endometrial ca Dx before 45yo
- R-sided CLR Ca with an undifferentiated pattern on histo evaluation, before 45 yo
- Signet-ring cell-type CLR Ca diagnosed before 45yo
- Adenoma diagnosed before 40yo.
Amsterdam Criteria I
At least 3 relatives with CRC; with all of the following present:
- One should be a 1st-deg relative of the other 2
- At least 2 successive generations must be affected
- at least one of the relatives with CRC must receive the Dx before 50 yo
- FAP excluded
- Tumor verified by pathological examination
Amsterdam criteria II
At least 3 lefties with cancer a/w LS (colorectal, endometrium, small bowel, ureter or renal pelvis); all criteria must be present:
- one must be a 1st-deg relative of the other 2
- tumors verified whenever possible
- at least 2 successive generations affected
- at least 1 relative with cancer a/w LS should be Dx before 50yo
- FAP excluded
Peutz-Jeghers clinical diagnosis:
2 or more of the following features:
- 2 or more PJ-type hamartomatous polyps of the small intestine
- mucocutaneous hyper pigmentation of the mouth, lips, nose, eyes, genitalia, or fingers
- FHx of PJS
Clinical Diagnosis of Juvenile Polyposis Syndrome:
At least one of the following:
- At least 3-5 juvenile polyps of the colon
- multiple juvenile polyps throughout the GI Tract
- Any number of juvenile polyps in an individual with FHx of JPS
Tell me about Trisomy 21 and ALL
Trisomy 21 have a higher risk for ALL up to 13 yo.
(But not in the neonatal period)
Extra copies of Chromosome 21 are a common finding, but carry no prognostic meaning.
In neonates:
- a transient myeloproliferative disease is seen that resolves spontaneously
AML M7 develops in those
What are the most common cancers in Lynch syndrome?
Colorectal
Endometrial
If MSI high tumor showing loss of MLH1 and PMS2 proteins, and BRAF mutation present, should the pt be referred for Germline genetic testing? Why?
NO
This is suggestive of somatic methylation of MLH1 due to concurrent presence of BRAF mutation
Indicative of sporadic tumor.
Explain what is penetrance
Penetrance is the probability of a genetic trait being expressed
What are the following genes associated with?
1) CTNNB1
2) DICER1
3) PTCH1
4) INI1/SMARCB1
5) SUFU
1) CTNNB1 - this is a beta catenin, undergoes somatic mutation in a number of tumors
2) DICER1 - Pulmonary pleuroblastoma
3) PTCH1 - Gorlin Syndrome
4) INI1/SMARCB1 - ATRT tumors (Atypical Teratoid/rhabdoid Tumor). 30% wil have this mutation
5) SUFU - medulloblastoma
What are the features of hereditary cancer?
Similar to highly penetrant AD disease mostly
1) Young age of onset
2) Multiple primary cancers in one individual
3) Multiple affected family members in at least 2 generations
4) Diverse cancer types that are part of a known cancer syndrome
5) Specific pathology known to be a/w a given syndrome
Tell me about hereditary diffuse gastric cancer syndrome (HDGC)
AD, highly penetrant
Mutations in E-cadherin gene (CDH1)
70% cumulative lifetime risk for diffuse gastric cancer, linitus plastica type without a distinct mass
40% lifetime risk for lobular breast cancer
Intensified surveillance with OGD + breast mammogram + MRI is recommended
Consider prophylactic gastrectomy esp as there is a limitation of OGD in detecting diffuse lesions.
What is used to detect large deletions?
Southern blot analysis and multiplex ligation-dependent prob amplification
What is penetrance?
Penetrance is the proportion of individuals with a mutant genotype who show any manifestation of the given disorder.
What is the Amsterdam Criteria?
All criteria must be met.
1) 3 or more family members with CLR Ca, at least 2 of whom must be 1st-deg relatives
2) Family members from at least 2 successive generations are affected
3) Development of CLR Ca occurred before 50yo in at least one family member
4) FAP excluded
Describe VHL syndrome
Defective gene =VHL
ccRCC
Retinal Angioma
Cerebellar and spinal haemangioblastoma
Describe Tuberous sclerosis complex (TSC)
Defective gene = TSC 1/2
RCC
Renal angiomyolipomas and cysts
CNS tumors
Skin
What are the genetic syndromes a/w RCC?
2-4% of RCCs are hereditary
1) vHL syndrome
2) Brit-Hogg-Dube syndrome
3) Hereditary Leiomyomatosis and RCC (HLRCC)
4) Hereditary papillary renal cell cancer (HPRCC)
5) SDH
6) Tuberous sclerosis complex
7) Chromosomal translocation
