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Flashcards in Genetics Deck (69):

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,
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
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
- 50% de novo

Mucocutaneous melanin spots
- dark blue to brown macules around mouth, eyes and nostrils, fingers (fade over time)
GI harmartomatous polyps
Ovarian tumors
Sex cord tumor (SCTAT)

May cause obstruction, intussusception


Describe Cowden

Gene = PTEN
PTEN multiple hamartoma syndrome

Multiple harmatomas
Mucocutaneous growths
Breast - Benign and malignant tumors
- 25%-50% lifetime risk of breast cancer
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

- 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

- 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
- 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


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

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

- 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

Rare, recessive childhood disease
Mutations in FA genes lead to chromosomal instability
Affected individuals are compound heterozygous

- 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)

- 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

- 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

Multi focal, bilateral, younger age, recurrent disease


What are the features of Cowden Syndrome

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

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


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
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
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?



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?


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?

3) PTCH1

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

Retinal Angioma
Cerebellar and spinal haemangioblastoma


Describe Tuberous sclerosis complex (TSC)

Defective gene = TSC 1/2

Renal angiomyolipomas and cysts
CNS tumors


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