Cancer genetics Flashcards
1
Q
Proto-oncogenes (2)
A
RET, MET
2
Q
Tumor Suppressor Genes (10)
A
APC, VHL, RB1, NF1, TP53, P16, PTCH, MEN1, BRCA1, BRCA2
3
Q
Mismatch Repair Genes
A
MAH2, MSH6, MLH1, PMS2, ATM, BLM, XP genes
4
Q
Recessive cancer genes
A
MUTYH, ATM
5
Q
Multiple endocrine neoplasia 2 (MEN2)
A
RET gene Medullary thyroid carcinoma 95-100% lifetime risk Can cause childhood cancer Pheochromocytomas Hyperparathyroidism
6
Q
Retinoblastoma
A
RB1 gene
30-40% inherited
Dx <1 year indicates hereditary mutation
7
Q
NF1
A
NF1 gene
50% de novo rate
Neurofibromas,CALs, axillary/inguinal freckling, optic glioma
8
Q
Mosaic Turner
A
Increased risk for gonadoblastoma
9
Q
XXY
A
Increased risk for breast cancer
Man with breast cancer is more likely XXY than BRCA positive
10
Q
Cowden syndrome
A
PTEN gene
20-30% lifetime risk of breast cancer
Macrocephaly
Multiple hamartoma syndrome
11
Q
Familial Adenomatous Polyposis (FAP)
A
APC gene
25% de novo
Tumors: Adenocarcinoma, brain (medulloblastoma), desmoid (benign), polyps
-Classic FAP: 100+ polyps
-Attenuated FAP: 10-100 polyps
Fam hx: CRC, heptoblastoma, desmoid tumors, dental abnormalities, CHRPE
12
Q
Juvenile Polyposis syndrome
A
SMAD4, BMPR1A
Tumors: colon, juvenile polyps (benign), stomach, small intestine
Clinical dx: 5+ juvenile polyps (most have one by age 20)
- mutations only account for 40%
*SMAD4: think HHT
13
Q
MYH-associated Polyposis syndrome
A
MYH biallelic mutations (AR)
- 15+ Adenomatous polyps and/or MSI-stable CRC under 50y
14
Q
Proto-oncogenes (2)
A
RET, MET
15
Q
Tumor Suppressor Genes (10)
A
APC, VHL, RB1, NF1, TP53, P16, PTCH, MEN1, BRCA1, BRCA2
16
Q
Mismatch Repair Genes
A
MAH2, MSH6, MLH1, PMS2, ATM, BLM, XP genes
17
Q
Recessive cancer genes
A
MUTYH, ATM
18
Q
Multiple endocrine neoplasia 2 (MEN2)
A
RET gene Medullary thyroid carcinoma 95-100% lifetime risk Can cause childhood cancer Pheochromocytomas Hyperparathyroidism
19
Q
Retinoblastoma
A
RB1 gene
30-40% inherited
Dx <1 year indicates hereditary mutation
20
Q
NF1
A
NF1 gene
50% de novo rate
Neurofibromas,CALs, axillary/inguinal freckling, optic glioma
21
Q
Trisomy 21
A
20x increased risk of leukemia
22
Q
Genes accounting for HBC by percent
A
52% BRCA1
32% BRCA2
16% other (PTEN, TP53, ATM, CDH1, NF1, MUTYH)
23
Q
Ataxia Telangiectasia
A
ATM, autosomal recessive
30-40% lifetime risk of cancer
Most common: NHL and leukemia
Others: medulloblastoma, glioma, gastric, uterine, BCC, breast
Radiation not recommended
Female heterozygous have 2x increased risk of breast cancer
24
Q
Birt-Hogg-Dube
A
FLCN, autosomal dominant 7x increased risk of kidney cancer Oncocytoma, chromophobe, clear cell Average age of cancer onset is 48 Other features: skin findings (benign tumors of the hair follicles called fibrofolliculomas & trichodiscomas), lung findings (lung cysts, spontaneous pneumothorax)
25
Bloom syndrome
BLM, autosomal recessive
Increased risk of cancer especially early in life
Often develop multiple primaries
Most common: colon cancer
Others: lymphoma, leukemia, Wilms tumor, breast, cervix, esophagus, skin, lung, stomach
Other features: IUGR, butterfly rash, hypersensitivity to sun, ID, sparse fat, male infertility and female reduced fertility
26
Hereditary Breast & Ovarian Cancer (BRCA1)
```
autosomal dominant
Breast cancer risk 50-80%
Ovarian cancer risk 40-60%
Male breast cancer risk 1%
Pancreatic cancer risk 1-7%
Prostate cancer risk 15%
Melanoma risk <2%
**BRCA1 earlier breast cancer than BRCA1
**80% BRCA1 tumors are triple negative
```
27
Hereditary Breast & Ovarian Cancer (BRCA2)
autosomal dominant
Breast cacner risk 40-70%
Ovarian cancer risk 15-20%
Male breast cancer risk 6-7% (more than BRCA1)
Pancreatic cancer risk 1-7% (more than BRCA1)
Prostate cancer risk 15%
Melanoma risk 2-5% (more than BRCA1)
28
Carney Complex
PRKAR1A, autosomal dominant
Increased risk of benign & malignant tumors
Large-cell calcifying Sertoli cell tumors (LCCSCTs), in almost all males,
Follicular thyroid adenomas (in 75%),
GH-producing adenomas (causes acromegaly),
Myxomas (cutaneous & cardiac) - benign,
Schwannomas
**skin findings: blue nevi, CAL macules, lentigines (increasing in puberty)
29
Familial Adenomatous Polyposis
APC, autosomal dominant
25% de novo
100% lifetime risk of colon cancer (hundreds of thousands of adenomatous polyps)
Other tumor risks: medulloblastoma, desmoid (benign, abdominal), hepatoblastoma (childhood), fundic gland polyps, dental abnormalities, CRPE, papillary thyroid cancer
30
FAP subtypes
AFAP, Gardners, Turcot, Deletion 5q22
31
AFAP
Fewer polyps (10-100) at older ages
32
Gardner syndrome
Polyposis, & CRC PLUS benign tumors in many different organs: epidermoid cysts, lipomas, desmoid tumors, fibromas, osteomas of mandible, dental abnormalities, CHRPE
33
Turcot syndrome
Polyposis & FAP PLUS brain tumors (medulloblastoma)
34
5q22 deletion
FAP PLUS mild/moderate intellectual disabilities and dysmorphisms
35
Fanconi Anemia
FANC__ (BRCA2, BRIP1, PALB2, etc)
65% FANCA
Autosomal recessive (FANCB X-linked)
Increased risk of Leukemia (usually AML)
Increased risk of squamous cell carcinoma, hepatocellular cancer, brain tumors, vulva & cervix cancer
Other features: aplastic anemia, BM failure, skin hyperpigmentation, thumb abnormalities, skeletal deformities, growth retardation
36
Hereditary Diffuse Gastric Cancer
CDH1, autosomal dominant
Increased risk gastric cancer (83% women, 67% men)
Surgical intervention: gastrectomy
Increased risk lobular breast cancer (39-52%)
Other cancer risks: Signet ring colon cancer, islet cell pancreatic cancer
37
Juvenile Polyposis syndrome
```
BMPR1A & SMAD4, autosomal dominant
(think HHT for SMAD4 also)
Mutations only account for 40%
Increased risk colon cancer (10-50%)
4-100 polyps, usually by the age of 20
Increased risk other GI cancer: stomach, duodenum, small intestine, pancreas
```
38
Hereditary Mixed Polyposis
BMPR1A, GREM1, autosomal dominant
Increased risk colon cancer
?Subtype of juvenile polyposis syndrome
Polyps of mixed histological type: juvenile, adenomas, hyperplastic lesions
39
Hereditary leiomyomatosis & RCC
FH, autosomal dominant
10-16% lifetime risk of renal cell carcinoma (most are papillary type II)
Other findings: skin lesions (cutaneous leiomyomas), gyn tumors in almost all women (uterine leiomyoma/fibroids)
40
Li-Fraumeni
TP53, autosomal dominant
90% cancer risk by 60, 50% risk by 30
Up to 50% risk of second cancer
Radiation not recommended
Sarcomas, brain tumors, (choroid plexus carcinoma & adrenal cortical carcinoma), leukemia, breast (6.4x increased risk)
Lifetime risk higher in women due to breast cancer
41
Lynch syndrome
```
MLH1, MSH2, MSH6, PMS2, EPCAM
Autosomal dominant
Causes 2-5% of all colon cancer
70-80% lifetime risk of CRC
30-60% risk endometrial cancer
Up to 19% risk stomach cancer
Up to 13% risk ovarian cancer
Other cancers: skin, glioblastoma, small intestine
Features of CRC: right-sided (proximal colon), signet ring histology, MSI-high, protein absence on IHC, sessile polyps (<10), negative BRAF V600 testing
```
42
Congenital mismatch repair deficiency syndrome (CMMRD)
Biallelic Lynch gene mutations, autosomal recessive
Very high risk cancer in childhood/adolesence
Cancer types: colon, stomach, small intestine, leukemia, lymphoma, brain tumors
>75% have 1+ CAL macule and NF1 may be initially suspected
43
Lynch subtypes
Muir-Torre syndrome, Turcot syndrome
44
Muir-Torre syndrome
Lynch PLUS higher risks of cancerous/precancerous skin lesions (subaceous adenomas, carcinomas, epitheliomas, keratocanthomas)
Many with mutations in MSH2 (Many Skin 2)
45
Turcot syndrome (Lynch subtype)
Lynch PLUS brain tumors (mostly glioblastomas)
| Families with PMS2 may have higher brain tumor risk
46
Familial atypical multiple mole & melanoma syndrome (FAMMM)
CDKN2A, CDK4, autosomal dominant (incomplete penetrance)
67% lifetime risk of cutaneous malignant melanoma,
Up to 17% risk of pancreatic cancer w/ CDKN2A,
Other genes to consider: XP genes, BAP1, TERT, RB1,
MC1R mutations have higher penetrance than CDKN2A mutations
Ocular melanoma? think BRCA2 & BAP1
47
Multiple endocrine neoplasia 1
MEN1, autosomal dominant (variable expressivity)
Mostly benign: pituitary, meningiomas, lipomas, leiomyomas, angiofibromas
Some malignant: GISTs, ACCs, nonmedullary thyroid, schwannomas/peripheral sheath tumors, insulinomas, gastriomas
48
Multiple endocrine neoplasia 2
Types: MEN2A, MEN2B, FMTC
RET, gain of function mutations only, autosomal dominant
95-100% risk of medullary thyroid cancer (~25% of mTCs will have RET mutations)
49
MEN2A
Most common subtype of MEN2 (70-80%)
95% MTC risk
50% pheo risk
20-30% parathyroid disease
50
MEN2B
100% MTC risk (often <10 years & aggressive)
50% pheo risk
40% diffuse ganglioneuromatosis
Marfanoid habitus, developmental delay, parathyroid disease (rare)
50% de novo, only accounts for 5% of MEN2
51
FMTC
MTC ONLY
| 16-20% of MEN2 cases
52
DICER1 syndrome
20% lifetime cancer risk (highest risk under age 7)
Cancers: pleuropulmonary blastomas (PPB), Wilms tumor, Sertoli-leydig (ovarian) tumors
Other features: cystic nephromas, goiter, nasal hamartomas, CHDs
53
MUTYH-Associated Polyposis (MAP)
MYH, autosomal recessive
1-2% of population carries one mutation
Up to 80% lifetime risk of CRC
Few to hundreds of polyps (average of ~20)
Significant overlap with FAP: fundic gland polyps, jaw osteomas, dental cysts, CHRPE
Need to rule out FAP and Lynch!
54
Neurofibromatosis 1
NF1, autosomal dominant
3-15% risk of malignant peripheral nerve sheath tumors
Other features: CAL macules, neurofibromas, optic gliomas, GISTS, breast cancer (3-5x increased risk), axillary & inguinal freckling, Lisch nodules, sphenoid dysplasia
55
Nevoid Basal Cell Carcinoma (NBCCS)/Gorlin syndrome
PTCH, autosomal dominant,
20-30% de novo, variable expressivity
Increased risk developing multiple BCCs (90% caucasians, 40% AA)
Average age of first BCC is 20-25
Other features: keratocystic jaw (75%), palmar/plantar pits (80%), lamellar calcification of the falx cerebri (90%), ovarian fibromas (20%), rib & skeletal anomalies, macrocephaly, medulloblastoma
56
Wilms Tumor
WT1, autosomal dominant (11p13)
>90% sporadic, 5-7% hereditary
think WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disability)
Risk until 8 years
57
Neuroblastoma
ALK, autosomal dominant (incomplete penetrance)
55-65% risk of NB
Ganglioneuroblastomas, ganglioneuromas
GI stuff
58
Hereditary Paraganglioma/Pheochromocytoma
SDHB, SDHC, SDHD, SDHAF2, MAX, TMEM127
Autosomal dominant
Highest risk of tumors in SDHB
SDHD tumors only if paternally inherited
Increased risk of paras and pheos
Other cancers; RCC, GIST, thyroid
10-20% chance of mutation in isolated paras/pheos
Secreting pheos release catecholamines causing increased BP (look for death in surgery), panic attacks, anxiety, palpitations
IHC can be done for SDHB to show loss of one of the SDH genes
59
Rhabdoid tumor
SMARCB1, autosomal dominant
Kidney/brain tumors
Schwannoma in later life
60
Peutz-Jeghers Syndrome
STK11, autosomal dominant
85% lifetime risk of cancer, namely GI tract
Other cancers: kidney, lung, thyroid, breast (30%)
Features: hamartomatous polyps, ovarian adenocarcinoma, SCTAT (benign ovary tumors), benign Sertoli tumors of the testes, blue/brown hyperpigmented macules, cervical adenoma malignum
61
Cowden syndrome
PTEN, autosomal dominant
25-50% lifetime risk of breast cancer
6-10% lifetime risk endometrial cancer
10% lifetime risk of thyroid cancer (mostly follicular)
Other cancers: CRC, kidney, uterine
Features: facial trichilemmomas, acral keratoses, palillomatous lesions, adult Lhermitte-Duelos Disease (LDD), intellectual disability, lipomas, macrocephaly, goiter
62
Hereditary Papillary RCC (HPRCC)
MET, autosomal dominant
Nearly 100% LT risk of kidney cancer (papillary type I RCC)
Cancer onset typically between 35-55
63
Retinoblastoma
RB!, autosomal dominant
Up to 33% de novo
90% risk of unilateral or bilateral retinal tumors
26% likelihood of second primary (mostly osteosarcomas)
40% of all RB cases are hereditary
64
Tuberous sclerosis complex
TSC1, TSC2, autosomal dominant
>60% de novo
6-14% risk of childhood brain tumors
2-5% risk of renal cell carcinomas (onset 28 years)
>50% born with cardiac rhabdomyomas
Benigh lesions: facial angiofibroma, ungual fibromas, shagreen patch, retinal hamartomas, cortical tubers (brain tumor), astrocytoma, LAM
80% have seizures, 50% severe LD/ADHD/autism
65
Von-Hippel-Lindau
VHL, autosomal dominant
20% de novo
25-40% risk of clear cell RCC
7-25% risk of islet cell tumors of the pancreas
3-17% risk of pheochromocytomas
70% have retinal angiomas (benign) - can occur in childhood
Pathognomonic: hemangioblastoma
Endolymphatic sac tumors can cause HL and vertigo/tinnitus
66
Philadelphia chromosome
cytogenetic finding used to diagnose CML (present in 90-95% of cases)
t(9;22)(q34;q11.2)
67
Nijmegen syndrome
NBN, autosomal recessive
50x increased risk of developing cancer
~50% risk of NHL
Other cancers: medulloblastoma, glioma, rhabdomyosarcoma
Features: short stature, intellectual disability, progressive microcephaly, facial dysmorphism, immunodeficiency, females infertile
68
Xeroderma Pigmentosum
XP__, autosomal recessive
Increased risk of skin cancer
~50% have had skin cancer by 10 years
Features: skin findings (severe freckling, blistering, irregular pigmentation), ocular defects & vision problems, internal malignancies, neurological problems (HL, intellectual disability, microcephaly, etc) in 30%
69
BAP1 tumor predisposition syndrome
BAP1`, autosomal dominant
Cancers: ocular melanoma, malignant mesothelioma, RCC, BCC, atpical melanocytic tumors (MBAITs)
Near the VHL locus
70
Oncogenes definition
dominant growth promoting genes that originate from proto-oncogenes
ex: RET
71
Tumor suppressor genes definition
Negatively regulate cell growth, causes cancer when inactivated
ex: TP53
72
Mismatch repair genes definition
Fix nucleotide errors made during replication
| ex: FANCC
73
Thyroid cancer histology
Follicular (Cowden, Carney)
Medullary (MEN2A, MEN2B, FMTC)
Papillary (FAP)
74
Renal cancer histology
```
Papillary type I (HPRCC, gene: C-MET)
Papillary type II (HLRCC, gene: FH)
Clear cell (VHL, BAP1)
Chromophobe/oncocytoma (BHD, gene: FLCN)
```
75
Neurofibromatosis 2
NF2
Vestibular schwannomas (AKA: Grace)
Ear things
76
Risk factors for male breast cancer
Genetic mutation (BRCA2)
Age
Gynecomastia (Klinefelters)
