17_Hereditary Cancer COPY Flashcards
1
Q
What distinguishes
hereditary cancer from
cancer predisposition syndrome?
A
- Hereditary cancer involves a specific inherited gene mutation which significantly raises the risk of a particular cancer type. It is associated with a strong family history of the same type of cancer.
- Predisposition syndrome involves any genetic factor that could potentially increase cancer risk. Less clear family pattern is present.
2
Q
What percentage of all cancers is hereditary?
A
Only 8-15% of all cancers are hereditary. (Mostcancersare sporadic caused by risk factors.)
3
Q
How does the incidence rate of hereditary cancers differ between children and adults?
A
The incidence rate of hereditary cancers is higher in kids.
4
Q
What does the term cancer penetrance mean?
A
Cancer penetrance is the likelihood that a person with a disease-causing gene mutation will develop cancer.
5
Q
What are the various levels of cancer penetrance?
A
There are three levels of cancer penetrance:
1-Complete penetrance: Every person with the mutation will develop cancer
2- Reduced penetrance: Some people with the mutation develop cancer, while others don’t
3-Low penetrance: A mutation that means someone has a lower or milder risk of developing cancer
6
Q
At what level/category of penetrance do hereditary cancers fall?
A
Most hereitary cancers have reduced penetrance.
7
Q
What is the inheritance pattern of hereditary cancers?
A
Mostly autosomal dominant (AD) meaing that the presence of a single copy of a mutated gene on one of the autosomal chromosomes is sufficient to cause the genetic disorder.
8
Q
Are hereditary cancers associated with germline or somatic mutations?
Are these mutations assoicated with oncogenes or tumor suppressor genes?
A
-Most hereditary cancers are caused by germline tumor suppressor gene mutations (Loss of function)
-Oncogene mutations usually happen somatically. (Apparently, oncogene mutations are incompatible with germline development)
9
Q
List the few oncogenes which may undergo mutations in predisposition syndromes.
A
MET
HRAS
KRAS/BRAF
ALK
EGFR
RET
10
Q
Which predisposition syndrome is driven by mutation in oncogene MET ?
A
hereditary papillary renal cell cancer
11
Q
Which oncogene mutation underlies hereditary papillary renal cell cancer?
A
MET
12
Q
Which predisposition syndromes are driven by mutations in oncogene HRAS?
A
- Costello syndrome,
- Transitional carcinoma of bladder,
- Rhabdomyosarcoma,
- Neuroblastoma
13
Q
Which mutant oncogene underlies costello syn, risk of transitional carcinoma of bladder, rhabdomyosarcoma, neuroblastoma?
A
HRAS
14
Q
Which predisposition syndromes are driven by mutations in oncogenes KRAS/BRAF?
A
- Cardio-Facio-Cutaneous,
- ALL
- NHL
15
Q
Which mutant oncogenes underlie Cardio-Facio-Cutaneous,
ALL, NHL?
A
KRAS/BRAF
16
Q
Which predisposition syndrome is driven by mutation in oncogene ALK?
A
Hereditary neuroblastoma
17
Q
Which mutant oncogene underlies hereditary neuroblastoma?
A
ALK
18
Q
Which predisposition syndrome and condition are driven by mutations in oncogene EGFR ?
(specifically V842I or T790M variants)
A
- Familial lung cancer (germline V842I or T790M)
- resistance to TKI therapy (somatic V842I or T790M)
19
Q
Which oncogene mutation underlies Familial lung cancer and resistance to TKI therapy?
A
EGFR
(V842I or T790M )
20
Q
What category of genes are associated with autosomal recessive types of cancer predisposing syndromes?
A
Autosomal recessive types of cancer predisposing syndromes are rare and involve genes regulating DNA repair or checkpoint response.
Examples of relavent diseases:
Bloom and Ataxia Telangiectasia
21
Q
When is the onset of hereditary cancer development?
A
early age
22
Q
What is the pattern of tumor formation in hereditary cancers?
A
- bilateral/multifocal
- specific core areas (breast, ovarian, colorectal, renal)
- unusual/rare tumors (e.g., breast cancer in men)
- constellation of related tumors (a pattern where multiple different types of tumors occur together in a single individual or family, often indicating a shared genetic predisposition or underlying cause)
23
Q
Which mutant gene drives low hypodiploid ALL as a specific hereditary cancer?
A
TP53
24
Q
Name one of the specific mutation profiles detected in hereditary cancers.
A
Hypermutation
Exampels:
-Hypermutated colorectal cancer (HCRC)
-Hereditary nonpolyposis colorectal cancer (HNCC)
25
Does lack of family history rule out predisposition syndrome?
NO- This may be due to:
* de novo mutations,
* reduced penetrance,
* young individuals not showing the disease “yet”, thus, obscuring the inheritance.
26
Why familial colorectal cancer (CRC) emerges
at late onsets, but retinoblastoma (RB) is pediatric?
Colorectal cancer requires several sequential
mutations in several genes which may take long.
Retinoblastoma requires one (in hereditary) or two (in sporadic) mutations.
**Age dependence may also reflect the number, timing, and rate of cell divisions in colon cells and in retinoblasts.
27
Which tumors with >10% chance of being hereditary are likely driven by ***RB1*** mutation?
Retinoblastoma
28
Name the most likely underlying mutant gene in hereditary Retinoblastoma.
*RB1*
29
Which tumors with >10% chance of being hereditary are likely driven by ***TP53*** mutation?
* Adrenocortical carcinoma
* Choroid plexus
* hypodiploid ALL
* Anaplastic rhabdomyosarcoma
* Early onset Breast
* Medulloblastoma with chromothripsis
30
Name the common and most likely underlying mutant gene in hereditary Adrenocortical carcinoma; Choroid plexus; hypodiploid ALL; Anaplastic rhabdomyosarcoma; Early onset Breast; Medulloblastoma with chromothripsis.
*TP53*
31
Which hereditary syndromes are asscociated with Adrenocortical carcinoma?
MEN1, BWS, and LFs.
32
Name the hereditary tumor commonly developed in MEN1, BWS, and LFs.
Adrenocortical carcinoma
33
What are the most likely genetic drivers of hereditary Pheochromocytoma/Paraganglioma?
VHL/NF1/RET/SDHA/SDHB/SDHC/SDHD/SDH5/SDHAF2/TMEM127
34
Which tumors with >10% chance of being hereditary are most likely driven by ***VHL*** mutation?
* Retinal/cerebral hemangioblastoma
* Endolymphatic Sac tumor
35
Name the common and most likely underlying mutant gene in hereditary Retinal/cerebral hemangioblastoma and Endolymphatic Sac tumor.
*VHL*
36
Which tumors with >10% chance of being hereditary are likely driven by ***NF1*** mutation?
* Optic pathway tumors
* Malignant peripheral sheath tumor
* JMML
37
Name the common and most likely underlying mutant gene in hereditary Optic pathway tumors, Malignant peripheral sheath tumor, and JMML.
*NF1*
38
Which tumor with >10% chance of being hereditary are likely driven by ***RET*** mutation?
Medullary thyroid tumor
39
Name the most likely underlying mutant gene in hereditary Medullary thyroid tumor.
*RET*
40
Which hereditary tumors/conditions are most likely driven by **SMARCB1 germline LOF**?
1-Rhabdoid tumor predisposition syndrome
* Mostly in kidney and other soft tissues
like muscle
* Rerely in CNS (called atypical teratoid
rhabdoid tumors (ATRT))
2-Familial Schwannomatosis Coffin-Siris (CSS)
| Do not confuse Rhabdoid tumors with Rhabdomyosarcoma!!!
41
Which condition is most likely driven by **SMARCB1 GOF missense/indels**?
Coffin-Siris which has no cancer risk.
42
Which hereditary tumors/conditions are most likely driven by ***SMARCA4* LOF** ?
* Rhabdoid tumors
* Ovarian small cell carcinoma
* hypercalcemic type
43
Which hereditary tumor is most likely driven by ***SMARCE1* LOF** ?
Clear cell meningioma
44
Are Rhabdoid tumors mainly associated with germline or somatic LOF mutations?
* Somatic LOF muts are found in
98% of Rhabdoid tumors
* Germline het LOF muts predispose to the same tumor (somatic loss of second allele is needed).
45
Which tumors with >10% chance of being hereditary are most likely driven by ***STK11*** mutation?
Ovarian sex cord tumors with annular tubules
46
Name the most likely underlying mutant gene in hereditary ovarian sex cord tumors with annular tubules.
*STK11*
47
Which tumors with >10% chance of being hereditary are most likely driven by ***NF2*** mutation?
Acoustic/vestibular schwannomas
48
Name the most likely underlying mutant gene in hereditary Acoustic/vestibular schwannomas.
*NF2*
49
Which tumors with >10% chance of being hereditary are most likely driven by ***DICER1*** mutation?
Pulmonary pleuroblastoma
Cystic nephroma
CNS sarcoma
50
Name the most likely underlying mutant gene in hereditary Pulmonary pleuroblastoma, Cystic nephroma, and CNS sarcoma.
*DICER1*
51
Which tumors with >10% chance of being hereditary are most likely driven by ***APC*** mutation?
Destoid tumor
Hepatoblastoma
Gardner fibroma
52
Name the most likely underlying mutant gene in hereditary Destoid tumor, Hepatoblastoma,
and Gardner fibroma.
*APC*
53
Which tumors with >10% chance of being hereditary are most likely driven by ***PTEN*** mutation?
Cerebellar dysplastic gangliocytoma
54
Name the most likely underlying mutant gene in hereditary Cerebellar dysplastic gangliocytoma.
*PTEN*
55
Which tumors with >10% chance of being hereditary are most likely driven by ***TSC1/2*** mutation?
Cardiac rhabdomyoma
56
Name the most likely underlying mutant gene in hereditary Cardiac rhabdomyoma.
*TSC1/2*
57
Which tumors with >10% chance of being hereditary are most likely driven by ***SDHA/B/C/D*** mutation?
Gastrointestinal stromal tumors (GIST)
58
Name the most likely underlying mutant gene in hereditary Gastrointestinal stromal tumors (GIST).
*SDHA/B/C/D*
59
Which hereditary condition is most likely driven by mutations in ***Turcot, Gorlin, NF2, MEN, Cowden***?
Syndromes associated with **Medulloblastoma**
60
List the most likely underlying mutant genes in hereditary syndromes associated with **Medulloblastoma**.
*Turcot, Gorlin, NF2, MEN, Cowden*
61
What does "Mitotic recombination"
refer to?
* A mechanism for LOH in tumor suppressors
* Can also lead to reversion
(loss of mutation and reverting homozygous wild type).
62
What are the biological roles of
the following cancer predisposing genes?
FGF4/PDGFB (**growth factor**)
EGFR (**receptor for growth factor**)
ABL/RAS/PIK3A (**signal transducer**)
GLI1/MYC (**transcription factor**)
CCND1 (**cell cycle regulator**)
BCL1/2 (**apoptosis**)
63
What is the most common eye tumor in children?
Retinoblastoma
64
What percentage of pediatric cancers is accounted for by retinoblastoma?
3-4%
65
Which tissue does retinoblastoma originate from?
Embryonic neural retina
66
What is the genetic driver of retinoblastoma?
LOF in RB1
In ~1% of cases no RB1 mutation is found, instead they have MYCN amp.
**MYCN is also amplified in neuroblastoma!!
67
What is the biological role of Rb1?
* RB1 promotes transition of cell cycle from G1 to S.
* Rb1 also binds E2F to stop transcription.
68
What is the activation mechanism of Rb1?
Rb1 is activated through phosphorylation.
69
What is the breakdown of the incidence of retinoblastoma in terms of sporadic and hereditary cases?
* 60% sporadic
* 40% hereditary
70
What is the percentage of de novo cases versus cases with a family history in retinoblastoma?
* 80% de novo
* 20% with family history
71
How does the age of incidence differ between sporadic and hereditary retinoblastoma?
Sporadic retinoblastoma has a later age of onset (2 years) compared to hereditary retinoblastoma (1 year).
72
What are the most common mutations of Rb1 in Retinoblastoma?
* LOF muts in RB1 has 90% penetrance
* Missense and splicing vars
have lower penetrance.
* most common second hit event is LOH.
73
What is the heredity percentage of bilateral retinoblastoma?
Bilateral RB is 100% hereditary.
74
Is bilateral retinoblastoma asscoiated with germline or somatic mutations?
All patients with bilateral RB have germline path variants.
75
What is the heredity percentage of unilateral retinoblastoma?
Unilaterral RB is 15% hereditary.
76
Is unilateral retinoblastoma asscoiated with germline or somatic mutations?
Germline muts.
77
What tumors are involved in trilateral retinoblastoma (in addition to retinoblastoma itself)?
Trilateral retinoblastoma includes
bilateral retinoblastoma+pinealoblastoma
78
What is the penetrance rate of retinoblastoma?
* >90% overall
```
```
* >99% in LOF vars
```
```
* There are low penetrance in some other variants including promoter, splice, missense, etc.
79
What other condition(s), **in adition to retinoblastoma**, manifest in case of contiguous deletion of 13q14.2 harboring RB1?
Developmental disabilities (DDs)/birth defects
80
Are retinoblastoma patients at risk of any late-onset tumors? If yes, name the tumors and their incidence rate, over lifetime.
* Yes
* Osteo and soft tissue sarcomas, uterine leiomyosarcoma, lung cancer, melanomas
* 15-20% incidence rate over lifetime
Note:Radiation therapy can double the risk of tumors, so it should be avoided.
81
What preventive care is recommended for *RB* mut carriers?
Eye exam every 3-4 weeks until age 1 .
82
What is the recurrence risk for RB assuming unaffected parents, **without testing**?
* Offspring of bilateral case (45%);
* Offspring of unilateral (7.5% [**15% hereditary** ÷ 2]);
* Siblings of bilateral (5-7%);
* Siblings of unilateral (0.5-1%)
Note: Analytic sensitivity is 95%; promoter/mosaicism/intron/rearrangements are issues.
83
What is the recurrence risk for RB assuming unaffected parents, **with negative blood genetic testing**?
* Offspring of bilateral cases (?%, need to investigate mosaicism, intron, etc.);
* Offspring of unilateral (<1%);
* Sib of bilateral (5% due to hidden parental mosaicism);
* Sib of unilateral (<0.1%)
84
In a family where the first child harbors *RB* germline mutation and the parents are negative, is there any risk of the disease for the second child?
* Yes
* Still assume ~5% risk for next child due to possible germline mosaicism.
85
Accoding to the guidelines for RB1 testing, when familial screening ***is*** or ***is not*** needed?
* Familial screening is always required.
* Only when the mutation is tumor in known and is confirmed to be absent in blood, familial screening is not needed.
86
What is the guideline for RB1 testing, if the blood tested positive in kid?
Test relatives and those poz need screening (negs don’t need)
87
What is the guideline for RB1 testing, if blood tested negative while tumor positive?
No further follow-up/testing for relatives.
88
What is the guideline for RB1 testing, if blood tested negative while tumor not tested?
Screening in relatives should be done according to the risk estimates listed in the previous slides.
89
What is the guideline for RB1 testing, if both blood and tumor tested negative ?
Screening in relatives should be done according to the risk estimates listed in the previous slides.
90
To which major category of hereditary cancers do *RET*-related syndromes belong?
Familial neuroendocrine syndromes
91
Which genes predispose to
**thyroid carcinomas**?
*RET, APC, PTEN, MUTYH*
(but not *MEN1*)
92
Name the major categories of familial neuroendocrine syndromes.
1- RET-related syndromes (AD)
2- Paraganglioma and pheochromocytoma tumor syndromes.
3- Carney Complex
4- CDC73-related conditions
93
Which disease associated with familial neuroendocrine syndromes, is driven by ***RET* LOF**?
Hirschsprung's disease
94
What gene and mutation underlie Hirschsprung's disease?
***RET* LOF**
RET (rearranged during transfection) is a receptor tyrosine kinase
95
What is the dominant phenotype in Familial neuroendocrine syndromes driven by ***RET* GOF** ?
Medullary Thyroid Carcinoma (MTC)
| RET GOF results in increased TK activity in the absence of ligand
96
What is the underlying genetic mutation for Medullary Thyroid Carcinoma (MTC) phenotype?
***RET*** **GOF**
97
What are the main Familial neuroendocrine cancers linked to ***RET* GOF**?
1- Familial Medullary Thyroid Carcinoma (**FMTC**)
2- Multiple Endocrine Neoplasia Type 2A (**MEN2A**)
3- Multiple Endocrine Neoplasia Type 2B (**MEN2B**)
98
Describe the inheritance pattern of Familial Medullary Thyroid Carcinoma (FMTC)?
* FMTC is inherited in an autosomal dominant manner
* Is always inherited (never de novo)
99
What percentage of families with RET GOF-related syndromes are affected by FMTC?
Around 20%
100
What is the age range for the incidence of FMTC?
Middle age
101
Which codon(s) and domain(s) of RET are involved in FMTC?
codons 768,790,804,891
located on tyrosine kinase domain
102
What percentage of all MTC cases are inherited?
25%
103
Name the clinical feature appearing in FMTC?
Only MTC
| (No Pheochromocytoma like other ).
104
How many affected cases in the family are needed to diagnose the diesease as FMTC?
4 affected cases
105
Which of the *RET* GOF associated conditions could be considered as a variant of MEN2A?
FMTC
106
What percentage of MEN2A (Multiple Endocrine Neoplasia Type 2A) cases develop de novo?
50%
107
What percentage of families with RET GOF-related syndromes are affected by MEN2A?
75%
108
Which codon(s)/exon(s)/residue(s) and domain(s) of RET are involved in FMTC?
* codons 609-634,
* exon 10-11,
* cysteine residues
* extracellular domain
109
What is the age range for the incidence of MEN2A?
Childhood
110
What clinical features are linked to with MEN2A?
* MTC
* Pheochromocytoma
* Parathyroid adenoma/hyperplasia and hyperparathyroidism (not in MEN2B)
111
What percentage of families with RET GOF-related conditions are affected by MEN2B?
5%
112
Which codon(s) and domain(s) of RET are involved in MEN2B?
* only codons 883/918
* tyrosine kinase domain
113
What are the clinical features of MEN2B?
* MTC
* Pheochromocytoma
* Mucosal neuromas [specific to MEN2B; thickening of nerves – benign neural tumors]
* Digestive problems due to nerve issues in GI (intestinal ganglioneuroma)
* Joint and spinal issue,
* marfanoid body habitus with a characteristic dysmorphic facial features including swollen lips and thick eyelids
114
What is the age range for the incidence of MEN2B?
childhood
115
What percentage of MEN2B cases develop de novo?
50%
(highest rate of de novo occurrence)
116
What is the only treatment recommended for RET GOF-related syndromes?
Prophylactic Thyroidectomy
117
What is the recommended timeline for treating RET GOF-related syndromes?
* The risk of MTC in childhood is highest in both MEN2A/B.
* in 2B the age of onset is considerably lower, so the treatment is recommended by **6mo-1yr** while
* in 2A, treatment should be done **by 5yr**
* in FMTC, treatment should be done
**between 5-10yr.**
118
Which hotspots should be tested for the diagnosis of RET GOF-related syndromes? What is the detection rate using this diagnostic test?
* Exons 5,8,10,11,13-16
* It gives 88-95% detection rates
119
What syndromes are considered as risk factors or tyhroid cancer (particularly papillary and follicular)?
* Familial adenomatous polyposis (FAP),
* Gardner syndrome,
* Cowden disease,
* Carney complex type I
Note: none of these syndromes cause pheochromocytoma like in MEN2/1.
120
Is cysteine the only residue involvd in RET-related syndromes?
* No
* few variants exist outside cysteine residues which cause both MEN2 (MEN2B? double check) and Hirschsprung’s (but doesn’t happen for MEN2A)
121
In which of the RET-related syndromes is the parathyroid involved?
Parathyroid involvement is:
* Rare in MEN2B
* Common in MEN2A
122
To which major category of hereditary cancers does MEN1 belong?
Familial neuroendocrine syndromes
123
What is the genetic driver of Multiple Endocrine Neoplasia Type 1 (MEN1) ?
LoF muts in MEN1 (a tumor suppressor)
124
What is the inheritence pattern of MEN1?
AD
125
Which organs/tissues/cell types become cancerous in MEN1?
* parathyroid, (NOT thyroid!)
* pancreas islet cells,
* adrenal
* pituitary,
* tumors in pancreas or duodenum (Zollinger-Ellison syn),
* enteropancreatic endocrine cell tumors,
adrenocortical carcinoma
Note: Only Parathyroid. No Thyroid tumor.
126
What are the guidelines for MEN1 screening?
* assess serum prolactin since age 5
* asses fasting total serum calcium from age 8
* assess gastrin from age 20
* head MRI from age 5
* abdominal CT/MRI from age 20
127
Sumerzie RET/MEN1 syndromes:
128
To which major category of hereditary cancers do paraganglioma and pheochromocytoma tumor syndromes belong?
Familial neuroendocrine syndromes
129
What are the genetic variants and inheritance patterns associated with paraganglioma and pheochromocytoma tumor syndromes?
* half cases have P/LP variants
* SDHD (30%, from dad [the imprinted one])
* SDHB (22-38%, AD, bad, tumor suppressor)
* VHL (25%)
* RET (50%, both MEN2A/B),
* **NF1**, SDHC, SDHAF2, SDHA (low penetrance), MAX, TMEM127, CHL
* AD for all
130
What are the common and rare tumors associated with paraganglioma and pheochromocytoma tumor syndromes?
* Common tumors: head and neck paragangliomas & adrenal pheochromocytomas
* Rare tumors: pituitary, renal cell, and Gastrointestinal stromal tumor (GIST)
131
What is the bilogical role of SDHB?
SDHB is involved in metabolizing succinate. Succinate stabilizes HIF (hypoxia induced factor for neovascularization which is involved in cell division also).
132
How SDHB mutation(s) is/are associated with tumorogenesis?
LOF in SDHB leads to increased succinate and higher HIF, leada to tumorigenesis.
| SDHD stands for succinate dehydrogenase complex subunit D which is a tum
133
What are the genetic driver(s) and inheritence patter of Von-Hippel-Lindau syndrome?
* VHL
* AD (second somatic hit needed)
134
Through which biological mechanism does the mutant *VHL* promote uncontrolled angiogenesis?
VHL suppresses HIF, a hypoxia inducible factor which promotes angiogenesis in low oxygen status. ***VHL* LOF** results in overactivation
of HIF and uncontrolled angiogenesis.
135
What specific tumor(s) and condition(s) are associated with Von-Hippel-Lindau?
* pheochromocytoma
* retinal angioma
* cerebella/spinal
* hemangioblastoma
* renal cell carcinoma
* pancreases and renal cysts
* endolymphatic sac tumor leading to deafness
136
What is the most common VHL variant in Von-Hippel-Lindau patients?
A significant percentage of patients (>35%) with VHL carries **missense** mutations.
137
Which type of VHL is more associated with missense mutations?
* Missense mutations are more associated with **Type II** VHL.
* The Type II families demonstrate increased risk of developing
**pheochromocytomas.**
138
What is the penetrance percentage of Von-Hippel-Lindau syndrome by age 65?
>90% by age 65
139
What gene is most somatically double mutated gene in renal cell carcinoma?
VHL
140
To which major category of hereditary cancers does Carney Complex belong?
Familial neuroendocrine syndromes
141
What are the associated gene and inheritence pattern in Carney Complex?
* *PRKAR1A* and possibly other loci yet to be found
* AD
142
What are the clinical features of Carney Complex?
1-**Multiple neoplasia syndrome** characterized by the following tumors:
-cardiac [cardiac myxoma],
-endocrine [Cushing syndrome],
-cutaneous,
-neural myxomatous
2-A variety of **pigmented lesions** of the
skin and mucosae (lentigines).
143
With which syndromes does Carney Complex share clinical similarities?
1-Carney complex may simultaneously involve multiple endocrine glands, like **classic MEN1/2 syndromes** [has pituitary adenomas].
2-Carney complex shows some similarities to **McCune-Albright syndrome**, a sporadic condition that is also characterized by multiple endocrine and nonendocrine tumors
3-Carney complex shares skin abnormalities and some nonendocrine tumors with
the lentiginose and certain of the Hamartomatous, particularly **Peutz-Jeghers syndrome.**
144
Which ***unusual*** tumors are associated with Carney Complex?
* large cell calcifying Sertoli cell tumor
* psammomatous melanotic schwannomas
145
Name the CDC73-related conditions.
* Hyperparathyrodism-jaw tumor (HPT-JT) syndrome
* CDC73-related parathyroid carcinoma
* Familial isolated hyperparathyroidism
146
What syndrome is considered the most common cause of pediatrics cancers? (>1%)
Li-Fraumeni syndrome
147
What is the genetic driver and inheritence pattern of Li-Fraumeni syndrome?
* TP53 mutant
```
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* AD
148
When does the onset of Li-Fraumeni syndrome occur?
From childhood to adulthood
149
Which cancers are associated with
Li-Fraumeni syndrome?
* Sarcomas of bone and soft tissue (anaplastic embryonal rhabdomyosarcoma)
* breast cancer,
* leukemia/lymphoma
* Hypodiploid pediatric ALL (1% of regular pediatric ALL is hypodiploid, but this is 50% in Li- Fraumeni related ALL)
* adrenocortical carcinoma
* brain tumor (choroid plexus carcinoma, medulloblastoma sonic hedgehog subtype with chromothripsis [cth], astrocytoma, glioblastoma), neuroblastoma
* ALL
* GI, stomach, CRC, Kidney, prostate [variable tumor freq by age]
150
What percentage is the penetrance rate of Li-Fraumeni syndrome?
Penetrance is high (90% by age 60).
Intensive surveillance is need.
151
Does the lifetime risk of Li-Fraumeni syndrome occurrence differ between men and women? Why?
Yes.
The lifetime risk is much higher in women than men (100% vs 73%) due to the occurrence of breast cancer in women.
152
What are the Chompret criteria, and what are they designed for?
The Chompret criteria are a set of guidelines used to identify the likelihood of TP53 mutation and Li-Fraumeni Syndrome occurence in an individual.
153
Briefly describe the involvment of TP53 mutation in cancers.
* TP53 is the most mutated gene in cancer;
* TP53 mutant found in >50% of all tumors, in the same hotspots as germline
* TP53 mutant is seen in adrenocortical, choroid
plexus, hypodiploid cancers, ALL, Rhabdomyosarcoma, medulloblastoma, etc.
154
What is the biological role of TP53 in normal cells?
* TP53 is the guardian of genome and cellular gatekeeper;
* it’s responsible for the repair of damaged DNA before S-phase by arresting the cell cycle in G1 until damage is repaired
155
Through which mutations and biological processes does TP53 contribute to cancer?
TP53 is involved in promoting cancer through various mechanisms including LOF, DN, and GOF
since besides gatekeeping and caretaking, it regulates proliferation, drug resistance, metastasis, etc.
156
What is the most common type of TP53 variant in cancer?
In which exons and domain do TP53 mutations mostly occur?
* ~70% of TP53 variants are **missense**
* Most muts occur in **ex5-10**, the DNA binding domain.
(hepatoblastoma is an exception caused by
codon 249 mutation (G>T, R>S) due to aflatoxin/HBV.)
157
What are the different mechanisms of TP53 mutations in cancer?
* Dominant negative inactivation for missense mutations
* LOF+LOH for others
Severity of phenotype: DN>LOF>other types;
For contiguous gene deletion, cancer risk is unknown;
158
On which TP53 domain is the R337H variant located? Which cancer is associated with this variant?
R337H is a founder Brazilian variant in tetramerization domain with low penetrance associated with Adenoid cystic carcinoma
159
Describe the association of TP53 mutation and Clonal hematopoiesis of indeterminate potential (CHIP).
TP53 is one of the genes that can become mutated in clonal hematopoiesis (CHIP, up to 30% of questionable TP53 muts are shown to be due to this).
Note: if you find **mosaic variants** or **suspect CHIP** you need to confirm germline status by testing other tissues.
160
What are the screening guidelines for individuals positive for TP53 mutations?
* Regular screening by total body MRI, colonoscopy, mammograms, etc. is needed. Screening improves survival significantly.
* Toronto protocol is designed for this purpose (very intensive; every 3-4 months)
161
What is the NCCN recommendation for TP53 testing in breast cancer screening?
TP53 testing in women with breast cancer at age <31
or <35 when BRCA testing is negative.
162
Name the diagnostic criteria for Li-Fraumeni syndrome.
Either of these:
1) LF spectrum tumors **before 46 + one first or second degree relative** with an LF tumor;
2) patient with **multiple tumors, 2 of which belong to LF (excluding** **breast** cancer);
3) patients with **adrenocortical carcinoma or choroid
plexus** **tumor** regardless of family Hx.
163
What percentage of breast cancer cases are hereditary and how many mutant genes are involved?
* 10-15% of breast cancers are inherited
* multiple genes
164
What are the indications for breast cancer genetic testing?
Genetic testing is indicated for individuals who have:
1- personal history of breast cancer diagnosed at a young age (<45),
2-bilateral breast cancer
3- A family history of breast, pancreatic, or high-grade/metastatic prostate cancer in a close relative
4-Triple-negative breast cancer,
5-Presence of ovarian cancer in the family
6-Male breast cancer
7-Ashkenazi Jewish ancestry:
8-BRCA mutation detected in a tumor sample (somatic testing)
165
Mention the algorithms for breast cancer risk.
1. **Gail model** is for healthy women (over age 35) wt. limited/no family Hx to predict risk of breast cancer (not for high-risk families).
2. **Claus tables** are designed to determine the risk of breast cancer in healthy women based on their family history of breast cancer.
3. **BRCAPro and BOADICEA models** tell the chance of finding a BRCA1/2 mut and developing breast cancer if you have a family Hx of breast cancer (+/- personal cancer Hx).
4. **Tyrer-Cuzick model** integrates family history, surrogate measures of endogenous estrogen exposure and benign breast disease in a comprehensive fashion and allows for the presence of multiple genes of differing penetrance. It can be used for anyone!
Note:The first two models above can’t be used once a woman is diagnosed with BrCa. The last two can still be used!
166
What is the most common cause of hereditary breast cancer?
The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 genes.
167
What percentage of hereditary breast cancers and all breast cancers are due to BRCA1/2 germline mutations?
* 20-25% of hereditary breast cancers
* and 5-10% of all breast cancers
are due to BRCA1/2 germline muts.
168
On which chromosomes are BRCA1 and BRCA2 loacted?
BRCA1 is on chr17 and BRCA2 is on chr13.
169
What are the penetrance/risk percentages for breast and ovarian cancer?
* For breast cancer: 57% and 49% by 70yrs for BRCA1 and 2, respectively. (Another source said 70% by age 80!!)
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* For ovarian cancer: 40% and 18% by 70yrs for BRCA1 and 2, respectively.
170
What kind of genetic model does BRCA follow?
**Two hit model**
meaning that an individual needs to inherit one mutated copy of the gene (the first hit) and then acquire a second mutation in the remaining normal copy (the second hit) in the same cell to develop cancer.
Note: first hit is inherited, second hit is usually found in tumors.
171
How do breast tumors associated with BRCA1 and BRCA2 mutations differ in terms of their phenotypes and classification?
* Breast cancers associated with BRCA1 mutations are **more** **likely to be triple-negative and basal-like.**
* Breast cancers associated with BRCA1 mutations tend to be **less triple negative.**
172
What are NCCN recommendations for BRCA1/2 testing?
* BRCA1/2 testing for all women under 60 years of age with triple negative breast cancer regardless of family history and ethnicity.
* Lack of ERBB (HER2) amp or high ER/PR means hormone and anti-ERBB therapy won’t work. Therefore, BRCA1/2 mut finding can provide other therapeutic options.
* When BRCA testing is negative and woman is <35, then TP53 must be tested.
Note: For Triple positive women, test HER2 with FISH to determine eligibility for Herceptin.
173
What are the 3 founder LOF variants with high freq in ASJ?
* BRCA1 c.68_69delAG
[1.1% freq in ASJ]
* BRCA1 c.5266dupC
* BRCA2 c.5946delT
Note 1: Targeted analysis of these 3 variants can be cost effective for ASJ ppl.
Note 2: Most BRCA variants are novel and truncating.
174
What are the biological roles of BRCA?
BRCA is involved in:
* chromosome stability,
* homologous recombination (HR) DNA repair,
* DNA replication fork stabilization,
* RNA-DNA hybrid processing during transcription
175
When PARP inhibitors are considered in the treatment plan of BRAC driven breast cancer?
When both copies are inactivated.
176
To what other cancers, besides breast and ovarian, do BRCA mutations predispose?
* Pancreas, prostate, colon, melanoma.
* BRCA1: Breast + ovary + tubal
* BRCA2: breast + male breast + ovary + prostate + pancreas
177
How do the lifetime risks of BRCA1 and BRCA2 mutations differ in men?
* BRCA1 and BRCA2 differ in their lifetime risks for men.
* The most significant increased risk is for pancreatic (10-15% risk –BRCA2>BRCA1).
* Prostate cancer has a risk of 16%.
* Risk of Breast cancer in men is 6% lifelong
(vs. 0.1% in non-carrier men -BRCA2>BRCA1).
* BRCA1/2 account for 10-20% of breast cancer in men.
178
In what condition Pre-symptomatic testing of BRCA1/2 **is not** recommended?
When testing and treatment plans are allowed/recommended for this group?
* Pre-symptomatic testing of BRCA1/2 is not recommended for those younger than 18.
* They should grow up and choose on their
own.
* Treatment begins at age 25 and before 18 no action is recommended. However, pre-symptomatic testing can be allowed when **mature adolescent** seek it. It should be ensured that the child is competent, and his decision is voluntary.
179
For which candidates is breast cancer preventive surgery not recommended?
Preventive surgery is not recommended for women carrying BRCA1/2 muts unlike APC mut carriers!
180
Name the main candidate susceptibility genes, other than BRCAs, for breast cancer.
* PALB2
* FGFR2
* BRIP1
* CDH1
* RECQL
* CHEK2
* RAD51C
181
What is the relation between PALB2 and breast cancer susceptibility?
* PALB2-susceptibility refers to the increased risk of developing breast cancer associated with mutations in the PALB2 gene.
* PALB2 is considered the third most common gene linked to hereditary breast cancer.
* PALB2 directly binds to and functions with the BRCA2 protein.
* Mutations in PALB2 can disrupt BRCA2 normal function, leading to a higher risk of breast cancer development.
| PALB2-susceptibility
182
What is the relation between FGFR2 and bresat cancer risk?
A polymorphism in FGFR2 is one of the most consistent GWAS hit for breat cancer susceptibility.
(FGFR2 caused craniosynostosis syndromes)
183
What is the relation between BRIP1 and ovarian cancer risk?
* BRIP1 interacts with BRCA1
* BRIP1germline muts increase the risk of aggressive ovarian cancer
184
What are the genetic driver(s) and pattern of genetic transmission for hereditary diffuse gastric cancer & lobular breast cancer.
* Both conditions are associated with a mutation in the CDH1 gene, which encodes the E-cadherin protein.
* CDH1 loss promotes metastasis by reducing cell-cell connections (also involved in cell growth).
* Both disorders are AD.
185
What are the clinical features of Hereditary diffuse gastric cancer & lobular breast cancer?
* lobular carcinoma of breast
* diffuse gastric cancer (F[80%]>M[60%])
* cleft lip/palate in some patients.
Note: Penetrance for gastric cancer is 80% in the absence of gastrectomy.
186
What is the relation between RECQL and breast cancer?
There is some evidence that mutations in the RECQL gene may increase the risk of developing breast cancer.
187
What is the relation between CHEK2 and breast cancer?
Founder 1100delC mutation in CHEK2 indicates a moderate risk of developing breast cancer, typically associated with a relative risk (RR) of around 2.
188
What is the relation between RAD51C and ovarian and breast cancers?
* only associated with ovarian cancer.
* No breast cancer!
189
What is the relation between ATM gene or Fanconi anemia genes with susceptibility to breast cancer?
ATM and Fanconi anemia heterozygote mutation carriers have susceptibility to breast cancer.
190
Name the syndromes/conditions which have hereditary contribution to breast cancer.
* Li-Fraumeni
* Peutz-Jeghers
* Cowden
* Hereditary defuse gastric cancer
* Lynch syndromes
Not Beckwith Wiedemann!!
Note: Carriers of t(11;22) who produce Emanuel syndrome kids have high risk of breast cancer.
191
How is the lifetime risk of CRC across different populations?
* Risk of CRC is general population is 5-6%,
* in those with personal Hx of CRC is 20%,
* in those with IBD is 15-40%,
* in Lynch 60-80%
* in FAP >95%
192
What percentage of CRC cases are attributed to specific, well-defined inherited syndromes?
* 2-3% Lynch syndrome
* <1% adenomatous polyposis
* <0.1% Hamartomatous polyposis and others (PJS, JPS, Cowden)
Note: 10-30% of CRC cases have familial risk.
Note: Pay attention to ‘adenomatous’ vs ‘Hamartomatous’ polyps. They belong to different disease groups bellow.
193
What is the order of risk for CRC?
FAP (95%) > HNPCC (70%) > JPC (50%) > PJS
194
Who should be considered for testing for polyposis tumors?
Testing for polyposis tumors must be considered for anyone with:
* personal Hx of ≥10 adenomas,
* presence of CHRPE,
* Hx of hepatoblastoma,
* desmoid tumor,
* meeting criteria with serrated polyposis syndrome with at least some adenomas.
195
What are the guidelines for testing for polyposis tumors?
* Testing should begin with APC seq with reflex to del/dup/rearrangements.
* Testing of MUTYH/POLD1/POLE is also recommended.
196
What are the genetic and clinical features of Familial Adenomatosis Polyposis (FAP)?
* AD
* APC LOF
* >100 polyps
* 100% risk of CRC
* elevated risk of extracolonic tumors (duodenal cancer, thyroid tumors, hepatoblastoma)
* avg age of polyp is 15
* symptoms appear at 33
* dx at 36
* cancer at 39;
* colectomy is needed by age 20.
197
What mutaions are required for tumor development in Familial Adenomatosis Polyposis (FAP)?
* Second hit somatic event is needed for tumor development.
* Somatic activating mutations in CTNNB1 (beta-catenin) and LoF germline variants in APC have similar effect on MYC dysregulation, causing the same phenotype (Adenomatous polyposis). They are both part of Wnt pathway, but with opposite effects; both events lead to beta-catenin activation in tumor. Normal APC targets beta-catenin for deactivation. Issue in one of the two is sufficient for tumor development.
Note: Somatic CTNNB1 muts are also seen in hepatoblastoma.
198
What is the realtion between Gardner’s syndrome and Familial Adenomatous Polyposis (FAP)?
Gardner’s syndrome is a variant of Familial Adenomatous Polyposis (FAP) meaning it shares the characteristic of numerous colon polyps with FAP, but also includes additional "extracolonic" features like:
* benign tumors such as osteomas,
* fibromas
* dental abnormalities,
* desmoid tumors (often abdominal)
* congenital hypertrophy of the retinal pigment epithelium. (CHRPE)
Note: Gardner’s syndrome is an old name, now is just spectrum of FAP.
Note: CHRPE is seen when mutation occurs in 5’ of APC.
199
What are the genetic drivers of Gardner’s syndrome and FAP?
Both are caused by a mutation in the APC gene, leading to the development of multiple polyps in the colon with a high risk of transforming into cancer.
Note: Other cancers in APC are Thyroid and Medulloblastoma (both ~1% risk)
200
What percentage of children with hepatoblastoma carry a mutation in the APC gene? (APC-related Hepatoblastoma)
~10% (they have FAP)
Note: Beckwith-Wiedemann syndrome also carries an increased risk of hepatoblastoma, higher than FAP!
201
What are the screening guidelines for patients with FAP?
* Annual colonoscopy from age 10-15
* Colectomy at late teen to 20s
* Upper GI endoscopy from late teens/20s
* Annual thyroid exam.
Note: Screening for hepatoblastoma in children is controversial.
202
In which context pre-symptomatic testing of APC is allowed?
In minors when there is a strong family history of FAP in order to guide medical management and plan on screening.
203
What are the genetics and clinical distinctions between FAP and Attenuated FAP (AFAP) a?
Both FAP and AFAP are caused by mutations in However, AFAP presents with:
* Delayed onset
* Fewer polyps (<100)
* A lower chance of cancer transformation (~70% vs. 100% in FAP)
Note: Mutations in the extreme 5’ or 3’ of APC are proposed to result in AFAP while others result in FAP.
204
What are the genetics and clinicals features of Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)?
* APC (Promoter mutations/methylation)
* AD
* less involvement of colon and more involvement of stomach (gastric polyps and carcinomas)
205
How are different APC transcripts (1A and 1B) expressed in different tissues?
* APC transcript 1A: colon expression only
* APC transcript 1B: stomach expression only (segregating mutation in YY1 domain in promoter of 1B [c.-191T>C, c.-192A>G,
and c.-195A>C])
Note: promoter of 1B is upstream of 1A, so u need to know when designing NGS panel.
206
How is MUTYH-associated polyposis (MAP) genetically and clinically characterized?
* "MUTYH" (also known as MYH) is the gene associated with "FAP2" or "MYH polyposis
* mutations in the MYH gene develop numerous colorectal adenomas
* AR
* incomplete penetrance
* Homs are affected (100% penetrance by age 65)
* Hets have 2-3-fold increased risk of CRC
* polyposis is very similar to attenuated FAP
207
What are th ebiological roles of the protein enoded by MYH (MUTYH)?
MYH/MUTYH encodes a protein that functions as a key component of the base-excision repair (BER) pathway, specifically targeting and repairing oxidative DNA damage.
208
# 1.
How are MYH and APC mutations associated ?
MYH mutations lead to increased somatic
APC mutations in colon (high GC>TA transversion).
209
What is the only the only method of differentiation between FAP and FAP2?
Genetic testing
210
Which variants of MYH have relatively high population frequency?
* (p.Tyr179Cys and p.Gly396Asp) account for 70-80% of Northern European cases.
* c.1437_1439delGGA accounts for 25% of Southern European (Mediterranean) cases.
Note: consider for variant filtering.
211
What are the diagnostic steps in a a FAP-suspected case?
* First line is APC seq.
* If neg, run APC del/dup.
* Still neg? MYH [two variants/seq].
* If neg, rule out FAP.
212
What is a hallmark of MYH polyposis that doesn’t happen in FAP?
Somatic KRAS mutation (c.34G>T in codon 12) which occur in 64% of cases.
213
What are the key genetic features of Polymerase Proofreading Associated Polyposis (PPAP) syndrome?
* AD
* High penetrance.
* Is caused by mutations in POLE and POLD1 which encode the catalytic and proofreading subunits of DNA polymerase.
* Only several specific missense muts in endonuclease proofreading domain of these genes predispose to CRC.
214
How do mutations in POLD1 and POLE contribute to DNA repair activity?
* Mutations in POLD1 and POLE can increase DNA repair activity, but in an error-prone manner. This results in MMR deficiencies and increased mutation rates. (Many more muts are seen than MMR deficient tumors.)
* So these genes are not classical tumor suppressors with 2 hits.
215
Which cancers are mostly associated with PPAP?
* Hypermutated colorectal and endometrial cancers
* CRC
* Gastric and duodenal cancers
Note: Responses to immune check point inhibitor like in Lynch cases.
216
What are the genetic characterizations of Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syn (MDPL)?
* POLD1 muts in polymerase domain
* AD
Note: Muts in other domains of POLD1 have no phenotype.
217
What is the only Only POLE variant confirmed for CRC?
* Leu424Val
* Other variants predispose to other cancers like breast and melanoma and their role in CRC is debated.
218
How is the tumor mutation burden different between POLE mutated tumors and Lynch tumors?
POLE mutated tumors have higher tumor mutation burden than Lynch tumors.
219
What are the genetic driver and inheritence pattern of the Birt-Hogg-Dubé (BHD) syndrome?
* Caused by a mutation in the FLCN gene (tumor supressor)
* AD
220
What are the clinical features of pattern of the Birt-Hogg-Dubé (BHD) syndrome?
* Chromophobe renal cancer,
* CRC polyps,
* medullary thyroid tumors,
* facial trichodiscomas,
* hair follicle hamartomas (fibrofolliculomas),
* spontaneous pneumothorax
221
What are the genetic cause and the clinical features of GREM1 polyposis?
* Dup upstream GREM1 (most in ASJ) or other chromosomal rearrangements have been reported as the cause
* adolescent onset;
* can resemble FAP or Lynch based on spectrum of polyps;
* extracolonic tumors also possible.
222
What is the diagnostic strategy If there is a family history of polyposis with unknown cause and unavailable proband (like a passed away relative)?
* First test APC, if negative u can
run NGS panel of colon cancer genes.
* Detection rate for APC seq is near 90% with sequencing.
* If the affected family member is
accessible, you need to first test him/her and determine the variant before cascade screening of others.
223
List the Hamartomatous Polyposis syndromes (rare and lower risk).
* Peutz-Jeghers syn
* Cowden syn
* Juvenile Polyposis syn (JPS)
* Lynch syn (HNPCC)
* Constitutional mismatch repair deficiency (CMMRD, aka Turcot syndrome)
* Polymerase proofreading associated polyposis (PPAP) syndromes.
224
What is the genetic cause of Peutz-Jeghers syndrome?
* STK11
* LOF
* 45% del/dup; 55% seq var
* Penetrance almost complete
225
What are the clinical characteristics of Peutz-Jeghers syndrome?
* Hamartoma polyps/CRC followed by cancers in breast (most common), ovary, testis, lung, pancreas;
* Hyperpigmentation (melanotic macules on the lips, buccal mucosa, and fingertips);
* Risk of intussusception, benign ovarian sex cord tumors with annular tubules, Large Cell Calcifying Sertoli Cell Tumor [ovary], and Sertoli cell testicular tumors.
* Minimal deviation adenocarcinoma (MDA) is another one!
226
What are the genetic cause and clinical signs of Cowden syn (aka PTEN hamartoma syndrome)?
* PTEN; LOF
* multiple hamartomas (in skin, intestinal epithelium, thyroid, breast, and oral mucosa), CRC, Cobblestone mucosa, RCC, mucocutaneous lesions, hyperplastic colon polyps, colonic adenomas, lipomas,
and ganglioneuromas, as well as hamartomas of the hair follicle, macrocephaly, autism, DD, adult Lhermitte-Duclos disease (LDD;
rare in children; cerebellar dysplastic gangliocytoma [benign] is the pathognomonic feature), mucocutaneous lesions
(Trichilemmomas [face], acral keratosis, papillomatous lesions, mucosal lesions, pigmented spots on penis); multinodular goiter;
non-colonic cancers: Breast, Thyroid, Endometrium, Testis
227
What is the most common cancer in both Cowden/PJS?
Breast cancer which is even more common than CRC.
228
What is the most common Thyroid cancer type in Cowden syndrome?
* Follicular.
* Medullary never happens in Cowden (restricted to MEN2)
229
Which tumor is involved in Cowden syndrome?
Trichilemmoma, a benign tumor of hair follicle.
230
How similar are Cowden and Cowden-like syndromes?
Cowden-like syndrome overlapps features with Cowden but is not quite the fit.
231
What are the genetic causes of Cowden-like syndrome?
* KLLN promoter hypermethylation,
* path variants in SDHB/C/D, PIK3CA, and AKT1
232
What are the clinical characteristics of Cowden-like syndrome?
* Cancer risk for thyroid, breast, and
endometrium;
* 85% lifetime cancer risk;
* macrocephaly,
* trichilemmomas, papillomatous papules
Names of conditions:
* Bannayan-Riley-Ruvalcaba syndrome;
* PTEN-related Proteus syndrome;
* Proteus-like syndrome.
233
Whar are the genetic features of Juvenile Polyposis syn (JPS)?
( Juvenile refers to polyp shape)
* SMAD4, BMPR1A muts in half of patients
* 1~2% PTEN muts
* penetrance >90%
Note : SMAD4 mutations also caused hereditary hemorrhagic telangiectasias (HHT) and a combined HHT/JPS is present in most cases with SMAD4 path variants.
234
What are the clinical manifestation of Juvenile Polyposis syn (JPS)?
* bleeding/anemia;
* childhood onset of polyps (most are benign);
* risk of CRC by 60 YO is ~68%
Note: prophylactic colectomy not recommended unless severe symptoms.
235
What are the specific clinicals characteristics of SMAD poz JPS cases?
* Some SMAD4 poz cases have JPC + hereditary hemorrhagic telangiectasia.
* Some studies found aortopathy.
* Pulmonary vascular imaging and CNS MRI for screening is recommended.
236
What is challenging about SMAD4 in WGS/WES?
SMAD4 has a processed pseudogene inside intron 18 of SCAI which is not on any panel (not disease gene) but can interfere with mapping in WGS/WES.
237
What is the function of MMR proteins?
* repair of DNA errors during synthesis,
* repair of double strand break,
* apoptosis,
* anti-recombination,
* destabilization of DNA
238
List the MMR DNA repair and non-polyposis CRC syndromes
* Lynch syn (HNPCC)
* Constitutional mismatch repair deficiency (CMMRD, aka Turcot syndrome)
* Polymerase proofreading associated polyposis (PPAP) syndromes
239
What are the genetic fearures of Lynch syn (HNPCC)?
* MMR genes;
* AD;
* MLH1 and MSH2 comprise 90% (10-20% CNV, due to Alu mediated del/inv in MSH2);
* PMS2 (5%);
* a rare cause (1-2%) is EPCAM (TACSTD1) gene deletion (Alu mediated), resulting in epigenetic silencing of MSH2 (hypermethylation);
* MSH6 and PMS2 are the rest;
Often due to high mut rates two genes with more CRC specific involvement get mutated (APC and TGFBR2). TGFBR2 is also an AD hereditary CRC gene
240
What are the clinical fearures of Lynch syn (HNPCC)?
* proximal colon (right side or ascending) neoplasia with no/few polyps;
* most common inherited form of CRC;
* Colon and Endometrium are the most commonly affected sites followed by ovary;
* life time risk of CRC is 80% and endometrial cancer is 60%
241
Mention a specific diagnostic marker of Lynch syn.
* microsatellite instability (MSI) is a diagnostic marker (90% of HNPCC, 30% of endometrial, and 10-15% of sporadic CRC’s), and is also used to decide on checkpoint inhibitors.
242
In the scope of Lynch syn, which two genes with more CRC specific involvement, get mutated ?
* Often due to high mut rates two genes with more CRC specific involvement get mutated (APC and TGFBR2).
* TGFBR2 is also an AD hereditary CRC gene.
243
What is the reason for the increased susceptibility of Lynch syn to immune checkpoint inhibitors?
high mut rate
[like having 100k muts in one cell]
244
Which mutations are Alu mediated?
* EPCAM del,
* MLH1 ex16 del,
* MSH2 ex4-5
* ex7 del,
* MSH2 inversion
245
# **
Which specific key points regarding PMS2 should be considered in the scope of Lynch syndorm?
* Inversion of exons 1-7 of PMS2 with breakpoints in introns happens in some families and needs inversion-specific PCR; can’t
be detected using regular assays.
* PMS2 has the lowest penetrance.
* PMS2 pseudogene: involving ex9 and ex11-15 showing highest seq similarity.
246
