Inherited Susceptibility in Cancer Flashcards
Why is studying inherited cancer syndromes important?
They have implications for sporadic cancers.
Helps us understand and predict genetic risk and do surveillance.
Provide clues to the rate limiting step of cancer development.
Guides therapy development
Why are inherited conditions earlier onset?
because they already have the first hit, only need the second. Rather than two hits in the gene/pathway of many.
There can be predisposition to common cancers and Rare familial cancer syndromes.
What do they have in common?
Familial clustering. Early age onset. Multiple primary tumours.
There can be predisposition to common cancers and Rare familial cancer syndromes. How are they different?
Common cancer predisposition - no particular phenotypic marker.
Rare familial cancer syndromes - Distinct phenotype. Clustering of rare cancers in individual.
What are clinic considerations for predisposition syndromes in terms of the cancer and risk etc.
What’s the likelihood of the cancer developing?
How common is the sporadic form of the cancer?
Will early detection alter outcome?
Is risk reducing surgery feasible?
How severe is the cancer?
What clinic considerations are their for predisposition syndromes are more emotional/mental etc.
The unaffected family member may be bereaved. They may be coming back to the same hospital. They may be dealing with the diagnosis of cancer already. Do we have the DNA stored of a terminally ill family member?
What are some risk factors of breast cancer?
Family history, known genetic variants, hormone replacement therapy, racial background. Age of first pregnancy, number of pregnancies, age of menarche & menopause, use of oral contraceptive, lactation
What portion of breast cancers are inherited?
20%
What are the most common genes involved in inherited breast cancer?
High Risk -
Moderate Risk -
Low Risk -
High Risk - 30-95% lifetime risk - BRCA1, BRCA2, CDH1, TP53, PTEN, STK11 PALB2
Moderate Risk - 15-25% lifetime risk - ATM, CHEK2, NF1
Low Risk - Up to 15% - GWAS variants like FGFR2.
What are Breast cancer Moderate risk and low risk variants used for?
Moderate - Used clinically if features suggest specific condition.
Low Risk - Not used clinically, but being used to develop polygenic risk scores.
What is the BRCA1 Life time risk for Breast cancer? and for Ovarian cancer?
Breast 60-80% Ovarian 50%
What is the BRCA2 Life time risk for Breast cancer? and for Ovarian cancer?
Breast 50-80% Ovarian 25%
What are the BRCA risks to men?
Increases risk of prostate cancer by 10-14% and breast cancer by 5-10%
Women with high risk breast cancer variants are offered what?
Breast surveillance MRIs, and risk reducing surgery to their breasts. Some may also get their ovaries and fallopian tubes removed.
What ages are people asked about risk reducing surgery if they have BRCA1 and BRCA2 variants?
35 for BRCA1 and 40 for BRCA2
PARP is very abundant in the nucleus. What does it do?
Repairs single stranded DNA breaks by base-excision repair
How does PARP-i lead to Breast cancer being killed?
if PARP is inhibited, then ssDNA breaks will turn to dsDNA breaks. Then Homologous recombination will do the repair. BUT if BRCA is mutated, then the cell will be defective in homologous recombination. So the cell will die.
What protein is measured in your blood to monitor PARPi use for your ovarian/fallopian tube/peritoneal cancer?
CA-125
Enter the percentages for CRC:
Sporadic -
Familial without known gene -
Lynch -
GAP -
Rare CRC Syndrome -
Enter the percentages for CRC:
Sporadic - 65-85%
Familial without known gene - 10-30%
Lynch - 5%
FAP - 1%
Rare CRC Syndrome - 0.1%
What are the 5 CRC predisposition syndromes?
Lynch
FAP
MYH Polyposis
Peutz Jeghers
Juvenile Polyposis
What inheritance pattern is FAP?
Autosomal Dominant
What is mutated in FAP?
APC on 5q21
If you’re at 50% risk of having FAP, and your familial mutation is known, what will happen?
Be offered testing at age 10-12. Carriers are then offered colonoscopies. If there a polyps, you can have an elective colectomy.
What’s the penetrance of the AD inherited Lynch syndrome?
80%
What genes involved in Lynch syndrome?
MLH1, MSH2, MSH6, PMS2
What technique is used to detect Lynch syndrome proteins being lost?
IHC
Briefly, what is the Amsterdam criteria to determine Lynch syndrome referral/testing?
3, 2, 1. 3 relatives across 2 generations, 1 with CRC under 50 (or 45 in modified version).
How often do Lynch carriers get colonoscopies?
Every 18-24 months
What’s your life time risk of different cancers if you have a lynch syndrome mutation?
78% for CRC.
43% for endometrial caner.
Also increased for gastric and renal
What risk reducing surgery might you have if you have lynch syndrome?
Ovary and fallopian tubes out
What are the main 2 mutations that cause lynch syndrome relevant to CRC?
MLH1 and MSH2
What are the main 2 mutations that cause lynch syndrome relevant to endometrial cancer?
MSH2 and MSH6
What happens to DNA when MMR is deficient?
Slippage during replication. Can be seen via MSI.
What does it mean that MMR deficient cells have a high frameshift peptide neoantigen load?
The slippage caused by MMR deficiency causes proteins to have frameshifts in them, so lots of aberrant proteins are made. These provide many therapeutic targets as they are new for the immune system to target as foreign bodies.
The outcome of Renal Cell Carcinomas heavily depends on what?
The stage of the carcinoma at presentation
How is localised, early stage RCC treated?
Nephron sparing surgery
What happens in later stage RCC?
The carcinoma breaches the capsule and then metastasises, worsening the prognosis
What percentage of RCC has metastasis at presentation?
30%
RCC has poor response to what treatments?
Immunotherapy and chemotherapy
What needs to be identified in RCC tumourigenesis?
The genetic and epigenetic events
What is the inheritance pattern and incidence of Von Hippel-Lindau disease?
Autosomal dominant, and 1 in 35,000
What are the symptoms of Von Hippel-Lindau syndrome?
(A bunch of tumour types)
Retinal angiomas, cerebellar hemangioblastoma (which disturbs gait and balance), Clear Cell RCC, Pheochromocytoma, and renal, pancreatic and epidydimal cysts
How is Von Hippel-Lindau syndrome caused?
germline mutations in VHL tumour suppressor gene
Somatic mutations of the VHL gene cause 60% of what?
Sporadic Clear Cell Renal Cell Carcinoma
What does the HIF gene do?
It’s a key Transcription Factor that senses oxygen levels in the cell
When VHL gene is inactivated, what does HIF do?
HIF gets overexpressed, it will then upregulate growth factors even though the cell is not hypoxic. This leads to increased metabolism and angiogenesis
What growth factors does HIF upregulate?
VEGF, PDGF, TGFalpha
What target do drugs for von hippel-lindau syndrome now target?
They target VEGF and PDGF to inhibit them
What does HLRCC Stand for?
Hereditary Leiomyomatosis and Renal Cell Carcinoma
What is the inheritance of HLRCC and what other important thing should you mention?
It’s autosomal dominant, but incomplete penetrance
What are the clinical features of HLRCC
Cutaneous Leiomyomata and uterine fibroids. And a life time risk of 21% of RCC, which can be very aggressive and can be quite early.
What is the cause of HLRCC?
Germline variants in FH gene
What’s the mean age of diagnosis of HLRCC?
41
What do most HLRCC patients die from?
Metastasis. 74% of them.
How is HLRCC treated?
A nephrectomy surgery of the affected region as well as some medicines…
How are HLRCC patients surveilled?
Annual contrast MRI
How rare is Cowden Syndrome?
1 in 200,000
What are the symptoms of Cowden syndrome?
Benign and malignant tumours - Cancers of breast, thyroid, endometrium, and RCC. Macrocephaly. Characteristic skin lesions.
How are Cowden syndrome patients monitored for RCC?
Ultrasound scans of renal system from age 40
How rare is Hereditary Papillary Renal Cancer type 1?
Very rare…
What is the cause of Hereditary Papillary Renal Cancer type 1
Activation of the MET oncogene (analogous to RET in MEN2). There’s also a sporadic type caused by amplification or activation of MET.
So the FH gene is mutated in HLRCC. What happens in the cell when it doesn’t work?
Fumarate builds up, so VHL won’t bind to HIF and degrade it. So HIF upregulates growth factors.
What is FH, what does it do?
Fumurate hydrogenase? Turns fumurate to malate
What is SDH what does it do?
Succinate dehydrogenase, turns succinate to fumurate
What happens when SDH is inactivated by germline variants?
It causes RCC with a similar mechanism to mutated FH. The succinate build up inhibits the PHD enzyme, so VHL can no longer bind to HIF, so HIF upregulates the growth factor genes
What are the most commonly mutated genes when you do NGS on RCC?
VHL is most common. Then PBRM1, SETD2, and BAP1. Also a loss of 3p where CHL is located as well as other tumour suppressors
What’s still a big challenge in understanding RCC mutations?
The incomplete penetrance and low risk variants, as well as genes involved in multiple pathways that are difficult to target for therapy
Current TKIs have limited ………
Current TKIs have limited impact on the VHL/HIF pathway
In Summary, familial cancer syndromes are characterised by:
Distinctive phenotypes and/or clustering of rare and early cancers
