Inherited Cancer Syndromes Flashcards
What is the incidence of lynch syndrome?
1 in 280 individuals
What cancers are associated with lynch syndrome?
Most commonly:
Colorectal cancer
Endometrial cancer
Also cancer of the:
ovary,
stomach,
small bowel,
urinary tract,
biliary tract,
brain (usually glioblastoma),
skin
pancreas
prostate
What genes and mutations are associated with lynch syndrome?
Autosomal dominant inheritence
MLH1
MSH2
MSH6
PMS2
Often frameshift or nonsense variants. Some missense mutations as well
What is the lynch lifetime risk of cancer?
MLH1 and MSH2 = 72%
MSH6 = 54%
PMS2 = 18%
How does the DNA MMR DNA repair pathway work?
The DNA MMR apparatus recognizes errors that elude the proofreading function of DNA polymerase.
The MSH2-MSH6 (MutSα) complex preferentially repairs single base mismatch or mononucleotide repeats.
The MSH-2-MSH3 complex (MutSβ) preferentially recognises larger loop out errors such as dinucleotide repeats.
MutS heterodimers signal the site for mispairing to MLH1-PMS2 (MutL). MutL has endonucelease activity which targted DNA between the mismatch and an adjacent nick to be excised by exonuclease 1 (EXO1) and the excised strand is re-synthesised and repaired by DNA polymerase β
Why do MSH6 and PMS2 mutations have a lower penetrance in lynch syndrome?
MSH2 and MLH1 are the dominant (obligate) constituents of their respective pairs. In the absence of MSH6, MSH2 can pair with MSH3, and in the absence of PMS2, MLH1 can pair with PMS1.
The MSH6 and PMS2 proteins are unstable in the absence of their respective dominant partner.
What is the role of EPCAM in lynch syndrome?
Deletions in EPCAM affecting the termination codon cause transcriotional readthrough to MSH2 leading to silencing of th MSH2 promoter
This mutation will only cause the lynch phenotype in tissues where EPCAM is expressed. This means that the cancers in these patients are normally restricted to the GI tract
If the deletion extends into the MSH2 deletion then behaves as a normal lynch case
Accounts for about 1% of lynch syndrome cases
What other MMR related syndromes are there?
Constitutional mismatch repair deficiency (CMMRD)
- Homozygous or compound heterozygous mutations in the MMR genes- a rare childhood cancer predisposition syndrome
Muir-torre syndrome
- Rare vairant of lynch
- Cutaneous adnexal cancers in combination with internal tumours
Turcot syndrome type 1
- Primary brain tumours with colorectal cancers
Why is PMS2 difficult to analyse by NGS?
Has highly homologous pseudogenes
Often requires specially designed primers to target specific PMS2 regions
How is lynch syndrome diagnosed?
R210
NGS/MLPA for sequence and copy number variants in MLH1, MSH2, MSH6, PMS2
If known familial variant, predictive testing carried out for specific variant using sanger sequencing or MLPA
Which tumours are tested for lynch syndrome?
NICE guidelines recommended for all patients diagnosed with colorectal and endometrial cancer
Outline the lynch reflex pathway
IHC for MMR proteins or MSI testing to identify deficient DNA mismatch repair (usually IHC used)
If the MLH1 loss on IHC result, use sequential BRAF V600E followed by MLH1 promoter hypermethylation testing to identify sporadic cases
If negative, confirm Lynch syndrome by requesting referral to Clinical Genomics Unit/Mainstreaming trained oncologist for genetic testing of germline DNA
If the MSH2, MSH6 or PMS2 IHC loss, confirm Lynch syndrome by germline testing
How affective is IHC for MMRd and what patterns are seen?
95% senstitive for dMMR but dMMR is seen in 15% of all colorectal cancers (most don’t have lynch)
Often concurrent loss of MSH2 and MSH6, or MLH1 and PMS2 is observed as these proteins form heterodimers in the MMR pathway
5% of cases have weak/patchy staining due to missense mutations that express a non-functional protein, unlike the more common truncating variants that are degraded via NMD resulting in no protein expression and consequent lack of staining on IHC
What is microsatellite instability and how does this relate to lynch syndrome?
Loss of MMR repair causes acquisition of hundreds of mutations and genetic instability
This alters the lengths of short tandem repeat sequences called microsatellites
MSI occurs in 90% of LS (germline MMR germline mutations) and 10-15% of sporadic CRC (MLH1 methylation).
How is MSI tested for?
Tests a panel of 5 (most commonly) mononucleotide markers (Bat25, Bat26, Mono27, NR21 and NR24) to assess microsatellite instability using fluorescent PCR.
If all of these mononculetoide markers show MSI then MSI-H, if 3+-MSI-L, if non, normal
What is the significance of MSI-H tumours?
MSI-H tumours frequent in the right colon, are more often associated with a younger age and show poor differentiation with a strong lymphocyte infiltrate.
MSI-H tumours have a better prognosis than MSS tumours
MSI respond well to immunotherapy and have shown no beneficial effect of 5-FU has been observed in this subgroup.
What is the role of MLH1 promoter methylation studies?
Hypermethylation of the MLH1 promoter results in absence of MLH1 protein on IHC
MLH1 promoter methylation is usually indicative of sporadic CRC.
However, rare cases of constitutional MLH1 promoter hypermethylation do occur in LS patients
What is the role of BRAF V600E testing in the lynch pathway?
Though V600E usually occurs in MSS tumours, it can occur in MSI tumours.
BRAF V600E mutation is rarely seen in LS and is therefore a marker of sporadic cancer.
BUT a recent study have demonstrated that the BRAF V600E mutations also occurs in MMR germline mutation carriers at a frequency of 1%
Also suggests patients may respond to BRAF/MEK inhibitors
What is the Amsterdam criteria?
Created to distinguish Lynch syndrome from non-Lynch syndrome families
- There are at least three relatives with an Lynch syndrome-associated cancer
- One affected person is a first-degree relative of the other two
- At least two successive generations are affected
- At least one person was diagnosed before the age of 50 years
- Familial adenomatous polyposis has been excluded
How are lynch syndrome patients managed?
Surveillance:
Colonoscopy with removal of precancerous adenomatous polyps (polypectomy) from age 25 for MLH1/MSH2 and 35 for MSH6/PMS2
Chemoprevention:
NSAID such as aspirin reduce the progression of polyps.
Prevention of primary manifestations:
Colectomy is considered in patients with an elevated risk of metachronous lesions, removal of the uterus and ovaries (prior to the development of cancer) can be considered after childbearing is complete.
What guidelines are used in lynch syndrome?
NICE- Lynch syndrome in colorectal/endometrial
NCCN guidelines
What is the incidence of familial adenomatous polyposis (FAP)?
1/8,300 individuals
Accounts for <1% of colorectal cancers
What is the clinical presentation of FAP?
Characterised by the development of <100 (hundreds to thousands) adenomatous colonic polyps during the second decade of life (range 7-36 years).
By age 35yrs, 95% of individuals with FAP have polyps and the number of polyps increases with age.
There is almost a 100% risk of CRC if not treated (colectomy) at an early stage, with CRCs tending to develop approximately one decade after the polyps appear. Colectomy is advised when >20-30 adenomas or multiples adenomas with advanced histology have occurred.
What is attenuated FAP?
Patient with <100 polyps/adenomas or presenting at advanced age (>age 40 years)
Later diagnosis and decreased risk of CRC (~70% risk by age 80yrs).
Associated with specific APC mutations
What is GAPPS?
Gastric adenocarcinoma and proximal polyposis of the stomach
Gastric polyps restricted to the body and fundus
Associated with the APC YYI promoter 1B variant and methylation of the 1A promoter
Type of FAP
What is the mechanism of pathogenicity of familial adenomatous polyposis?
APC functions in the Wnt signaling pathway and regulates B catenin degradation
Mutated APC prevents B catenin degradation and leads to increased activation of Wnt signaling- activates genes such as MYC
Loss of AOC also results in chromosomal instability
What types of APC mutations are seen in FAP?
Codons 1284 and 1580 and contains over 60% of known mutations. Mainly truncating
5’, 3’ or exon 9 mutations are associated with attenuated FAP
The alternatively spliced isoform of exon 9 lacks codons 312 to 412. This isoform is present in normal tissues. If the mutated codon is within this region, it can be ruled out by normal splicing in the colonic mucosa, resulting in a milder phenotype.
How are FAP patients managed?
Patients have a 100% risk of CRFC but risk can be reduced with screening programme
Surveillance – colonoscopy from early adolescence to guide colectomy.
Chemoprevention – non-steroidal anti-inflammatory drug (NSAID) or aspirin can delay development of adenomas (but not CRC) in the upper and lower gastrointestinal tract
Prophaylactic / curative surgery to remove the colon – reduces risk of developing colon cancer in high-risk family members. However, polyps will still form ni remaining GI tract
Future treatments: erlotinib in combination with NSAIDs, and use of monoclonal antibody (Guselkumab) for reducing polyp burden
What is Polymerase proofreading-associated polyposis (PPAP)
Very rare autosomal dominant condition resulting in predisposition to colorectal, endometrial, breast, ovarian and CNS tumours
How to patients with Polymerase proofreading-associated (PPAP) present?
Patients present with multiple adenomas and carcinoma of the colon
Colorectal cancer is early onset with median age of 45 years
What genes are associated with PPAP?
POLD1- 30% lifetime risk
POLE- 80% lifetime risk
What is the role of POLE and POLD1?
POLD1 gene encodes the catalytic and proofreading subunit of DNA polymerase-delta, which is responsible for DNA synthesis of the lagging strand during DNA replication
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon. Involved in DNA repair and possibly also in replication of chromosomal DNA.
The exonuclease functions of these genes is critical for DNA repair and pathogenic variants reduce rapie and increase risk of transformation
How are patients with PPAP managed?
Colonoscopy should be started between the age of 18 and 20 years, and repeated according to polyp burden- removal of polyps
If adenomas become endoscopically unmanageable, surgery is required, followed by continued surveillence
Regular upper GI endoscopy should start at around 30 years of age.
How does Peutz-Jeghers syndrome (PJS) present?
Hamartomatous polyps
Mucocutaneous pigmentation: Dark blue to brown macules in around mouth, eyes, nostrils, perianal area, buccal mucosa and fingers
What cancers is PJS associated with?
Colorectal
Gastric
Pancreatic
Breast
Ovarian
What gene is associated with PJS?
Autosomal dominant R212: STK11
How are PJS patients managed?
3 yearly GI surveillance by upper GI endoscopy, colonoscopy from age 8
Earlier investigation of the GI tract should be performed in symptomatic patients.
We suggest elective polypectomy to prevent polyp related complications.
What is Mutyh association polyposis (MAP)?
MAP is autosomal recessive inherited disorder caused by biallelic mutations in MUTYH
typically associated with ten to a few hundred colonic adenomatous polyps,
A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
A personal cumulative lifetime history of 20 or more colorectal adenomas in an individual of any age
What is the incidence of mutyh assoication polyposis
1-2% of European population are heterozygous for pathogenic MUTYH variants
Incidence of MAP is 1:20,000 to 1:60,000
0.7% of all CRC
What is the molecular pathogenesis of MAP?
The MUTYH gene encodes a DNA glycosylase enzyme involved in base excision repair. It corrects oxidative DNA damage by excising adenines misincorporated opposite 8-oxo-guanine
Biallelic mutations in MUTYH impair this repair mechanism, leading to an accumulation of DNA mutations, particularly G
to T
c.536A>G p.Y179C and c.1187G>A p.G396D account for at least 90%
KRAS G12C also commonly found
Usually MSS stable
How does MAP present?
Patients typically develop numerous colorectal adenomas, but the number is usually fewer than in familial adenomatous polyposis (FAP). T
Increased risk of developing colorectal cancer, often at a younger age compared to the general population.
Symptoms may include rectal bleeding, changes in bowel habits, abdominal pain, and anemia.
How are patients with MAP managed?
Colonoscopy: Regular colonoscopic surveillance starting in early adulthood (typically by age 20-25)
Surgery: Surgical intervention, such as colectomy, may be necessary if there are numerous polyps that cannot be managed endoscopically
Chemoprevention: Use NSAIDs like sulindac or COX-2 inhibitors may reduce the number and size of polyps
Genetic Counseling: at-risk family members carrier testing
What is Juvenile Polyposis Syndrome (JPS)?
Juvenile Polyposis Syndrome (JPS) is an autosomal dominant hereditary condition characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract.
It is associated with an increased risk of gastrointestinal cancers.
Mutations in BMPR1A, SMAD4
What is the pathogenesis of JPS?
BMPR1A: Encodes a bone morphogenetic protein receptor involved in cell growth and differentiation.
SMAD4: Encodes a protein involved in the TGF-beta signaling pathway, which regulates cell proliferation, differentiation, and apoptosis.
Mutations in these genes disrupt normal cellular signaling and lead to uncontrolled cell growth and the formation of hamartomatous polyps.
How does JPS present?
Multiple juvenile polyps (before age 20), which are typically benign but have malignant potential.
Symptoms:
Gastrointestinal bleeding
Anemia
Abdominal pain
Diarrhea
Rectal prolapse (in severe cases)
10-50% lifetime risk of colorectal cancer.
How are JPS patients managed?
Colonoscopy every 1-3 years, starting from age 15 or earlier if symptomatic; upper endoscopy every 1-3 years if gastric polyps are present
Colectomy if polyps are unmanageable
Counselling for patients and at risk families
How many breast cancers are hereditary?
27% of BC due to hereditary factors, 5-10% of BC has a strong inherited component and only 4-5% due to highly penetrant autosomal dominantly inherited mutations.
When might hereditary breast and ovarian cancer be suspected?
There is early onset of disease (<50 years)
Two or more breast primaries
Breast and ovarian cancer in a single individual
Breast and ovarian cancers in close (first- second- and third-degree) relatives(s) from the same side of the family
At risk populations (e.g., Ashkenazi Jewish)
Family member with a confirmed BRCA1 or BRCA2 mutation
Male breast cancer
Ovarian cancer at any age
Why is indentifying at risk hereditary breast cancer families difficult?
Clinical diagnosis complicated by incomplete penetrance, high prevalence of sporadic breast cancer and different individuals in the same family can develop different types of cancer (phenocopies).
Probability models have been developed but all have their limitations
What genes are associated with hereditary breast and ovarian cancer (HBOC) syndrome and what is their life time risk?
BRCA1: 60-85% for BC, 40-60% for ovarian cancer
BRCA2: 40-85% for BC, 30% for ovarian cancer
5-7% of all breast cancer cases
Also increased risk of prostate and pancreatic
What is the molecular pathogenesis of BRCA1/2 hereditary cancers?
Both have roles in DNA repair including homologous recombination repair of double-stranded DNA breaks and nucleotide excision repair
BRCA1 forms complexes with a protein called BARD1, and co-localises with BRCA2 and RAD51 at sites of DNA damage. BRCA2/RAD51 to mediate homologous recombination repair of double-stranded DNA breaks.
BRCA1 also has role in controlling cell cycle progression and check-point control, gene transcription regulation and ubiquitination
Loss of function of BRCA results in defects in DNA repair, defects in transcription, abnormal centrosome duplication, defective G2/M cell cycle checkpoint regulation, impaired spindle checkpoint, and chromosome damage.
What types of mutations are seen in BRCA1/2?
> 1600 mutations in BRCA1, >1800 in BRCA2 reported located throughout the coding regions
Majority are nonsense and frameshift mutations
Missense mutations = ~2% of pathogenic BRCA1 mutations. A large number also found in BRCA2
10-15% are variants of uncertain clinical significance (~1/3 of BRCA1 variants, ~2/3 of BRCA2 variants)
15-27% of BRCA1 mutations are large rearrangements, whole exon deletions and insertions/duplications - these are rarer in BRCA2 (about 6% of mutations)
What genotype phenotype relationships are known in BRCA?
BC risk reported as lower with BRCA1 mutations in the central region compared with 5’ region and ovarian cancer risk was significantly reduced with mutations 3’
BRCA2 mutations in the exon 11 ovarian cluster region (nucleotides 3035-6629) have been reported to result in increased risk of ovarian cancer, but this has not been replicated
Of the common Jewish mutations BRCA1 c. 185delAG conveys a higher risk of ovarian cancer than c.5266dupC
What patients are eligible for germline BRCA testing?
Mainstreaming (from oncologist)
- Individuals diagnosed with breast cancer before the age of 40
- Individuals with triple-negative breast cancer diagnosed before the age of 50
- Individuals with male breast cancer.
- Individuals with high grade serous ovarian cancer
- Patients with metastatic prostate cancer
Clinical genetics
- Strong family history
- Confirmed BRCA variant in a first degree relative
What genes are tested for breast and ovarian cancer?
R207-ovarian
BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, MLH1, MSH2, MSH6
R208-breast
BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D
What is the significance of SNPs in breast cancer?
Genome wide association studies have identified a number of polymorphisms associated with an increased breast cancer risk
Each expected to impact only to a minor extent on individual risk
As most occur at high frequency in the investigated populations they have significant impact on the breast cancer risk e.g. FGFR2, LSP1, MAP3K1, TGFB1, TOX3
SNPs also modify the susceptibility of BCRA1 and BRCA2 carriers of developing breast cancer
How are patients with HBOC managed?
Surveillence
- Mammogram starting at age 30
Surgery
- Bilateral prophylactic mastectomy reduces the risk of BC by about 90%.
- Bilateral prophylactic oophrectomy also results in a 53% reduction in risk of ovarian cancer
Chemoprevention:
- Tamoxifen (an oestrogen antagonist that competitively binds OR’s) can be used to reduce risk of BC by 30-50%
Treatment
- PARP inhibitors- synthetic lethality, blocks single strand DNA repair (base excision repair mechanism). Homologous recombination is impaired by BRCA variant so cells die
What is Neurofibromatosis Type 1 (NF1)?
Autosomal dominant disease resulting in growth of benign tumors called neurofibromas along nerves in the skin, brain, and other parts of the body.
Caused by defects in NF1, 50% are de novo
What is the incidence of NF1 syndrome?
Affects 1 in 2,500-3,000 people worldwide
How do patients with NF1 present?
NF1 is highly variable in its manifestations, but common signs and symptoms include:
Café-au-lait Spots: Light brown skin patches that usually appear in early childhood.
Neurofibromas: >2 benign, soft tumors that develop on the skin or along nerves.
Lisch Nodules: Hamartomas of the iris detectable by an eye examination.
Freckling: In the armpits or groin area.
Optic Pathway Gliomas: Tumors of the optic nerve, which can affect vision.
Skeletal Abnormalities: Such as scoliosis
Learning Disabilities: Occur in about 50% of individuals with NF1, including attention deficit hyperactivity disorder (ADHD)
Increased risk of JMML
What is the molecular pathogenicity of NF1?
NF1 is a tumour suppressor by regulating cell growth and division. Neurofibromin negatively regulates the RAS/MAPK signaling pathway, which is involved in cell proliferation, differentiation, and survival.
Mutations in the NF1 gene typically result in a loss of function of neurofibromin, leading to uncontrolled cell growth and the formation of tumors.
What kind of mutations are seen in NF1
50% are de novo and mosaicism is common due to the high mutation rate
- not always suitable to test blood, sometimes tumour is better
90% are sequence variants, including splicing variants
4-5% are whole gene deletions- associated with an earlier onset of neurofibromas
How is NF1 managed?
Surgery: principal mode of treatment for neurofibromas, but with a high recurrence rate
Chemotherapy
Targeted therapy:
- Agents targeting Ras signaling are in clinical trials
- MEK inhibitor selumetinib induces partial responses in children with NF1. FDA approved for patients >2 with inoperable neurofibromas
- Rapamycin is an inhibitor of the mTOR pathway
What is Neurofibromatosis Type 2 (NF2)?
Autosomal dominant disease caused by variants in NF2
Characterized by the development of benign tumors primarily affecting the nervous system, particularly the brain and spinal cord.
How does NF2 present?
Bilateral vestibular schwannomas (benign intracranial tumour of myelin-forming cells of vestibulocochlear nerve. Following symptoms may result: gradual, progressive hearing loss, tinnitus, balance problems)
Other tumours include meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
Also increased risk of cataracts and benign skin tumours
What is the molecular pathology of NF2?
The NF2 gene encodes a protein called merlin (or schwannomin), which acts as a tumor suppressor by regulating the cytoskeleton- cell growth and maintaining cell shape and adhesion. Also regulated RAF/MEK pathway.
Mutations in the NF2 gene typically result in a loss of function of merlin, leading to uncontrolled cell growth and tumor formation.
What kinds of mutations are seen in NF2?
50% de novo and mosaicism is common, diagnosis with blood difficult
Large deletions and missense- assoaciated with milder phenotype
Nonsense and frameshift- servere disease
How is NF2 managed?
No established effective treatment for NF2
Vestibular schwannoma = primarily surgical
Hearing loss= lip-reading + sign language instruction, cochlear stem implants
Bevacizumab is recently considered as a first-line medical therapy for rapidly growing vestibular schwannomas
Targeted therapy, such as inhibitor of the mTORC1, MEK1 and MEK2, HIF-1
