Inherited Cancer Syndromes Flashcards

Question

What is GAPPS?

Answer 1

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

Answer 2

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

Answer 3

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.

Answer 4

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

Answer 5

Very rare autosomal dominant condition resulting in predisposition to colorectal, endometrial, breast, ovarian and CNS tumours

Answer 6

Patients present with multiple adenomas and carcinoma of the colon Colorectal cancer is early onset with median age of 45 years

Answer 7

POLD1- 30% lifetime risk POLE- 80% lifetime risk

Answer 8

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

Answer 9

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.

Answer 10

Hamartomatous polyps Mucocutaneous pigmentation: Dark blue to brown macules in around mouth, eyes, nostrils, perianal area, buccal mucosa and fingers

Answer 11

Colorectal Gastric Pancreatic Breast Ovarian

Answer 12

Autosomal dominant R212: STK11

Answer 13

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.

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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.

Answer 18

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

Answer 19

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

Answer 20

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.

Answer 21

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.

Answer 22

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

Answer 23

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.

Answer 24

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

Answer 25

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

Answer 26

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

Answer 27

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.

Answer 28

>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)

Answer 29

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

Answer 30

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

Answer 31

R207-ovarian BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, MLH1, MSH2, MSH6 R208-breast BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

Affects 1 in 2,500-3,000 people worldwide

Answer 36

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

Answer 37

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.

Answer 38

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

Answer 39

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

Answer 40

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.

Answer 41

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

Answer 42

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.

Answer 43

50% de novo and mosaicism is common, diagnosis with blood difficult Large deletions and missense- assoaciated with milder phenotype Nonsense and frameshift- servere disease

Answer 44

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

Answer 45

Rarest form of NF characterized by multiple schwannomas in the absence of bilateral vestibular schwannomas inherited via autosomal dominance in 15–20% Caused by mutations in SMARCB1 and LZTR1 genes

Answer 46

TSC is an autosomal dominant disorder characterised by a highly variable phenotype and the development of multiple hamartomas (benign tumour-like malformation) in multiple organs throughout the body. Tuberous sclerosis is often first found during infancy or childhood.

Answer 47

TSC is relatively common: incidence ~ 1 in 6,000 – 10,000 although may be higher due to variable penetrance and subtle disease presentation.

Answer 48

CNS: - Cortical Tubers: Brain lesions - Subependymal Nodules (SENs): Tumors in the walls of the brain's ventricles - Seizures: - Behavioral and Psychiatric Disorders Renal: - Angiomyolipomas: Benign kidney tumors Cardiac: - Rhabdomyomas: Benign heart tumors Lungs: - Lymphangioleiomyomatosis (LAM): Affects women and causes lung cysts, leading to respiratory issues. Skin: - Hypomelanotic Macules: White patches on the skin. - Facial Angiofibromas: Red bumps on the face, especially the cheeks and nose.

Answer 49

TSC is caused by mutations in either the TSC1 or TSC2 genes. TSC1 and TSC2 proteins bind to each other (along with TBC1D7) to form a heterodimeric complex that functions as a GTPase activating protein (GAP). The complex inhibits the mTOR (mechanistic target of rapamycin) signaling pathway. Mutations lead to dysregulation of the mTOR pathway.

Answer 50

31% in TSC1 69% in TSC2- more severe phenotypes Mostly truncating variants Often de novo and mosaic TSC2/PKD1 co deletion also seen which is associated with severe and early onset

Answer 51

Mosaicism is considered to account for a significant number of TSC patients with no detectable pathogenic variant with 5% of patients considered to have somatic mosiaicism. DNA testing of other tissues (tumours, saliva, skin, hair follicles) somatic mosaicism is suspected and routine testing of blood DNA does not reveal a pathogenic variant.  Germline mosaicism has also been reported.

Answer 52

R228 TSC1 and TSC2 NGS and MLPA Around 15% of those with a clinical diagnosis, no pathogenic variants are identified in either TSC1 or TSC2. As some of these individuals may be mosaic, deep sequencing of blood (R228.3) is subsequently performed. Alternatively, another (ideally affected) tissue (such as a facial angiofibroma or skin biopsy) may be considered for testing.

Answer 53

Affected patients require regular monitoring; MRI, ultrasound, blood tests, CT scan to detect early tumours and monitor lung/ kidney/heart function. mTOR inhibitors - Everolimus and rapamycin can shrink tumors by inhibiting the mTOR pathway, used for SEGAs, renal angiomyolipomas, and LAM. - Not NICE approved- trials PDGFRB inhibition - imatinib - trial

Answer 54

TP53 germline variants Li-Fraumeni syndrome (LFS) is characterized by early onset (often in children and young adults) High life time risk of variety of cancers including breast, CNS, sarcomas, leukaemias

Answer 55

1 in 500 to 1 in 5000 births, and account for as many as 17% of all familial cancer. TP53 is mutated in the germline of 1.4% of studied childhood and adolescent patients diagnosed with cancer.

Answer 56

The p53 protein is a multifunctional transcription factor involved in the control of cell cycle progression, DNA integrity and apoptosis. In LFS-associated tumours, mutant p53 isoforms differ from each other in the extent to which they have lost suppressor function and in their capacity to inhibit wildtype p53 in a dominant negative manner. In addition, some p53 mutants seem to exert oncogenic activity, but the molecular basis of this gain-of-function phenotype is still unclear

Answer 57

Chompret Criteria is a set of criteria used to diagnose Li-Fraumeni syndrome (LFS). The criteria are as follows: A tumor belonging to the LFS tumor spectrum, before the age of 46. At least 1 first-degree or second-degree family member with an LFS-related tumor, except breast cancer if the individual has breast cancer, before the age of 56 or with multiple tumors

Answer 58

Childhood phase with adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma, and medulloblastoma; Childhood-to-young adulthood transition phase with osteosarcoma, leukaemia, and various glioma subtypes; early adulthood phase with breast, gastrointestinal, and lung cancers and different sarcomas; Late adulthood phase with pancreatic, prostate and lung cancer. There is a wide range of age of onset for soft tissue sarcomas 

Answer 59

R216 TP53 NGS/MLPA The ClinGen TP53 VCEP recommends the use of the TP53-specific ACMG/AMP Guidelines as the standard strategy for TP53 germline variant classification 

Answer 60

Characterized by combined occurrence of tumours involving two or more endocrine glands within single patient. Categorised into 4 major types (all AD): - MEN1 (aka Wermer syndrome) associated with menin (MEN1) germline-inactivating gene mutations - MEN2 (previously MEN2A, aka Sipple syndrome) associated with germline-activating mutations of RET - MEN3 (previously MEN2B) associated with germline-activating RET mutations - MEN4 associated with CDKN1B germline-inactivating gene mutations

Answer 61

Parathyroid Tumors: Leading to primary hyperparathyroidism and hypercalcemia. Pituitary Tumors: Including prolactinomas, growth hormone-secreting tumors, and non-functional adenomas. Pancreatic Neuroendocrine Tumors (NETs): Such as gastrinomas, insulinomas, glucagonomas, and non-functional pancreatic tumors. Other Manifestations: Adrenal adenomas, thymic and bronchial carcinoids, and facial angiofibromas.

Answer 62

MEN1 gene Menin, a tumor suppressor protein that interacts with several transcription factors and is involved in DNA repair, transcriptional regulation, and maintaining genomic stability. Loss-of-function mutations in the MEN1 gene lead to unregulated cell growth and tumor development.

Answer 63

At least one first-degree relative with one or more of these endocrine tumours Single-organ involvement and an MEN1 disease-associated germline (heterozygous) pathogenic mutation

Answer 64

Surgical resection of tumours, chemotherapy and radiation therapy Surveillance: regular biochemical screening and imaging studies. Age of screening depends on individual but normally starts in childhood

Answer 65

Medullary Thyroid Carcinoma (MTC): Almost all individuals develop MTC. Pheochromocytomas: Adrenal tumors that can cause severe hypertension. Primary Hyperparathyroidism: Due to parathyroid adenomas or hyperplasia.

Answer 66

Often present in 1st year of life Medullary Thyroid Carcinoma (MTC): More aggressive and earlier onset compared to MEN2A. Pheochromocytomas: Similar to MEN2A. Mucosal Neuromas: Benign growths on the lips, tongue, and intestinal tract. Marfanoid Habitus: Features include a tall, thin body with long limbs and fingers.

Answer 67

Associated with GOF mutations in RET MEN2: Mutations in exons 5, 7, 8, 10, 11, and 13-16 of the RET gene have been identified in >98% MEN2 cases MEN3: Approximately 95% of individuals with the MEN3 (formally MEN2B) phenotype have a single point mutation, p.Met918Thr (p.M918T) in exon 16 of the RET gene

Answer 68

Rare subtype of MEN Develop MEN1 associated tumours but caused by germline LOF mutations in CDKN1B

Answer 69

Autosomal dominant condition caused by germline variants in VHL Characterized by the development of multiple benign and malignant tumors and cysts in various organs. It affects about 1 in 36,000 individuals worldwide.

Answer 70

Central Nervous System: - Hemangioblastomas: Benign, highly vascular tumors of the brain, spinal cord, and retina. Retinal Hemangioblastomas: Can lead to vision loss if untreated. Renal Cell Carcinoma (RCC): Often clear cell type, occurring in 40-70% of patients. Pheochromocytomas: Tumors that produce catecholamines Pancreatic Neuroendocrine Tumors: Can be functional (hormone-producing) or non-functional. Endolymphatic Sac Tumors: Can cause hearing loss, tinnitus, and balance problems. Epididymis (in males) and Broad Ligament (in females): Cystadenomas: Benign tumors that are usually asymptomatic.

Answer 71

VHL protein, a tumor suppressor that is part of a complex involved in ubiquitination and degradation of hypoxia-inducible factors (HIFs). Loss of function VHL, resulting in the accumulation of HIFs. This causes increased expression of hypoxia-inducible genes, promoting angiogenesis (formation of new blood vessels), cell proliferation, and tumor development.

Answer 72

Annual surveillance Surgery Genetic counselling

Answer 73

Gorlin syndrome, also known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS), is a rare genetic disorder that predisposes individuals to develop multiple basal cell carcinomas (BCCs), jaw cysts, and various other abnormalities. It is inherited in an autosomal dominant pattern.

Answer 74

Basal Cell Carcinomas (BCCs): Multiple BCCs appearing in adolescence or early adulthood. Palmar/Plantar Pits: Small depressions on the palms and soles. Jaw Cysts: Odontogenic keratocysts (OKCs) in the jaws, often presenting in adolescence. Skeletal Abnormalities: Such as bifid ribs, scoliosis, and abnormal bone structure. Neurological: Medulloblastoma: A type of brain tumor, particularly in early childhood. Intracranial Ocular Abnormalities: Including cataracts, strabismus, and coloboma. Ovarian Fibromas: In females. Characteristic Appearance: Frontal bossing, broad nasal root, hypertelorism (widely spaced eyes). Management

Answer 75

PTCH1 gene on chromosome 9, and less commonly the SUFU gene. Mutations in PTCH1 or SUFU lead to dysregulation of the Hedgehog pathway, resulting in uncontrolled cell proliferation and the development of various tumors and malformations.

Answer 76

PTEN Hamartoma Tumor Syndromes (PHTS) are a group of disorders caused by mutations in the PTEN gene. These syndromes are characterized by the development of multiple benign tumors (hamartomas) and an increased risk of certain cancers. Includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome, and Proteus-like syndrome.

Answer 77

A multiple hamartoma syndrome associated with high risk of developing benign and malignant tumours of the breast, thyroid and endometrium. Affected individuals usually have macrocephaly, trichilemmomas (benign tumour of hair follicle) and papillomatous papules; typically appear in the late 20s (major criteria). Intellectual disability (IQ under 75), Autism spectrum Disorder (ASD)

Answer 78

PTEN is a tumour suppressor. It modifies other proteins and lipids removing phosphate groups. PTEN regulates the PI3K/Akt/mTOR pathway and the MAPK pathway. PTEN dephosphorylates FAK, which can inhibit cell migration and cell spreading.

Answer 79

A rare congenital disorder characterised by macrocephaly, lipomatosis, haemangiomatosis and pigmented macules of glans penis. Other features include developmental delay and intellectual disability (50%), vascular anomalies, high birth weight, myopathic process in proximal muscles (60%), pectus excavatum, scoliosis (50%), and joint hyperextensibility. ~50-60% of patients have a germline PTEN mutation.

Answer 80

Characterized by progressive segmental or patchy overgrowth of multiple tissues of all germ layers, but most commonly connective tissue, and epidermal naevi and skeleton—hypertosis (bone overgrowth). There are minimal or no manifestation at birth, but beginning in the toddler period, they rapidly progress through childhood, which cause severe overgrowth and disfigurement. PTEN germline mutations have been detected in ~20% of PS patients. Somatic mutations in the AKT1 gene have been implicated as the main cause of Proteus Syndrome

Answer 81

Approximately 10% of melanoma cases are hereditary, with 7-15% of cases occurring in patient with a family history of melanoma (however this does not necessarily indicate that a single genetic mutation is transmitted—may be simply due to shared sun exposure experiences with susceptible skin types).

Answer 82

CDKN2A - Encodes two transcripts and two separate proteins p16/INK4a and p14/ARF. Both the p16/INK4a and p14/ARF proteins are involved in cell cycle regulation and function as tumour suppressor genes, however, they function in completely independent pathways: BAP1 - encodes a protein that plays a tumour suppressor role through transcription regulation by chromatin remodelling and the ubiquitin-proteasome system.

Answer 83

A very rare autosomal dominant disorder affecting approximately 1:500,000 live births. 40-45% of cases are inherited in an autosomal dominant pattern. 55-60% of cases appear somatically/de novo.

Answer 84

Bone marrow shows normal haematopoiesis in the platelet and lymphoid lineages, but a reduction in the erythroid precursors 90% of patients present within the 1st year of life with severe macrocytic anaemia and normochromic anaemia Other symptoms include reticulocytopenia, physical malformations (such as triphalangeal thumb), craniofacial abnormalities (microcephaly) and short stature

Answer 85

Autosomal dominant disorder 60-70% have mutations within ribosomal genes - RPS19 (20-25%) - RPD24, RPS17, SPL5 & RPL11 30-35% have unknown cause Some non ribosomal causes identified: GATA1

Answer 86

RPS19 is a component of the 40S ribosomal subunit. This is required for the development of 18S rRNA and the formation of the pre-40S and pre-60S particles during ribosome biogenesis. This decrease in ribosome biogenesis leads to the binding of ribosomal protein to MDM2, which is an inhibitor of p53. Due to decreased availability of MDM2, this leads to an increase in p53 proteins that trigger apoptosis as part of the ‘ribosomal stress’ response. This apoptosis leads to bone marrow failure via the termination of cell lines- erythroid cell lines are more sensitive to p53 accumulation

Answer 87

R91- Cytopenia (not fanconi anaemia) 84 days TaT- includes ribosomal genes

Answer 88

Age of onset <12 months. Macrocytic anaemia. Normal leukocytes and platelets. Reticulocytopenia. Bone marrow assessment allows for tri-lineage investigation. Should see normal cellularity of platelet and lymphoid lineages, with markedly reduced erythroid precursors. Major supporting evidence is the presence of a variant within a DBA gene (such as RSP19) and a positive family history of DBA (crucial to take an accurate family history at clinic/diagnosis).

Answer 89

There is currently no therapeutic cure for DBA, only treatments to alleviate symptoms. First-line treatment is corticosteroids as it aids in the production of red cells. However, there are short and long-term implications and some become resistant Second line: red cell transfusions to alleviate the anaemia- risk of iron overload lead. Those dependant on transfusions are eligible for haematopoietic stem cell transplant Gene therapy developments: L-leucine (improves erythropoiesis) and trifluoperazine (inhibits calmodulin-dependant kinases leading to the destabilisation of TP53 and a reduction in apoptosis.

Answer 90

Patients are at an increased risk of developing both solid cancer (colorectal, osteocarcinoma) and myeloid malignancies (MDS and AML). Incidence of cancer with DBA cases is 20% by the age of 46.

Answer 91

Rare heterogeneous disorder, with an incidence in the general public of 1-9 per million

Answer 92

Patients typically present between the years of 5 and 13, clinically characterised by physical abnormalities. These include abnormal nails, reticular skin pigmentation (hyperpigmentation of upper torso and head) and oral leucoplakia

Answer 93

DC is characterised by a shorter telomere length for the age of the patient. These repeat regions cap DNA to protect it from degradation and maintain chromosomal integrity. During cell division, these regions naturally shorten due to incomplete 3’ replication. Older patients therefore have naturally shorter telomere regions. There is a complex interaction of proteins/complexes that maintain the telomere length in normal cell division. This involves interactions between the telomerase complex (that extends the telomere) and the shelterin complex (that caps the telomere during replication and regulating its length). Variants in these process cause DC

Answer 94

DKC1: Seen in 16-35% of cases. Part of the telomerase complex, acting as a scaffolding protein to increase stability. Can cause Hoyeraal-Hreidarsson syndrome: Severe variant of DC associated with variants in DKC1. TERT: Seen in 20% of cases. Is a core component of the telomerase complex that is involved in telomere elongation RTEL1: Seen in 15% of cases. Involved in the stability and unwinding of the T-loop (a key chromosomal feature of telomeres). TERC: Seen in 15% of cases. Encodes an nTR-RNA (non-translated RNA) that acts as a template for telomere elongation TINF2: Seen in 12.5% of cases. A key component of the Shelterin complex, involved in telomere protection (from DNA Damage Response) and telomere recruitment.

Answer 95

Due to the characteristic shortening of telomeres, diagnostic testing is performed via telomerase shortening assays- qPCR or gold standard flow-FISH on peripheral blood (lymphocytes gated by flow, plotted as a trend as shown in the image below). Fluorescent probes are hybridised to the telomeres, with the overall intensity measured and compared to published age-adjusted values. NGS to identify causative variant

Answer 96

There are currently no known treatments for DC. Encouraged to not undertake carcinogenic habits such as smoking, drinking and unprotected sun exposure. Patients are at increased risk of developing cancer, therefore it is imperative to undergo varied routine surveillance such as annual skin screening, dental examinations, pulmonary function tests (for lung fibrosis) and full blood counts. 90% experience bone marrow failure transfusions Stem cell transplant but poor outcomes

Answer 97

Patients are at a higher risk of developing cancer, with the most common being head & neck squamous cell carcinoma, stomach and lung cancers. Haematological malignancies such as AML have also been reported. Incidence of cancer was 40-50% by the age of 50, with around 40% of cancers being head and neck squamous cell carcinoma.

Answer 98

A very rare disorder, affecting 1 out of every 136000 live births. Autosomal recessive disorder

Answer 99

Pancytopenia, with the classical symptoms of anaemia (dizziness, fatigue), thrombocytopenia (epistaxis, unstoppable bleeding) and leukopenia (recurrent infections, fever). 75% of cases have associated birth defects such as short stature, café-au-lait spots and structural abnormalities in the extremities. Hypogonadism is also common in both sexes. Median age of diagnosis is 7 years

Answer 100

Dysfunction in the pathway for the repairing of interstrand crosslinks (ICL). These bonds prevent strand separation during DNA replication, leading to S-phase stalling and requiring excision via the Fanconi Anaemia Pathway: - During DNA replication, replication forks meets an ICL which stalls replication. - This recruits FANCM, FAAP24 and MHF in order to stabilise the strands and recruit the strand repair pathway. - FANCM recruits RPA (replication protein A), which binds to ssDNA for stabilisation and the activation of ATR - ATR phosphorylates multiple protein targets, including MRN complex, FANCD2 and FANCI. - The Fanconi Anaemia core complex forms, consisting of numerous proteins, that form around FANCM, FAAP24 and MHF that bind to the DNA. - This active form of FA core complex mono-ubiquitinates FANCD2 and FANCI, allowing incision of the ICL via recruited endonucleases - FA core complex and FANCD2-FANCI relocates to the chromatin, allowing recruitment of TLS polymerases REV1-Pol ζ-Pol η. - The endonucleases introduce double strand breaks, which is repaired by homologous recombination, via RAD51 and BRCA complexes.

Answer 101

Loss of function in FANC genes - 21 genes are associated with autosomal recessive FA. - Hemizygous variants in FANCB are associated with X-linked recessive FA. - Variants within RAD51 (FANCR) cause autosomal dominant FA As the conclusion of the pathway relies on the HR machinery, variants within these genes have also been associated with FA (they are also known as FANC genes as per HGNC): BRCA2 (FANCD1): 2%. BRCA1 (FANCS): Rare. RAD51 (FANCR): Rare. PALB2 (FANCN): Rare.

Answer 102

BRCA2: Intervening sequence 7 (IVS7) variants lead to acute myeloid leukaemia by age 3, with other pathogenic variants leading to AML by age 6. FANCC: C.456+4A>T, p.R548* and p.L554P associated with earlier onset of haematological abnormalities and severe congenital abnormalities. C.64delG and p.Q13* associated with lower risk of congenital abnormalities and later progression to bone marrow failure.

Answer 103

Fanconi breakage studies Small panel for FANCA, FANCB, FANCD2, PALB2 Turnaround time is 42 days

Answer 104

The current gold-standard diagnostic testing for FA is chromosomal breakage studies. Lymphocytes are cultured and treated with alkylating agents (such as diepoxybutane) and screened for increased spontaneous and mutagen-induced chromosomal breakage. Karyotyping of these cultured cells, if FA is present, leads to abnormal chromosomal structures. FA gene panel testing is becoming more common. Either single gene panels (i.e. looking for FANCA) or multi-gene panels.

Answer 105

One of the primary concerns with FA is that of bone marrow failure. The 3 most common gene variants (FANCA, FANCC and FANCG) had an average age of onset of 7.6 years, with around 90% of FA patients suffering BMF by the age of 40. Routine blood counts show thrombocytopenia and leukopenia preceding anaemia. Associated findings include macrocytosis and elevated HbF. The pancytopenia worsens over time, with the severity of the bone marrow failure classified by the degree of pancytopenia

Answer 106

There are currently no curative therapeutic strategies for patients with FA. Surgical procedures are often performed on those with structural deformaties. These include splitting of hand abnormalities, congenital heart defects and repairing trachea-oesophagus fistulas. For haematological defects, supportive treatment for cytopenias involve blood transfusions and granulocyte colony stimulating factors.

Answer 107

For solid cancers, there is an average 50 fold increase in risk, however the most common are head and neck squamous cell carcinomas (HNSCC) The most common cancer progression in MDS, with a 6000 fold increase in risk. There is then a 500-700 fold increase in AML risk compared to the general population. - Most of the individuals diagnosed with AML are between the ages of 15 and 35. - The increased risk is commonly associated with monosomy 7 and del(7q), both of which are adverse cytogenetic risks.

Answer 108

Only curative option is haematopoietic stem cell transplantation (HSCT)- significantly lower overall survival of 46%, owing to clonal evolution. For sibling/family matches, it is important to perform chromosome breakage analysis prior to transplantation. Due to dysfunctional DNA repair, patients are sensitive to alkylating agents, radio therapy and other bone marrow ablation drugs. Alternatives are to be sought and used, such as the use of fludarabine strategies. Not only does this increase patient eligibility, but patients are at reduced risk of GVHD (which is increased in FA patients).

Answer 109

Rare inherited bone marrow failure syndrome, occurring in 1:75,000 live births. There is a male:female skew of 1.7/1.

Answer 110

SDS is an autosomal recessive genetic disorder. Due to defects in haematopoietic stem cells, SDS is considered a leukaemia predisposition disorder as 10-30% of cases transform into myeloid neoplasm, myelodysplastic syndrome or acute myeloid leukaemia.

Answer 111

Characterised by neutropenia, exocrine pancreatic insufficiency (second most common after cystic fibrosis) and skeletal abnormalities. Macrocytic or normocytic anaemia is seen in about 80% of cases. Bone marrow examination typically shows a decrease in CD34+ cells (marker for haematopoietic stem cell).

Answer 112

Over 90% of patients’ harbour biallelic mutations in the SBDS gene (7q11). The most common pathogenic variants seen in SDS is c.258+2T>C and c.183_184TA>CT.

Answer 113

SBDS is a protein that cooperates with the GTPase EFL1 on the pre-60S ribosomal subunit, catalysing the removal of the nuclear shuttle protein eIF6 the leads to the formation of the mature 80S ribosome. Loss of SBDS leads to eIF6 remaining bound to the 60S subunit, impairing its’ association to 40S subunit. This leads to reduced translation efficiency within the cell. Ultimately, this leads to decreased fitness of the haematopoietic stem cells via increased activation of cell cycle checkpoints (and subsequent increased TP53 activation). This ribosomal stress also activates cellular senescence pathways

Answer 114

Peripheral blood and bone marrow assessment is performed to identify the characteristics of SDS, however can show a differential diagnosis to other bone marrow failure syndromes. Sequencing (NGS, whole exome sequencing or whole genome sequencing) can be performed to identify variants within the SBDS gene. However, sequencing of the SBDS for the identification of variants is complicated by having a 97% homology to a pseudogene (SBDSP1).

Answer 115

There are currently no curative therapeutic drugs available. Due to the increased risk of leukaemia development, life long surveillance is required Peripheral blood surveillance should be performed every 3-6 months, with bone marrow assessments performed every 12 months (timings of which are dependent on the case presentations). The clinical benefit is to identify high-risk features of transformation such as: - Falling blood counts, particularly paired with increasing bone marrow cellularity. - Progressive bone marrow dysplasia (particularly in the erythroid lineage). - Large and/or rapidly expanding TP53-mutated clones. - High-risk cytogenetic abnormalities (such as -17p, -7, -7q, complex karyotype).

Answer 116

Characterised by mutations in genes that bypass the fitness defects caused by SBDS mutations - Isochromosome 7q leads to duplication of the SBDS gene, however is not linked to malignancy transformation (instead linked to more severe bone marrow failure). - Del(20q) leads to loss of the EIF6 gene, leading to improved outcome via an adaptive mechanism. - Other chromosome abnormalities (-7, -7q) are more concerning for a transformation. - Complex karyotypes are common in MDS/AML transformed patients.

Answer 117

Characterised by mutations in genes that bypass the fitness defects caused by SBDS mutations EIF6 TP53

Answer 118

Familial CLL (F-CLL) is defined as a CLL case with at least one blood relative with CLL. Genome-wide association studies have identified SNPs in nearly 30 loci that are associated with familial CLL, demonstrating that common genetic variation contributes to heritable risk.

Answer 119

Among patients who are registered in the CLL Research Consortium, 9% of patients have a relative with CLL. First-degree relatives of patients with CLL have an 8.5-fold increased risk of developing this disease

Answer 120

Some linkage studies have identified seven genetic variants (located on chromosomes 2q13, 2q37.1, 6p25.3, 11q24.1, 15q23, and 19q13.32) that increase the risk of CLL by 1.35–1.54 fold. Region 6p25.3, includes the interferon regulatory factor 4 gene (IRF4), a known regulator of lymphocyte development and proliferation. LEF1- high expression of lymphoid enhancer-binding factor 1 BCL2- encodes an anti-apoptotic protein that is expressed at high levels PMAIP1- encodes a pro-apoptotic protein. mir-15a and mir-16-1- increased resistance to cell death or enhanced BCR signalling.

Answer 121

Myeloid neoplasms with germline predisposition without a pre-existing platelet disorder/organ dysfunction, including: - Germline CEBPA P/LP variant (CEBPA-associated familial AML) - Germline DDX41 P/LP variant - Germline TP53 P/LP variant (Li-Fraumeni syndrome) – please refer to separate notes Myeloid neoplasms with germline predisposition and pre-existing platelet disorder, including: - Germline RUNX1 P/LP variant (Familial Platelet Disorder with associated myeloid malignancy (FPD-MM)) - Germline ANKRD26 P/LP variant (Thrombocytopenia 2) - Germline ETV6 P/LP variant (Thrombocytopenia 5) Myeloid neoplasms with germline predisposition and potential organ dysfunction, including: - Myeloid neoplasms associated with bone marrow failure syndromes - Germline GATA2 P/LP variant (GATA2-deficiency) - Down syndrome - Telomere biology disorders (Dyskeratosis congenita) - Bone marrow failure syndromes - Germline SAMD9 P/LP variant (MIRAGE syndrome) - Germline SAMD9L P/LP variant (SAMD9L-related Ataxia Pancytopenia syndrome) - Biallelic germline BLM P/LP variant (Bloom syndrome)

Answer 122

All are included in paediatric and/or germline mutation-associated disorders due to their overlap with other childhood disorders Also includes a subgroup for ALL with germline predisposition which includes ALL with germline variants in PAX5 and IKZF1.

Answer 123

Between 4–13% of paediatric and 5–15% of adult MDS/AML Each individual syndrome is quite rare

Answer 124

According to ELN 2022 - Personal history >2 cancers (1 HM) - Personal history plus another relative within 2 generations with a HM or tumour diagnosed less than 50 - Pathogenic variant detected in tumour - young age of onset

Answer 125

Blood can't be used Need to use saliva, skin (can be contaminated) or hair follicles or remission blood sample Testing should be carried out with NGS, MPLA WGS

Answer 126

Autosomal recessive disorder caused by variants in BLM Affected individuals show abnormal growth, feeding difficulties, skin changes, immune deficiency, an increased risk of diabetes, and an increased risk of a variety of cancer types at a younger age, with a variety of haematological malignancies, including AML, lymphoblastic leukaemia/lymphoma (ALL/LBL), and lymphoma. AML diagnosed at 18 and ALL at 20

Answer 127

Autosomal recessive disorder caused by ATM Pleiotropic disorder with multiple manifestations, including immunodeficiency, neurological deficits, and an increased propensity for the development of cancer Predisposition to lymphoid leukaemia and lymphoma is observed from childhood, with a high propensity for the development of acute lymphoblastic leukaemia

Answer 128

Autosomal dominant condition caused by germline variants in PTPN11, NRAS, KRAS, CBL, NF1 cerebellar degeneration with progressive ataxia, oculocutaneous telangiectasia, immunodeficiency, susceptibility to bronchopulmonary disease, and lymphoid tumours

Answer 129

Autosomal dominant in SMAD9 Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, and Enteropathy; may present as non-syndromic monosomy 7, MDS or bone marrow failure

Answer 130

Autosomal dominant in SMAD9L cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure, myelodysplasia, and myeloid leukemia, sometimes associated with monosomy 7

Answer 131

GATA1 in the presence of trisomy 21 There is a wide spectrum of clinical outcomes and although it often resolves spontaneously (15-20% of cases result in early death, 20-23% of survivors will develop acute myeloid leukaemia of Down Syndrome (ML-DS

Answer 132

Autosomal dominant in GATA2 Often present with infections followed by bone marrow failure. This can progress to AML, MDS or CMML Present in 15% of advanced MDS cases and and in 72% of adolescents with MDS and monosomy 7  Penetrance, expressivity, and age of disease onset can be variable Hematopoietic stem cell transplantation (HSCT) is the only effective therapy for GATA2 deficiency, and results in hematopoietic reconstitution and reversal of the clinical phenotype

Answer 133

Autosomal dominant in RUNX1 Associated with lifelong thrombocytopenia and qualitative platelet defects. Can lead to AML, MDS (occasionally ALL)

Answer 134

Autosomal dominant in ANKRD26 No syndromic features, thrombocytopenia, variable platelet function abnormalities Increased risk for myeloid malignancies (including MDS, AML and CML – cumulative lifetime risk 8%)

Answer 135

Autosomal dominant in ETV6Lifelong thrombocytopenia B-ALL most common malignancy

Answer 136

Autosomal dominant associated with CEBPA 10% of CEBPA-mutant AML Myeloid malignancies are relatively chemosensitive; without allogeneic stem cell transplant, individuals are susceptible to additional independent malignancies (not relapses)

Answer 137

Autosomal dominant in DDX41 Increased risk of myeloid neoplasms, lymphoid neoplasms, adult-onset single- or multiple-lineage cytopenias (including aplastic anemia), and red blood cell macrocytosis. The most common myeloid neoplasms include MDS, AML, and therapy-related myeloid neoplasms. Life long risk of 50%

Answer 138

Like in all inherited predispositions to AML, great care needs to be taken to avoid use of a stem cell donor who carries a germline CEBPA pathogenic variant. Lifelong surveillance with blood count every 6 to 12 months Genetic counselling: 50% risk

Answer 139

Truncating germline DDX41 variants in patients who develop MDS are associated with faster transformation to AML better response to hypomethylating agents Surveillance: Complete blood count with differential every six to 12 months Genetic counselling: DDX41-associated familial MDS/AML is inherited in an autosomal dominant manner.- 50% risk of affective relatives

Answer 140

CDAs belong to a group of inherited conditions characterized by a maturation arrest during erythropoiesis with a reduced reticulocyte production in contrast with erythroid hyperplasia in bone marrow. Classified into 5 types: CDA types I CDA types II CDA types III familial and sporadic CDA types IV (Transcription factor-related CDA) The CDA variants

Answer 141

Chronic anaemia Fatigue and lack of energy Jaundice (a high level of a pigment called bilirubin in the blood) Pale skin Enlarged spleen Gallstones Small stature Abnormalities of the skeleton. In people with CDA 1, this can include unusually small fingers and toes,or fingers and toes that are fused together.

Answer 142

Autosomal recessive in CDAN1 mild or moderate anaemia, which is generally macrocytic, and relative reticulocytopenia and congenital anomalies, such as skeletal abnormalities, chest deformity, and short stature

Answer 143

Autosomal recessive disorder in SEC23B CDA typeII is the most common form among the CDAs. Clinically, this condition is characterized by normocytic anaemia of variable degrees, with normal or slightly increased reticulocyte counts. CDAII is often accompanied by jaundice and splenomegaly because of the haemolytic component

Answer 144

Autosomal dominant inheritance pattern A unique causative variant c.2747C.G (p.P916R) in the KIF23 gene Rare The patients show absent or moderate anaemia, with normal or slightly increased mean corpuscular volume (MCV), slight relative reticulocytopenia, jaundice, and signs of haemolysis. Splenomegaly is usually absent.

Answer 145

Four criteria 1 Evidence of congenital anemia/jaundice or of heredity 2 Evidence of ineffective erythropoiesis 3 Typical morphological appearance of bone marrow erythroblasts 4 Exclusion of congenital anemias which fulfill criteria one and two, but have been classified according to the underlying defect, such as the thalassemia syndromes, some types of pathological hemoglobins, or hereditary sideroblastic anemias

Answer 146

Autosomal dominant inheritance pattern. Heterozygous variant c.973G.A (p.E325K) in the KLF1 gene Only 8 patients recorded They have hemolytic anemia, which is generally severe, with normal or slightly increased reticulocyte count, and markedly elevated fetal hemoglobin levels.

Answer 147

The standard treatment of cases with severe anemia (hemoglobin, <7 g/dL) is transfusion. Hematopoietic stem cell transplantation (HSCT) is another therapeutic option in severe cases. One specific treatment that is available for CDAI patients is interferon-α. The standard clinical management of CDA patients is evaluation of the complete blood count and the iron balance parameters, with monitoring every 6 months.

Inherited Cancer Syndromes Flashcards

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