Cancer susceptibility syndromes

1. Cancer Susceptibility Syndromes
Dr. Kiran

2. Principles of Cancer Susceptibility
• “Cancer susceptibility syndrome” - encompass
the overall susceptibility of all individuals to
develop cancer during their lifetimes.
• Influenced by
1)multiple somatic genetic and epigenetic
changes
2)number of inherited mutations or variants in
low-penetrance complex modifiers

3. The RB Paradigm
• Alfred Knudson : the “two-hit hypothesis”-
postulated that the predisposition
arises as a consequence of a heterozygous
germline mutation in a tumor suppressor,
while a second acquired somatic mutation
would be required for the tumor to develop.

4. • hypothesis was validated –
by the cloning of the RB1 gene and the
realization that both alleles of the RB1 gene
are indeed frequently mutated in tumors from
retinoblastoma patients.

5. • remarkable milestone
• tumor suppressors are typically expected to be
invariably recessive in their mode of action
and thus their complete functional loss would
be a prerequisite for a cellular phenotype to
manifest and for cancer to develop.

6. What Is the Function of a Tumor Suppressor?
• For cancer to initiate
1)acquire the ability to proliferate
2)to prolong its overall lifespan
through the abrogation of programmed cell
death

7. 2 classes of tumor suppressors
• Gatekeepers - the ones that control
proliferation and survival .
• Caretakers - the genes involved in the control
of genomic integrity .

8. • Apoptosis or cellular senescence.
• Angiogenesis - genes that oppose or regulate
such processes could be potent tumor
suppressors

9. PTEN Paradigm
• PTEN - haplo-insufficient tumor suppressor to
oppose tumor initiation in distinct tissues.
cancer can develop in the absence of
its complete genetic loss.
• 20% reduction in PTEN expression can induce
tumor formation .
• loss of PTEN expression to 50% levels or below
further enhances tumorigenesis.

10. • complete PTEN loss - antitumorigenic because
it triggers a cellular senescence response that
needs to be evaded for cancer to progress

11. Examples of Haplo-Insufficient Cancer Susceptibility Genes
Regulation of translation
• PTEN -Cowden syndrome
• LKB1 - Peutz-Jeghers syndrome
• PTCH1 - Nevoid basal cell syndrome
Regulation of proliferation
• NF1 - Neurofibromatosis type 1
• APC - Familial adenomatous polyposis
Genomic integrity and apoptosis
• BLM - Bloom's syndrome
• TP53 - Li-Fraumeni syndrome

12. Genetic Testing
• multiple endocrine neoplasia type 2
• von Hippel-Lindau disease
• familial adenomatous polyposis

13. • low-penetrance variants that confer moderate
to weak cancer susceptibility.
• high-penetrance genes - it can be beneficial to
family members when a familial Cancer
Susceptibility syndrome is suspected.

14. How might a patient with a familial Cancer
susceptibility be identified?
• if a patient presents with a cancer at an
unusually young age
• multifocal or bilateral tumor development.
• A high rate of cancer within the patient's
family strongly suggests a hereditary cancer
susceptibility .

15. RB as the Paradigm
Incidence and Inheritance
• Retinoblastoma is a tumor of the retinal
photoreceptor precursor cells.
• 1 in 20,000 children
• the tumors develops btw birth and 8 yrs
• occurs in both an inherited - 40%
sporadic fashion- 60%

16. • Genetic Basis
• Knudson's two-hit hypothesis
• was noticed that a fraction of chromosome
13q14 was sometimes missing in
retinoblastoma cells.
• RB1 gene – mutated.

17. Clinical Features and Therapeutic Intervention
• Familial cases - multifocal or B/L tumors
• Sporadic cases - unilateral.
• Familial retinoblastoma - at increased risk of
osteosarcomas and other nonocular primary
tumors.
• Surgery, chemotherapy, or radiation.

18. Most Prevalent Syndromes
• HNPCC and HBOC - mutations in caretaker
genes responsible for DNA repair and
therefore genomic integrity.
• NF1 and FAP - mutation of gatekeeper genes
that restrain cellular proliferation.

19. Hereditary Nonpolyposis Colon Cancer
Incidence
• Lynch syndrome
• most common cancer susceptibility disease
• 2% to 3% of total colon cancer cases
• 1 in 400.
• Autosomal dominant fashion with a penetrance of
about 90%.
• Males are affected at a higher penetrance,
• Females being less affected but at an additional risk
of endometrial cancer.

20. Genetic Basis
• Germline mutation in one of six genes:
MLH1, MSH2, MSH3, MSH6, PMS1, or PMS2.
• Function in DNA mismatch repair, so
mutations in these genes affect genomic
integrity.
• 90% - MLH1, MSH2, or MSH6
• minority - PMS genes,

21. • Patients generally inherit one inactivated
(mutated) allele and the other, functional, allele
is eventually lost through LOH.
• Microsatellite instability - a phenomenon in
which errors in replication of highly repetitive
sequences cannot be repaired, resulting in
alterations of the length of the total repeat
sequence.
• Thus these genes are classified as caretakers
• Somatic mutations of these genes in pts with
sporadic colon cancer are very rare.

22. Clinical Features and Therapeutic Intervention
• colon cancer at a younger average age
• rarely exhibit polyps
• colonic adenomas rapidly progress to
carcinoma compared with sporadic colon
cancer patients.
• elevated risks for stomach, ovary, small
intestine, ureter, and kidney cancers.

23. • screened annually by colonoscopy starting
around age 20
• Women are recommended to undergo yearly
pelvic examinations and ultrasound
examination.

24. Hereditary Breast-Ovarian Cancer Syndrome
Incidence
• 1 in 500 or 1,000.
• Autosomal dominant fashion with a
penetrance of approximately 85%.
• Ashkenazi Jewish - higher rates of mutation
than the general population.

25. Genetic Basis
• Germline mutations in BRCA1 & BRCA2 – 90%
• Somatic cancer - the function of at least one
BRCA1 or BRCA2 allele is lost in 30% to 70% of
sporadic breast and ovarian cancer cases.

26. Clinical Features and Therapeutic Intervention
• exhibit early onset breast cancer
• elevated risk - pancreatic cancer, stomach
cancer, laryngeal cancer, fallopian tube cancer,
and prostate cancer in male BRCA carriers
• Breast cancers arising in BRCA1 mutant -
high-grade IDC negative for ER and HER2/neu.
• Risk-reducing prophylactic breast surgery.

27. Neurofibromatosis Type 1
Incidence
• 1 in 3,500 people worldwide.
• Autosomal dominant fashion, with a
penetrance of 100% for neurofibromas.

28. Genetic Basis
• Mutations in the NF1 gene
• NF 2 - inactivation of an unrelated gene, NF2.
• Inherit one mutant allele of NF1, with frequent
LOH for the wild type allele
• 30% to 50% occur because of de novo germline
mutations in the NF1 gene.
• The other cases occur in families with H/O
neurofibromatosis and result from inherited
germline alleles.
• SPRED1

29. Clinical Features
• Multiple benign neurofibromas, tumors formed
from the cell sheaths of peripheral nervous system
nerves.
• Lesions will progress to neurofibrosarcomas.
• Elevated risks for glioblastomas,
pheochromocytomas, and myeloid leukemias.
• Café au lait macules are found in 100% & these
increase in size and frequency with age.
• A subset of patients may develop seizures and
learning disabilities or mental retardation.

30. Familial Adenomatous Polyposis
Incidence
• FAP is a highly penetrant
• Autosomal dominant disorder
• 1 in 5,000 and 1 in 10,000.
• 1% of all colon cancer cases.

31. Genetic Basis
• Germline mutations in the APC gene on
chromosome 5q
• Mutations are seen in 90% to 95% of FAP
families.
• Approximately 75% - familial germline
mutations
• remainder - first-generation de novo germline
mutations

32. Clinical Features and Therapeutic Intervention
• The hallmark - 100 (and often over 1,000)
adenomatous polyps in the colorectum.
• Polyps will progress to malignant colon cancer.
• The cancer risk - 100% by age 40,
• Prophylactic colectomy – reduce risk.
Patients with a positive genotype
and significant polyp burden .
NSAIDs.

33. • Elevated risk - upper GI tract neoplasms.
• Other phenotypes - congenital hypertrophy
of the retinal pigment epithelium, dental
anomalies, epidermoid cysts, osteomas,
desmoid tumors, and mesenteric fibrosis.

34. Other Syndromes, by Function
• Genomic Integrity and Apoptosis
1) HNPCC and HBOC
2) Xeroderma pigmentosum (XP)
3) Ataxia telangiectasia
4) Werner syndrome
5) Rothmund-Thomson syndrome
6) Bloom syndrome
7) Fanconi anemia

35. Xeroderma pigmentosum (XP)
• XP is a rare autosomal recessive syndrome that results
in sensitivity to sun damage
• 100% chance of developing skin cancer.
• XP results from mutation of any of eight genes - (XPA,
XPB, XPC, XPD, XPE, XPF, XPG, and XPV).
• The first seven XP genes encode proteins that
participate in a nucleotide excision repair (NER)
complex.
• NER is a DNA repair process by which chemically altered
nucleotides are first recognized by the alteration of the
DNA double-helix structure and are then removed

36. Fanconi anemia
• Autosomal recessive syndrome - mutations in genes
required for recognition or repair of DNA damage.
• Increased risk of leukemias (mainly acute myelogenous)
and cancers of H&N, esophagus, and vulva.
• Biallelic mutations in BRCA2 give rise to a form of FA
• Monoallelic mutations result in HBOC.
• Mutations in any of the 13 responsible genes (FANCA,
FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF,
FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCM/Hef, and
FANCN) .

37. • Bloom syndrome, Werner syndrome, and
Rothmund-Thomson syndrome - autosomal
recessive syndromes
• mutations of the human RecQ helicases BLM,
WRN, and RECQ4.
• In Bloom syndrome, patients rapidly develop
non-Hodgkin's lymphoma, leukemias, and
breast, stomach, and skin cancers

38. Li-Fraumeni syndrome
• Missense mutations in p53
• A rare autosomal dominant familial cancer
syndrome with a penetrance of 90% to 95%.
• The most common cancers found in Li-
Fraumeni patients are sarcomas, breast
cancer, and brain tumors.

39. Regulation of Translation
• Regulation of protein translation has been
indirectly implicated in cancer progression
because many proto-oncogenes and tumor
suppressors can regulate or modulate
ribosome function and translation.
• 1) DKC1 gene - Dyskeratosis congenita
• 2) PTEN - Cowden syndrome
• 3) TSC1, TSC2 - Tuberous sclerosis

40. Cowden syndrome
• autosomal dominant disorder in which patients
develop numerous hamartomas of the skin, breast,
thyroid, GI tract, and central nervous system.
• Elevated risk - breast cancer (30%)
• Germline mutations in the PTEN tumor suppressor
• a lipid phosphatase that negatively regulates the
proto-oncogene PI3K through modification of
specific phosphoinositides at the plasma membrane

41. Tuberous sclerosis
• TSC1 and TSC2 genes are inactivated
• Autosomal dominant disorder
• Characterized by cortical tubers, hamartomas,
multiple other benign lesions
• Increased risk of brain tumors and renal
cancer.

42. Dyskeratosis congenita
• X-linked recessive disorder caused by mutations in
the DKC1 gene
• autosomal recessive and autosomal dominant
forms (less than 15% of all DC cases).
• These rarer forms - TERC or TERT, which encode for
telomerase complex components.
• Patients are susceptible to premature aging,
anemia, hyperkeratosis of the skin, and possibly
various malignancies, including myelodysplasia and
carcinomas of the lung, larynx, esophagus,
pancreas, and skin.

43. Peutz-Jeghers syndrome
• Caused by defects in translation.
• Autosomal dominant disorder
• Characterized by hamartomas of multiple
tissues (in particular the GI tract)
• 20% to 50% chance of developing malignant
tumors of the GI tract, pancreas, breast, or
testis.
• Mutations in LKB1/STK11, a serine threonine
kinase, underlie the disorder.

44. Proliferation
• mutations in proteins that regulate cellular
proliferation (gatekeepers).
• These syndromes include
• 1) NF1 and FAP
• 2) Familial renal cell carcinoma
• 3) Familial malignant melanoma
• 4) Multiple endocrine neoplasia type 2
• 5) Gorlin syndrome.

45. Gorlin syndrome
• Nevoid basal cell carcinoma syndrome
• Characterized by the early onset of numerous
basal cell carcinomas of the skin.
• Mutations in the Patched1 (PTCH1) gene,
which encodes for a cell-surface protein that
acts as a negative regulator of pro-proliferative
Sonic Hedgehog signaling

46. • Mutation of - pro-proliferative receptor tyrosine
kinase RET.
• Hereditary papillary renal cancer - MET gene
• Familial gastrointestinal stromal tumour - KIT gene
• Costello syndrome- is caused by activating HRAS
mutations
• Familial malignant melanoma - loss-of-function
mutations in the tumor suppressor gene CDKN2A

47. Angiogenesis
• Von Hippel-Lindau disease (VHL)- VHL gene
• Autosomal dominant disorder
• Characterized by a high incidence of renal cysts
and clear cell renal carcinoma, benign
pancreatic cysts, and hemangioblastomas of the
CNS.
• VHL loss therefore results in accumulation of
HIFs under normoxic conditions, stimulating
enhanced angiogenesis.

48. Angiogenesis
• Hereditary leiomyomatosis
• Renal cell cancer .

49. THANK YOU