This document discusses various cancer susceptibility syndromes. It begins by defining cancer susceptibility and the genetic and epigenetic factors that influence it. It then discusses several key syndromes in more detail, focusing on the genes involved, inheritance patterns, clinical features, and cancer risks. These include retinoblastoma (RB1 gene), Lynch syndrome (DNA mismatch repair genes), hereditary breast-ovarian cancer (BRCA1/2), neurofibromatosis type 1 (NF1 gene), and familial adenomatous polyposis (APC gene). It also outlines other syndromes categorized by the genes' functions in genomic integrity, proliferation, translation regulation, and angiogenesis.

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