Inherited (familial) Cancer syndromes

• Inherited (Familial) Cancer Syndromes

  Genetic conditions that predispose individuals to developing certain types of cancer

  
• Inherited (Familial) Cancer Syndromes are the focus of this module

  
• Classes of familial cancer genes

  • Gatekeepers (Tumour suppressor genes)
  • Caretakers (DNA maintenance/repair genes)
• Gatekeepers (Tumour suppressor genes)


  • Control the biology of cells (proliferation, differentiation, apoptosis)
  • Trigger cellular responses to oncogenic damage, primarily apoptosis and cell-cycle arrest
  • Their inactivation is rate-limiting for direct tumor initiation and growth
• Caretakers (DNA maintenance/repair genes)

  • Repair oncogenic damage
  • Their inactivation does not directly promote tumor initiation but leads to genetic instability and increased mutation of all genes

  
• Lynch syndrome


  • Also known as Hereditary Non Polyposis Colorectal Cancer (HNPCC)
  • Causes colorectal, endometrial, stomach, small intestine, pancreas, brain, hepatobiliary tract, and urinary tract cancers

  
• Microsatellite instability can occur in non-coding or coding microsatellite sequences, e.g. the BATRII region of the TGFBR2 gene

  
• Microsatellite instability in TGFBR2 gene

  Leads to dysregulation of the TGF-beta signalling pathway

  
• TGF-beta signalling pathway


  • Ligands bind to type 1 and type 2 receptors, forming a complex that phosphorylates SMAD2 and SMAD3
  • SMAD2/3 then bind to SMAD4 and translocate to the nucleus to regulate transcription of target genes

  
• TGF-beta can act as both a tumour suppressor and a tumour promoter

  
• Germline mutations in the TGF-beta signalling pathway stop its tumour suppressor role

  
• Juvenile polyposis


  Autosomal dominant hamartoma syndrome characterised by multiple juvenile polyps in the GI tract, congenital anomalies, and increased risk of colorectal, gastric, duodenal and pancreatic cancers
• Familial adenomatous polyposis (FAP)


  Autosomal dominant disorder that typically presents with colorectal cancer in early adult life due to extensive adenomatous polyps of the colon, as well as other cancers and conditions
• APC protein


  • Tumour suppressor involved in cell cycle control, differentiation, migration, and apoptosis through the Wnt signalling pathway

  
• Wnt signalling pathway


  1. In the absence of Wnt, APC is part of a degradation complex that phosphorylates and degrades beta-catenin

  2. In the presence of Wnt, the degradation complex is disrupted, allowing beta-catenin to translocate to the nucleus and activate transcription of target genes like cyclin D1

  
• Absence of APC in FAP

  Leads to stabilisation of beta-catenin and continuous transcription of proliferative target genes
• The high cell turnover in the GI tract, with proliferating stem cells at the bottom of the crypt, contributes to the development of colorectal cancer in FAP
• Inherited defects in DNA repair mechanisms can contribute to tumourigenesis
• Inherited defects in genes like VHL can facilitate the progression of tumours

  
• Studying inherited cancer syndromes has enhanced our understanding of normal cell and molecular function, the origins and mechanisms of carcinogenesis, and the role of alleles and locus heterogeneity in sporadic forms of cancer

  
• Wnt signalling pathway


  7TM receptor

  
• Absence of wnt


  1. Degradation complex assembled consisting of APC which phosphorylates beta catenin and causes proteasomal degradation

  2. APC is part of the degradation complex

  
• Beta catenin


  Has low half-life of 20 mins = no proliferation
• Presence of wnt


  1. Releases the degradation complex

  2. Beta catenin able to move into nucleus and bind to TcF transcription factors and transcribe cyclin D1

  
• Cyclin D1


  Role in cell cycle = cell proliferation

  
• Absence of APC in FAP disease

  1. Does not need wnt to activate the pathway anymore

  2. Degradation complex cannot assemble

  3. Stabilisation of beta catenin and continuous transcription of target genes eg cyclin D1

  4. Continuous proliferative signals

  
• Why does this cause colorectal cancer?
• Wild type: GI tract = very high turnover tissue, bottom of crypt = proliferating stem cells resides here which are signalled by wnt signalling to keep proliferating, as they proliferate they migrate up towards the lumen but when they reach the threshold (dotted line)- they stop proliferating and start differentiate as the wnt signal disappears, at the top once differentiated, they shed and are done
• Mutation in APC: when reach the threshold, they keep proliferating even without wnt agonist and are unable to differentiate = causes the polyps formation at that site

  
• Xeroderma pigmentosum (XP)


  Cancer syndrome characterised by UV hypersensitivity resulting in 2000x increased risk of cancer, Genetically heterogeneous disease with seven complementation groups XPA to XPG and a variant form XPV

  
• What is the result of a loss of nucleotide excision repair activity in human cells?
• Hereditary breast ovarian cancer (HBOC)


  Predisposition to early onset of breast and ovarian cancer, as well as to cancers of fallopian tubes, pancreas, stomach, larynges, prostate

  
• Causes: Germline mutations in two unrelated genes: BRCA1 or BRCA2

  
• BRCA1 and BRCA2 are unusual as there are no mutations in sporadic cancer, all the conditions before we looked at can occur sporadically too along with germline except BRCA1/2 cannot be sporadics

  
• Loss of function of BRCA1 and BRCA2 is associated with genomic instability

  
• Founder effect in Ashkenazi Jewish population: certain hotspot mutation found in ashkenazi jewish pop, Founder effect- reproductive isolation causes certain disease to be popular in certain population

  
• BRCA1 vd BRCA2 Have Different locus, different allele, same phenotype

  
• BRCA and DNA repair mechanisms

  BRCA1 interacts with a variety of proteins including p53 and hRAD51, BRCA1 also associates with NBS1/MRE11/ RAD50 complex in double strand break repair, BRCA2 also interacts with hRAD51, BRCA2 directs hRAD51 localisation to nucleus and facilitates binding to damaged regions of DNA, BRCA2 tumour mutations fail to do this and so contribute to genomic instability

  
• Synthetic lethality


  When one pathway is damaged, so the other cooperative/compensative pathways is activated, but if the cooperative pathways is damaged as well = causes synthetic lethality, in this case: Normally, BRACA1 and 2 involved in a type of DNA repair which can be also compensated by PARP's dna repair pathway, when BRACA1 and 2 are mutated = genomic stability and a lot of mutation happening, so you also inhibit the PARP pathway too so the cell is not viable anymore and the cancer cell dies = synthetic lethality

  
• pRB (retinoblastoma)


  A tumour suppressor gene, one copy mutated - normal phenotype - normal allele compensates the mutated allele, both allele mutation - thru deletion or mutation =cancer, First identified as the gene defective in inherited cancer syndrome retinoblastoma, most common eye tumour in children, also in bone, breast, lung, bladder, tumours, inherited can be bilateral retinoblastoma, Gene encodes a protein of 105 kDa which can be phosphorylated, germline or sporadic, in germline - children mostly likely develop bilateral retinoblastoma, can happen sporadically ( later in life)= causes unilateral retinoblastoma (in one eye)