Molecular Basis of Cancer and Heriditary Cancer Syndromes

Question 1

Four classes of genes that are the principle targets of cancer forming mutations:

Answer 1

1. Growth-promoting procto-oncogenes (gain of function)
   
   1. Usually only require one mutated gene for transformation → cancer
2. Growth-inhibiting tumour suppressor genes (loss of function)
   
   1. Both alleles must be damaged before transformation can occur
3. Genes that regulate apoptosis - both gain and loss of function
4. Genes responsible for DNA repair - usually loss of function

Question 2

Examples of proto-oncogenes

Answer 2

• Proto-oncogenes: normal cellular genes whose products promote cell proliferation
• Oncogenes: mutated or ocer-expressed versions of proto-oncogenes that function autonomously, having lost dependne on normal growth promoting signals
• Oncoproteins: protein encoded by an oncogene that drives increased cancer cell proliferation

Question 3

Examples of tumour suppressor genes

Answer 3

Question 4

Difference between germline vs sporadic mutations

Answer 4

Germline

• Mutation present in egg or sperm (germ cell)
• If passed onto offspring → present in all cells
• Heritable conditions

Somatic

• Mutation present in non egg/sperm cells
• Can reproduce abnormality in clonal cells
• Non-heritable

Note: mutations now called “genetic variants”. Gene variants classified into 5 categories

1. Pathogenic (Class 5)
2. Likely pathogenic
3. Variant of Uncertain significance
4. Likely benign
5. Benign (Class 1)

Question 5

Notes on penetrance

Answer 5

• The proportion of individuals carrying a pathogenic variant who will manifest the disease
• BRCA example of high penetrance gene
• Pathogenic variants that cause disability early in life usually rare → adverse effect on life expectancy and reproduction
• Pathogenic variants that cause health effects in middle/older age may be relatively common (≥1%)
• Pathogenic variants that is AR in inheritane may also be relatively common in the general population

Question 6

Notes on gene mutations in hereditary breast and ovarian cancer

Answer 6

Question 7

Notes on hereditary cancer syndromes associated with colorectal cancer

Answer 7

Question 8

Notes on autosomal dominant inheritance in herediatry cancer syndromes

Answer 8

• The majority

Incomplete penetrance

• Not all who carry the gene mutation will develop the disease
• Cancer risks for most HCS are not associated with 100% penetrance risk
• Can appear to skip a generation if cancer type is predominantly A/W one sex specific cancer e.g. gynaecological and the variant is carried by the male parent in a male dominant family

Question 9

Notes on autosomal recessive inheritance in herediatry cancer syndromes

Answer 9

Examples

• MYH → attenuated FAP
• BML - Bloom syndrome
• FANC → Fanconi anaemia
• ATM → Ataxic telangiectasia (biallelic and monoallelic risk)

An increased cancer risk may be associated with individuals who are heterozygous for pathogenic variants

Question 10

Notes on founder effect

Answer 10

• High frequency of a specific gene mutation in a population founded by a small ancestral group

Consanguinity and Bi-allelic inheritance

• Significant Founder effect in communities/cultures with consanguinous marriage
• Bi-allelic inheritance may result in:
  
  • Foetal death
  • High risk syndromes with significant increase in childhood cancers → Constitutional Mismatch Repair deficiency syndrome, Werner’s syndrome, Biallelic BRCA 2 (Bloom syndrome/Fanconi anaemia)

Question 11

Notes on spontaneous germline events

Answer 11

Rate of spontaneous mutations varies according to gene

• FAP: 15-20% de novo
• TP53 (Li Fraumeni): 15% de novo
• BRCA½: extremely rare

Testing of parents still recommended even if family history suggests spontaneous new mutation

De-novo mutations → siblings not at risk - no testing needed, offspring remain at 50% risk (if autosomal dominant inheritance)

Question 12

Notes on Lynch-related CRC

Answer 12

• Mismatch repair deficiency hallmark
• Histological features can predict dMMR using the presence of any three of the following factors:
  
  • Mucinous histology
  • Poor differentiation
  • R) sided
  • Lymphocytic infiltrate
  • Expanding growth pattern
  • Absence of intraglandular neutrophil-rich necrosis
• Immunohistochemistry can be utilised to determine expression of mismatch repair proteins, indicated MMR function (MLH1, MSH2, MSH6, PMS2)
• Germline 3%
• Somatic variant and methylation
• MLH1/PMS2 loss → impact to MLH1 gene function. Either:
  
  • Acquired hypermethylation of MLH1
  • Somatic tumoural pathogenic variant (non-hereditary)
  • Germline pathogenic variant

Question 13

Screening for hereditary cancers syndromes: BRCA½,PALB2, Lynch syndrome, FAP, VHL

Answer 13

BRCA1, 2, PALB2

Breast screening from 25 years

Prophylactic BSO from 40 years

Or 5 years earlier than the youngest person affected

Lynch syndrome

ML1/MSH2: Screening colonoscopy from 25 years

PMS2/MSH6: Screening colonoscopy from 30 years

Prophylactic TAHBSO from 40 years. Subtotal vs hemi-colectomy

Or 5 years younger than the youngest person affected

FAP

Screening colonoscopies from 12 years

Colectomy vs proctocolectomy

VHL

Annual exam with BP from 2 years

Annual plasma or urine metanephrine from 2 years

Annual abdominal screening alternating US/MRI from 10 years

Surgery → Nephron sparing surgery ideal approach given high liklihood of multiple and bilateral renal cancers