Genetics of Cancer MBBS1 2024.pdf

Genetics of Cancer DR ADAM SHAW  Genetic variation The human genome consists of ~ 3 billion base pairs which encode approximately 20 000 genes Typical difference between two individuals’ genomes estimated at 20 million base pairs Gene change = ‘variant’ Makes us unique - ’polymorphisms’ Is t...

Genetics of Cancer DR ADAM SHAW  Genetic variation The human genome consists of ~ 3 billion base pairs which encode approximately 20 000 genes Typical difference between two individuals’ genomes estimated at 20 million base pairs Gene change = ‘variant’ Makes us unique - ’polymorphisms’ Is the basis for evolution Is also the basis for disease - ‘pathogenic variants’ Examining the genome The ‘microscope’ has become exponentially more powerful - and exponentially cheaper 1956 1969 2008 2011/12 Examining the genome Next generation sequencing has revolutionised our understanding of cancer Explosion in availability of commercial somatic and germline NGS panels 100 000 genomes project enabled whole genome sequencing as routine in NHS Breast cancer Colonic mucosa Entire mucosa replaced every 5 days 10 billion cells die and are replaced every day DNA replication Human Genome: ◦ ~3 billion base pairs ◦ ~20,000 genes DNA polymerase replicates c. 1,000 nucleotides per second Thanks to many thousand DNA polymerase enzyme molecules in each nucleus, a cell can replicate in only a few hours Error rate of only 1 per 100,000 base pairs Reduced by DNA proofreading to 1 per 10,000,000 Reduced further by DNA Mis-Match Repair (MMR) to only ~10 per cell division DNA damage Content of the Human Genome Genes (1.5%) ◦ Proteins ◦ Non-coding RNA Related sequences (40%) ◦ Introns ◦ Transcriptional regulatory regions including 5’ and 3’ UTRs ◦ Pseudogenes and segmental duplication Repetitive DNA (45%) ◦ Interspersed repeats ◦ Mini and microsatellites ◦ Telomeres ◦ Centromeres Somatic mutations DNA damage within a cell May cause cell death ◦Limited consequence May damage DNA that is non-coding or inactive ◦Limited consequence May damage gene controlling cell growth ◦Potential consequence Somatic mutations Could inactive a “tumour suppressor gene” ◦Missense, nonsense, frameshift mutations ◦Chromosome deletions / rearrangements ◦Allows cell to divide faster Could active an “oncogene” ◦Missense mutations causing “gain of function” ◦Drives cell to divide faster Could create a new “fusion gene” ◦Chromosome rearrangements ◦Typically gives cell a growth advantage Somatic versus germline Knudson’s two-hit hypothesis Cancer: a disease of the genome Cancer caused by accumulation of mutations in cell cycle regulatory genes Cells have intrinsic mechanisms to protect their genomic integrity Cancer arises when these mechanisms fail causing abnormal cell cycle regulation Hereditary cancers are typically characterised by inherited mutations in DNA repair and tumour suppressor genes The majority of cancers are sporadic and driven by somatic gene mutations Cancer Risk Factors Age Environment ◦ Smoking, diet, occupational exposure Exercise, Obesity Infection ◦ eg HPV association with cervical cancer Genetics / Family history Tumour development Tumours are clonal expansions of genetically abnormal cells Targeted therapies Bevacizumab ◦Glioblastoma ◦Binds to VEGF ◦Reduces blood vessel formation Imatinib ◦CML ◦Blocks tyrosine kinase activity Genes associated with cancer predisposition Tumour suppressor genes  Important for controlling rate of cell growth  Typically diploid  Sporadic cancer occurs with bi-allelic loss/mutation  Heterozygous constitutional mutations result in increased cancer risk  e.g. APC in sporadic colon cancer and familial adenomatous polyposis Oncogenes  Accelerate cell division  Cancer arises when stuck in “on” mode – a gain of function mutation  e.g. KRAS, BRAF DNA damage-response/repair genes  Constantly repairing DNA  Cancer arises due to the accumulation of mutations across the genome  e.g. BRCA1, BRCA2 DNA repair mechanisms Mismatch repair ◦Lynch syndrome ◦Colon, ovarian, endometrial cancer Double strand break repair ◦BRCA1 ◦BRCA2 Nucleotide excision repair ◦XP Hoeijmakers Nature 2001 Features of inherited cancer susceptibility Young age of onset of cancer Multiple primary cancers in same person Same type of cancer in several relatives Or recognisable pattern of cancers in family High penetrance cancer susceptibility syndromes BRCA1/BRCA2 Lynch syndrome (mis-match repair deficiency) Li-Fraumeni syndrome Cowden syndrome Multiple endocrine neoplasia Hereditary leiomyomatosis and renal cancer FAP, MUTYH-AP, XP, VHL, BHD, PJS… Hereditary cancer syndromes Tumour type Proportion Examples Breast cancer 5-10% BRCA1/2 (HBOC) TP53 (LFS) Ovarian cancer 15-20% BRCA1/2 (HBOC) MMR genes (Lynch syndrome) Colorectal cancer 5-10% MMR genes (Lynch syndrome) APC (FAP) Melanoma 5- 10% p16 (FAMM) Medullary thyroid 25% RET (MEN2) Retinoblastoma 40% RB1 (Familial retinoblastoma) Phaeochromocytoma 30% SDHx (Familial paraganglioma and phaechromocytoma syndrome)  Hereditary breast and ovarian cancer BRCA1 and BRCA2 - Homologous recombination DNA repair ?Ovarian Ca Breast, ovarian, prostate, pancreatic age 61y NICE CG164 (June 2013) ◦ Offer genetic testing to individuals with >10% likelihood of carrying a mutation Prostate Ca Consider paternal transmission, small male- age 59y dominated families Genetic testing most informative if it takes place Breast Ca in individual with cancer age 34y  Hereditary breast and ovarian cancer Histology can give you a clue… Ovarian cancer 15-20% epithelial (not germ cell) ovarian cancers caused by germline BRCA1/2 mutation Ov Ca Triple negative breast cancer (TNBC) age 65y 10-15% TNBC diagnosed