Cancer Genomes How to Analyze Your Own Genome

Transcription

1 Cancer Genomes How to Analyze Your Own Genome

2 Cancer vs. Heritable Diseases So far, we mostly discussed heritable diseases, where the disease causing mutaaons are inherited from one individual to his/her offsprings The cause of cancer is also mainly in the geneacs, but includes non- heritable component Germline polymorphisms: the mutaaons one inherited from parents SomaAc mutaaons: the mutaaons that each cell accumulated during the lifeame of the individual Both germline polymorphisms and somaac mutaaons are studied in cancer research

3 Data Collection for Cancer Research IdenAfying cancer- causing germline mutaaons Genotype data are collected for a large number of normals and cancer paaents (case/control studies) IdenAfying cancer- causing somaac mutaaons Genotype data are collected for blood (normal) and cancer cells for each cancer paaent, for a large number of cancer paaents. Usually, other types of data are also collected along with genome data Tumor gene expressions, epigeneac data, clinical data etc. The Cancer Genome Atlas ConsorAum hpp://cancergenome.nih.gov

4 Development of Cancer Cells Types of cancers Carcinomas: cancers arising from epithelial cells Sarcomas: cancers arising from connecave Assue or muscle cells Leukemias and lymphomas: cancers derived from white blood cells and their precursors Agents that trigger carcinogenesis Chemical carcinogens (causes local DNA alteraaons) RadiaAon such as x- rays (causes chromosome breaks and translocaaons), UV light (causes DNA base alteraaons) Viruses: HepaAAs- B, HepaAAs- C virus for liver cancer

5 Cancer Progression

6 Tumors Cancer cells Reproduce in defiance of the normal restraints on cell growth and division Invade and colonize territories normally reserved for other cells

7 Defective Control of Cell Death and Differentiation in Cancer Cells Both increased cell division and decreased apoptosis (cell death) can contribute to tumorigenesis

8 Pathways of Tumorigenesis

9 Cancer-Causing Genes Oncogenes MutaAons that confer gain of funcaons to oncogenes can promote cancer MutaAons with growth- promoang effects on the cell OYen heterozygous mutaaon is enough to make cells cancerous. Why? Tumor suppressor genes MutaAons that confer loss of funcaon can contribute to cancer Typically homozygous mutaaon is required to make cells cancerous. Why? DNA maintenance genes Indirect effects on cancer development

10 Mutations in Tumor Suppressor Genes

11 Mutations in Oncogenes

12 Replication of DNA Damages

13 Driver and Passenger Mutations Driver mutaaons Causally implicated in oncogenesis Gives growth advantage to cancer cells posiavely selected in the microenvironment of the Assue E.g., mutaaons that de- acavate tumor suppressor genes Passenger mutaaons SomaAc mutaaons with no funcaonal consequences Does not give growth advantage to cancer cells However, the passenger mutaaons are propagated to daughter cells just because they are linked to the driver mutaaon Key ScienAfic QuesAon: How can we disanguish between driver and passenger mutaaons?

14 Identifying Driver Mutations Typically involves sequencing tumor DNA and the matched normal DNA for the same individuals Comparison with reference genome and other known DNA polymorphisms Signatures of driver mutaaons Frequently observed mutaaons across tumors. MutaAons that cluster in subset of genes. Passenger mutaaons are more randomly distributed across genomes

15 Challenges ComputaAonal challenges unique to cancer genome analysis Sequence alignment and assembly can be significantly more challenging because of highly rearranged chromosomes and high variaaon across cancer genomes SomaAc mutaaon calling is more challenging the impurity of the sample Normal genomes have allele copies of 0, 1, or 2 Cancer genomes can have allele copies of fracaons of 0, 1, or 2 Most somaac mutaaons are rare Different cancer types have different rates of mutaaons. Mutator phenotype may or may not present. Infrequently occurring driver mutaaons are hard to idenafy.

16 Methods for Detecting Driver Mutations SIFT A tool that uses sequence homology to predict whether a subsatuaon affects protein funcaon Classifies a subsatuaon into tolerated or deleterious ones PolyPhen SoYware for predicang damaging effects of missense mutaaons

17 PolyPhen Features Black: candidates, blue: selected

18 Summary The geneac causes of cancer include both heritable germline mutaaons and somaac mutaaons In cancer genome study, genome data are collected for both normal and cancer cells for the same individual The key challenge in studying the geneac causes of cancer is to idenafy driver mutaaons from background passenger mutaaons