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Questions and Answers

What percentage of variants detected during tumor sequencing is typically somatic?

1/2000

1/1000 (correct)

1/100

1/500

What is the False Discovery Rate when the sensitivity for detecting variants is 99.9%?

35%

50% (correct)

25%

75%

Which type of read pairs are indicative of structural variation?

Discordant read pairs (correct)

Concordant read pairs

Reverse strand read pairs

Forward strand read pairs

What is the primary purpose of the VCF file format in variant calling?

Precise definition of the variant Signup and view all the answers

What portion of the human genome is transcribed into protein-coding mRNAs?

3% Signup and view all the answers

What are non-coding RNAs (ncRNAs) primarily characterized by?

Their size and shape Signup and view all the answers

What is the approximate size of microRNAs (miRNAs)?

22 nucleotides Signup and view all the answers

Which of the following tools is commonly used to manage or convert VCF files?

Samtools Signup and view all the answers

What is the primary function of tumor suppressor genes?

To protect cells from uncontrolled growth Signup and view all the answers

How do oncogenes contribute to cancer development?

By promoting cell growth and division when mutated or overactivated Signup and view all the answers

What does Knudson’s Two-Hit Hypothesis explain?

How tumor suppressor genes are inactivated in cancer Signup and view all the answers

What is the output format of basecalling in DNA sequencing?

FASTQ Signup and view all the answers

Why is reference mapping important in DNA sequencing?

It identifies variants by comparing reads to a reference genome Signup and view all the answers

What percentage of the reference genome is derived from a single male from Buffalo, NY?

70% Signup and view all the answers

What is one challenge of reference mapping?

The genome being repetitive and large Signup and view all the answers

Which genomic alterations can be identified using variant calling algorithms?

Somatic mutations and inherited variants Signup and view all the answers

What primary role do PIWI-interacting RNAs (piRNAs) play in germline cells?

Bind to complementary sequences in mRNAs leading to mRNA degradation Signup and view all the answers

Which type of non-coding RNA is primarily involved in chromatin remodeling and gene expression control?

lncRNA Signup and view all the answers

What is a potential therapeutic target of non-coding RNAs in cancer therapy?

Oncogenic non-coding RNAs Signup and view all the answers

How do ncRNAs influence chemotherapy resistance mechanisms?

They modulate gene regulation pathways affecting drug metabolism. Signup and view all the answers

Which of the following ncRNAs is known to promote uncontrolled cell growth?

miR-21 Signup and view all the answers

What is a significant characteristic of circular RNAs (circRNAs)?

They are circular or ring-like in structure. Signup and view all the answers

Which of the following non-coding RNAs can serve as biomarkers for cancer detection?

miRNAs like miR-141 Signup and view all the answers

How do ncRNAs contribute to angiogenesis in cancer?

They regulate angiogenic factors like VEGF. Signup and view all the answers

What is the impact of rare genetic variants associated with diseases?

Rare variants tend to have larger effects. Signup and view all the answers

Which statement accurately describes common genetic variants identified in GWAS studies?

They usually have smaller effects with modest odds ratios. Signup and view all the answers

What is a significant limitation of GWAS studies?

They often neglect gene-gene and gene-environment interactions. Signup and view all the answers

What types of mutations lead to cancer development?

Somatic mutations accumulated during a person's life. Signup and view all the answers

Which of the following is an example of a hereditary mutation that increases cancer risk?

BRCA1 Signup and view all the answers

How does cancer genomics approach the study of cancer?

Examines the overall molecular makeup of the tumor ecosystem. Signup and view all the answers

Why is there a missing heritability problem in genetic studies of diseases?

Rare variants with larger effects are often overlooked. Signup and view all the answers

What is a critical focus for cancer genomics research?

Understanding somatic mutations and their role in tumor biology. Signup and view all the answers

What is the first step in the development of colorectal cancer (CRC)?

Global hypomethylation Signup and view all the answers

CIMP-high (CIMP-H) colorectal cancers are significantly associated with which of the following?

Proximal colon location and poor differentiation Signup and view all the answers

What is the role of TET genes in cancer?

They impair 5mC oxidation Signup and view all the answers

Which of the following is associated with an increase in genomic instability in cancer?

Global hypomethylation Signup and view all the answers

How does TET1 function as a tumor suppressor in colorectal cancer?

By decreasing levels of 5hmC in primary colon cancers Signup and view all the answers

Which of the following statements regarding 5fC and 5caC is correct?

They are present at very low levels in mammalian genomes. Signup and view all the answers

Which methylation phenotype is categorized by a significant number of colorectal cancers and is linked to specific mutations?

CIMP-high Signup and view all the answers

What is the primary effect of TET mutations in solid tumors?

Markedly reduced levels of 5hmC Signup and view all the answers

What role does miR-34a play in the regulation of p53 activity?

It represses SIRT1, increasing p53 activity. Signup and view all the answers

Which lncRNA is known to enhance p53 stability by suppressing MDM2 expression?

MEG3 Signup and view all the answers

What is the function of Circ-FOXO3 in relation to p53?

It serves as a tumor suppressor by interacting with p53. Signup and view all the answers

How does lncRNA HOTAIR contribute to cancer progression?

By interacting with PRC2 and LSD1 to silence genes. Signup and view all the answers

Which of the following lncRNAs is involved in suppressing p53-mediated apoptosis?

MALAT1 Signup and view all the answers

What effect does lncRNA EPIC1 have in cancer due to its interaction with MYC?

It enhances MYC-MAX binding to DNA. Signup and view all the answers

Which lncRNA is directly regulated by p53 and inhibits genes involved in cell proliferation?

LincRNA-p21 Signup and view all the answers

What mechanism does lncRNA HOTAIR use to induce epithelial-to-mesenchymal transition (EMT)?

By suppressing HNF4α expression with SNAIL recruitment. Signup and view all the answers

Study Notes

Introduction to Computational Cancer Genomic

Personalized/Precision Medicine aims to discover genetic mechanisms, risk factors for diseases (like inherited conditions, cancer, and autoimmune disorders), and provide DNA-based predictions of future diseases.
It uses precision diagnostics to classify existing conditions and tailoring treatments to individual genetic profiles.
Genomic insights enhance drug efficacy and specificity.

Genetic Penetrance

Definition: The proportion of individuals with a specific genetic variant (genotype) who exhibit the associated trait or condition (phenotype).
High penetrance: The genetic variant almost always leads to the condition.
Low penetrance: Other factors (environment, additional genes) are more significant in manifesting the condition.

Challenges for Risk Prediction

Low impact of individual variants. Most common complex traits have minimal effect.
Difficulty with complex trait prediction. Combining multiple variants for risk prediction remains challenging.
Missing heritability. Large portions of heritability (the ability to inherit traits) remain unexplained by known genetic factors.

How Are Genetic Variants Discovered?

Genome-Wide Association Studies (GWAS). Compares genetic variants across large populations to identify statistical associations with traits; requires thousands to millions of participants to detect small effect sizes and results visualized as a Manhattan plot.
Family-based studies and linkage analysis. Focuses on identifying genetic variants shared among affected family members.

Cancer

Cancer is understood as a complex disease, moving from cancer cells to understanding the ecosystem of the tumor.
Cancer genomics has shifted toward an understanding of the entire tumor ecosystem.
Cancer is strongly technologically driven, leveraging wet lab and computational analyses.

Somatic Mutations

Cancer arises from acquired mutations in cells during a lifetime. These mutations drive uncontrolled cell growth and survival.
They are not heritable (not passed on from parents to offspring).
Occur in somatic cells, not germline cells, unlike genetic diseases.

Cancer Susceptibility Genes

Some hereditary mutations (e.g., BRCA1, BRCA2) increase cancer risk.
These predispositions interact with somatic mutations to initiate cancer.
Cancer genomics focuses on understanding somatic mutations and their role in tumor biology and identifying actionable targets for therapy.

Cancer Cells Accumulate Mutations Over Time

Mutation burden varies by cancer type, exposure, age of onset, and DNA repair ability.

Identify Genomic Alterations: Variant Calling Algorithms

General DNA Sequencing Workflow: Includes genomic DNA or RNA acquisition, DNA fragment library preparation, sequencing, and computational analysis.

Basecalling

Prediction of DNA sequence from images. Output (result) format is FASTQ.

Reference Mapping

Mapping reads to a reference genome to identify variants. Output in FASTA format.
Reference genomes are maintained by the Genome Reference Consortium (GRC).
70% of the reference genome is derived from a male subject in Buffalo, New York.
Reference version: GRCh38 (2013), later improved to hg38 with alternative configurations for highly polymorphic regions like HLA genes.

What Is a Mutation?

In NGS, a mutation is a position where we detect a non-reference allele, always relative to the reference genome.
This might not necessarily be unusual since the reference allele may be extremely rare or not match the ethnicity of the samples.

Types of Variants

Single Nucleotide Variants/Substitutions (SNVs).
Short Insertions/Deletions (indels).
Short Tandem Repeats (STRs).
Structural variants (SV). Copy number variants (CNVs).

Germline Variants

For Europeans relative to reference genomes, there are about 3-4 million single nucleotide variants, 1.2 million homozygous variants, 500,000 short insertions/deletions, 22,000 coding variants (10,000 non-synonymous, 200 loss-of-function variants), and thousands of structural variations (5-100,000 bp).

Somatic Variants

Rare, estimated at one per megabase.
Exome (50Mb): ~50 somatic mutations.
Genome (3Gb): ~3,000 somatic mutations.

Cancer Genomes Have Specific Properties

Tumor DNA is often contaminated with non-cancerous DNA.
Cancer is often a mosaic of different genetically distinct cellular populations.
Genomic instability distorts expected allelic distributions (copy number changes, loss of heterozygosity, and genomic rearrangements).

Non-Coding RNA in Cancer

Overview of Human Genome Transcription: 75% of the human genome is transcribed into RNA, and 3% is protein-coding mRNA.
Non-coding RNAs (ncRNAs) are RNA molecules that do not code proteins and are categorized by length (long vs. short), shape (linear/circular), and location (cytoplasmic, nuclear, or mitochondrial).
Major types include microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and long non-coding RNAs (lncRNAs), playing regulatory roles in cancer (gene expression, chromatin remodeling, proliferation).

Statistical Issues in Cancer Sequencing

When sequencing tumors, one in every thousand found variants might be actually a false positive due to limited sensitivity of detection processes, from matched germline DNA.

Copy Number Variations (CNVs) and Cancer

Classifications of copy number alteration include single copy gain, diploid, homozygous amplification, heterozygous deletion, copy neutral loss-of-heterozygosity.

Read Pair Orientation and Structural Variants (SVS)

One read on the forward strand, one on the reverse strand.
Fragment size determined by library preparation.
Concordant pairs match expectation for orientation and distance, while discordant pairs indicate structural variation.

VCF Format for Variant Calling

Metadata and precise variant definition in tab-delimited fields. Tools for managing and converting include BCFtools, R's VariantAnnotation package.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

Test your knowledge on the fundamental concepts of genetics, tumor sequencing, and the mechanisms of cancer development. This quiz covers important topics such as variant calling, tumor suppressor genes, and microRNAs. A great way to assess your understanding of molecular genetics and oncology.