FOM-7 Biochemistry: GI Cancer Aspects

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Questions and Answers

Which signaling pathway is NOT listed as commonly altered in gastrointestinal cancers?

Wnt/β-catenin/FZD signaling pathway

EPH/Ephrin signaling Pathway (correct)

TGF-β signaling pathway

IGF/IGFR signaling pathway

A mutation in which gene is most closely associated with Familial Adenomatous Polyposis (FAP)?

KIT

SMAD4

MLH1

APC (correct)

Which of the following is a characteristic of Gastrointestinal Stromal Tumors (GIST)?

They are primarily associated with the mismatch repair pathway.

They arise from mesenchymal pacemaker cells lining the GI tract. (correct)

They originate from epithelial cells of the GI tract.

They are commonly diagnosed in children and adolescents.

Which gene mutation is associated with a FAP type that also involves tumors in other body locations, as well as brain tumors?

MLH1 Signup and view all the answers

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is characterized by mutations in genes associated with what process?

Mismatch repair Signup and view all the answers

A projecting growth of tissue from a mucous membrane is known as a:

Polyp Signup and view all the answers

Which of the following signaling pathways is associated with esophageal cancer, but not specifically with pancreatic cancer, according to the text?

VEGF signaling pathway Signup and view all the answers

Which mutation is linked with FAP cases that involve multiple tumors at other body locations?

STK11 Signup and view all the answers

What is the primary effect of a mutation in the APC gene on β-catenin?

It inhibits the phosphorylation of β-catenin, leading to its accumulation. Signup and view all the answers

In Familial Adenomatous Polyposis (FAP), what is the typical outcome of increased β-catenin accumulation?

Increased cell proliferation and polyp formation Signup and view all the answers

What is the typical inheritance pattern of Familial Adenomatous Polyposis (FAP)?

Autosomal dominant Signup and view all the answers

At what age does polyposis typically begin to appear in FAP patients?

Adolescence (mid teens) Signup and view all the answers

How many polyps are characteristically present in patients with Familial Adenomatous Polyposis (FAP)?

More than 100 polyps,potentially in the thousands. Signup and view all the answers

If left untreated, what is a high risk consequence of the polyps associated with FAP?

The polyps have a high potential of becoming cancerous in the 40s. Signup and view all the answers

What is the primary function of the MYH gene in relation to DNA?

It encodes an enzyme that prevents G:C to T:A transversion. Signup and view all the answers

What is the typical role of 8-Oxoguanine glycosylase (OGG1) in DNA maintenance?

It eliminates and replaces oxidized guanine with guanine. Signup and view all the answers

Which of the following best describes the role of Wnt signaling in cancer development?

Its aberrant activation promotes cancer stem cell renewal, proliferation, and metastasis. Signup and view all the answers

What is the primary function of the tumor suppressor genes APC and Axin in relation to Wnt signaling?

They control Wnt signaling, preventing over activation. Signup and view all the answers

How does the interaction of Wnt signaling with Notch signaling affect colorectal cancer?

It plays a role in the pathogenesis of colorectal cancer. Signup and view all the answers

What is the dual role of TGF-β in cancer?

It acts as both a tumor suppressor and a tumor promoter. Signup and view all the answers

What role does TGF-β-induced epithelial-to-mesenchymal transition (EMT) play in chemotherapy resistance?

It contributes to a chemoresistant phenotype of tumor cells. Signup and view all the answers

Which of the following gene mutations related to TGF-β signaling is associated with colorectal cancers exhibiting microsatellite instability?

TGFBR2 mutations. Signup and view all the answers

What happens when there's a loss-of-function mutation in SMAD4 or BMPs?

It promotes tumor progression. Signup and view all the answers

How does activated Wnt signaling contribute to tumor development?

By initiating epithelial-to-mesenchymal transition (EMT). Signup and view all the answers

What is the inheritance pattern of MYH mutations?

Autosomal recessive Signup and view all the answers

In the context of Familial Adenomatous Polyposis (FAP), what percentage of classical cases are attributed to MYH mutations when an APC mutation is absent?

10%-20% Signup and view all the answers

What is the typical presentation of Attenuated FAP (AFAP) associated with MYH mutations?

20 to 100 polyps with colorectal cancer onset around 50-55 years. Signup and view all the answers

Besides colorectal cancer, what other type of cancer has an increased risk associated with MYH mutations?

Thyroid cancer Signup and view all the answers

What specific DNA base transversion is associated with mutated MUTYH?

G:C to T:A. Signup and view all the answers

Which of the following describes the typical sequence of mutations in the pathogenesis of FAP to colorectal cancer?

APC, K-Ras, then p53. Signup and view all the answers

Which of the following is a characteristic of Hereditary Nonpolyposis Colon Cancer (HNPCC) or Lynch Syndrome?

Mutation in DNA mismatch repair genes. Signup and view all the answers

What is the role of COX-2 in relation to colon cancer?

Its overexpression is associated with increased incidence of colon cancer Signup and view all the answers

What is the primary function of G-protein coupled receptors (GPCRs)?

To mediate cellular responses to hormones and neurotransmitters. Signup and view all the answers

Which of the following best describes the role of COX enzymes in the context of cancer?

They promote angiogenesis, inflammation, and carcinogenesis. Signup and view all the answers

What is a common consequence of mutations in GPCRs?

Aberrant downstream signaling regulating cell survival. Signup and view all the answers

What is the primary effect of increased COX-2 activity on β-catenin levels?

It increases β-catenin levels through activation of the EP2 receptor. Signup and view all the answers

Which of the following is NOT an example of a GPCR involved in gastrointestinal (GI) cancers?

Insulin receptors. Signup and view all the answers

How do receptor tyrosine kinases (RTKs) regulate cellular function?

By binding to growth factors which initiate signaling pathways. Signup and view all the answers

How do NSAIDs and COX-2 inhibitors affect cancer incidence?

They decrease cancer incidence by inhibiting prostaglandin production. Signup and view all the answers

What is the direct product of arachidonic acid conversion by COX-1 or COX-2?

Prostaglandin G2 (PGG2) Signup and view all the answers

What is the role of the KRAS gene in cellular function?

It encodes a protein within the RAS/MAPK pathway that regulates cell division. Signup and view all the answers

How does mutation in the RAS oncogene contribute to carcinogenesis?

By increasing cell cycle progression and survival of cancer cells. Signup and view all the answers

Which of the following is NOT a typical role of arachidonic acid in the context of cancer?

Acting as an anti-tumor agent in cells with high fatty acid synthase levels. Signup and view all the answers

Which cellular processes are regulated by both GPCRs and RTKs?

Cell proliferation, survival, growth, and metabolism. Signup and view all the answers

In which phase of the cell cycle would you expect Ki67 expression to be low or absent?

G0 phase Signup and view all the answers

What is a primary difference between the signaling mechanisms of GPCRs and RTKs?

GPCRs respond to hormones and neurotransmitters, whiles RTKs respond to growth factors. Signup and view all the answers

Why is the combination of multiple tumor markers considered better for predictive consideration?

Because each marker provides unique information, boosting the accuracy and specificity of predictions. Signup and view all the answers

Which of the following genetic variations requires screening via genetic testing for patients and family members?

A variant of APC, MutYH, or DNA mismatch repair genes Signup and view all the answers

Study Notes

FOM-7 Biochemistry - Molecular Aspects of GI Cancer

Date: January 14, 2025
Lecturer: Vikrant Rai, MBBS, PhD
Contact: [email protected]
Course: FOM7 Biochemistry
Topic: Molecular Aspects of GI Cancer
Discussion Forum: Elentra forum for FOM7 biochemistry

Learning Objectives

Describe the role of mutations in GI cancers.
Describe molecular pathways associated with GI cancers.
Describe molecular pathways associated with major susceptibility genes:
- APC
- MYH
- KIT
- WNT
- Mismatch repair genes
Describe molecular pathways involved in familial adenomatous polyposis (FAP) and Lynch syndrome.
Recognize clinical symptoms (or presentation) of FAP and stromal tumors and describe the molecular mechanisms underlying the disease.
Recognize clinical symptoms (or presentation) of Lynch syndrome, including family history of relevant cancers, and describe the molecular mechanisms underlying the disease.

Gastrointestinal Cancer

GI cancers account for 26% of global cancer incidence and 35% of cancer-related deaths.
Cancers include those of the esophagus, stomach, gall bladder, bile duct, liver, pancreas, small intestine, and large intestine.
Incidence and mortality data provided in the presentation.

Mutation in Gastrointestinal Cancer

Mutations in genes (specific mutant genes) result in activation or inactivation of gene function.
This results in signaling aberrations in tumor cells.
Oncogenes: Activating mutations enhance cell proliferation via transcriptional activation
Tumor suppressor genes (TSGs): Inhibition due to mutation causes uninterrupted cell proliferation
DNA repair genes: Inactivating mutations increase chromosomal instability and cell proliferation

Molecular Pathways Altered in Cancer

G-protein coupled receptor (GPCR)
Receptor tyrosine kinase (RTKs)
Mitogen-activated protein (MAP) kinase pathway
Notch receptor pathway
Wnt (wingless-related integration) pathway
Sonic hedgehog (SHH) pathway
Transforming growth factor-β (TGF-β) pathway
All these pathways regulate cell cycle, proliferation, growth, migration, and metabolism. Mutations in signaling pathways result in uncontrolled proliferation and prolonged survival.

DNA Repair Pathways

Direct reversal pathway
Mismatch repair pathway
Base excision repair pathway
Nucleotide excision repair pathway
Homologous recombination pathway
Non-homologous end joining (NHEJ) pathway
These pathways are active throughout the cell cycle, regulating and mediating the repair of endogenous or exogenous DNA damage.

Molecular Pathways Altered in GI Cancer (specific cancers)

Specific pathways and associated PMIDs for Gastric cancer, Colorectal cancer, and Liver cancer are detailed.
Additional cancers like Esophageal cancer and Pancreatic cancer also have specific pathways listed.

Polyps

Polyps are precursors to colon cancer.
A polyp is a projecting growth of tissue usually from a mucous membrane.

Gastrointestinal Syndromes

Classification of syndromes associated with polyps (e.g., FAP, Gardner's syndrome, Turcot's syndrome, MYH-associated polyposis, Nonpolyposis syndrome...).
Syndromes associated with multiple tumors and genetic mutations (e.g., Peutz-Jeghers syndrome...).

Genes/Pathways and GI Cancers

Gastrointestinal stromal tumors (GIST)
Family adenomatous polyposis (APC, MYH associated)
Hereditary nonpolyposis colon cancer (Lynch syndrome)
Details of the specific genes and pathways associated with colorectal cancer.

Gastrointestinal stromal tumors (GIST): KIT mutation

The presentation discusses GISTs, KIT mutations, symptoms, and familial GISTs.

Summary of Oncogenic Signaling Pathways

Key signaling pathways (WNT, EGFR, TGF-β) which play a role in tumor development, progression, invasion, and metastasis.
Oncogenic mutations in these pathways are detailed.

Summary

Summary of the key takeaways about mutations in GI cancer.

Supplementary Material

Differentiation between FAP and HNPCC and their various characteristics.

Cell Cycle

Diagram of the cell cycle with detailed explanations for each phase.

Notch signaling

The role of Notch signaling in regulating intestinal epithelium and initiating colorectal cancer.
Note the effects on goblet cell differentiation, Epithelial to Mesenchymal Transition (EMT) and its function on promoting invasiveness and metastasis.

Wnt signaling

Description of the Wnt signaling pathway and its role in colorectal cancer, including aberrant Wnt/β-catenin signaling.

Transforming Growth Factor-β (TGF-β)

TGF-β is a cytokine with dual roles as a tumor suppressor and promoter.
Role of the TGF-β pathway in tumorigenesis, migration, and EMT.

G-Protein Coupled Receptor (GPCR) Signaling Pathways

Description of GPCRs, their roles in GI cancers, and how mutations in related pathways influence cancer development.

Receptor Tyrosine Kinases (RTKs)

RTKs and their role in regulating cell function.
Signaling pathways and aberrant signaling associated with tumor development within various RTKs, including FGFR, EGFR, MET, VEGFR. Importance of their use in cancer therapy.

RAS signaling

KRAS, a protein in the MAPK pathway, and its role in cell division, growth, and cancer development.

MAP kinases (ERK, JNK1/2, p38)

Description of the role of MAP kinases in various cellular responses (e.g., proliferation).

Sonic Hedgehog (SHH) Signaling Pathway

Importance of SHH pathway components (PTCH1, SMO, SUFU, GLI) in regulating cell proliferation, survival, and differentiation, and how mutation in this pathway results in carcinogenesis

Other (Relevant Topics/Information)

Genetic testing and tumor markers (e.g., CA-125, CEA, CA-19-9, Ki67).
Importance of genetic counseling before genetic testing.

Studying That Suits You

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Description

This quiz covers the molecular aspects of gastrointestinal (GI) cancers, focusing on mutations, pathways, and susceptibility genes associated with various syndromes such as familial adenomatous polyposis (FAP) and Lynch syndrome. Assess your understanding of the clinical symptoms and underlying molecular mechanisms that contribute to these diseases.