Somatic Mutations- Endogenous Mistakes in Replication

Genetic Basis of Cancer PPT 5

What are somatic mutations?

Mutations that arise after birth, only in certain cells (not inherited)

How do somatic mutations arise?

From errors in DNA replication over time or environmental exposure (carcinogens)

Are somatic mutations found in all cells?

No, only in certain cells (e.g., cancer cells)

What are germline mutations?

Mutations inherited from germ cells (egg/sperm), present in all cells since birth

Give examples of germline mutations/diseases.

Cystic fibrosis, sickle cell disease, BRCA variants

How does the prevalence of somatic mutations vary across human cancer types?

Mutation number increases with environmental carcinogen exposure

What are mutational signatures?

Patterns of base substitutions that are common and characteristic of certain exposures or processes

What are endogenous error mutations?

Mutations that occur during DNA replication due to proofreading or repair errors

What enzyme activity corrects DNA replication errors in real time?

Exonuclease activity (proofreading)

Is proofreading 100% effective?

No, some errors persist

What does the “Bad Luck Theory” state?

More stem cell divisions = higher cancer risk in that tissue

What is the correlation between stem cell divisions and cancer risk across tissues?

~0.80 correlation (strong)

How many mutations occur every time a human stem cell divides?

About 3 mutations

Can random replication errors be prevented?

No, they cannot

What is the role of “secondary prevention” in cancer risk?

Early detection and biomarker monitoring

What is the median age for cancer diagnosis?

64–66 years

Why does cancer risk decrease after age 90?

Stem cell division rates decrease with age

Which tissues have the largest number of somatic mutations?

Skin, esophagus, and lung

How does age affect somatic mutation rates in normal tissue?

Mutation rates increase with age

What types of mutations are found in normal tissue?

Driver mutations in common oncogenes and tumor suppressor genes

What is the goal of the SMaHT Network?

To catalog somatic genetic variation in normal tissues

How many tissues and donors will be sampled?

10-15 tissues from ~150 post-mortem donors

What types of tissues will be included?

Brain, blood, skin, muscle, colon, spleen, uterus, vas deferens, ovaries, testis, etc.

Why is diverse representation important in the SMaHT Network?

To capture variation across ancestries and life stages.

What is the broader impact of the SMaHT Network?

Understanding somatic mosaicism, aging, undiagnosed diseases, and cancer; supports the Cancer Moonshot initiative

What are “jumping genes”?

Transposable elements that can move within the genome and contribute to somatic mutations

What is microchimerism?

Presence of a small number of genetically distinct cells from another individual

What is fetal microchimerism (FMC)?

Fetal cells persisting in the mother after pregnancy

How is FMC linked to cancer?

Mixed findings:

• Fewer FMCs in breast cancer & lymphoma.

• Higher FMCs in colorectal cancer.

• FMCs associated with ↑ survival in glioblastoma.

• FMCs more common in high-grade breast carcinomas

is the role of FMC in cancer protective or harmful?

Unclear- may be both; research is ongoing

How common is cancer in children compared to adults?

Cancer is rare in children compared to adults

How do mutation rates in childhood cancers compare to adult cancers?

Childhood cancers have lower mutation rates

Are the same genes mutated in childhood and adult cancers?

No, different genes are mutated in childhood cancers

What tissue types do adult cancers usually arise from?

Mostly epithelial tissues

What tissue lineages do childhood cancers usually arise from?

Mesodermal and ectodermal lineages

What typically drives adult cancers?

Many somatic mutations accumulated over time

What typically drives childhood cancers?

Often a single somatic variant

What does the “maturation block” in childhood cancers mean?

Cells are stuck in a stem-cell- like state, unable to differentiate into the final mature cell type

Are most childhood cancers unique to children?

Yes, they often involve cells of origin not present in mature tissues

What phenotype do childhood cancer cells exhibit?

“Arrested development” (stem-cell-like)

What is a therapeutic strategy for childhood cancers with blocked differentiation?

Target proteins/pathways to push cells to differentiate