Genetics of Adult Lung Cancer

Frederic J. Kaye, M.D.

Genetics Branch, CCR, NCI andNational Naval Medical Center

Types of Neuroendocrine Lung Tumors

• Small cell lung cancer (SCLC)/RB gene inactivation• Pulmonary carcinoid• Non-SCLC with neuroendocrine phenotype• Primary undifferentiated cancer (mediastinal/thymic/lung)• Primitive neuroectodermal tumors

• Extrapulmonary SCLC• Merkel cell tumor

• Retinoblastoma• MEN1/MEN2-like: pituitary, MTC, islet cell, pheochromocytoma

? SCLC-related non-lung tumors

Types of non-Neuroendocrine Lung Tumors

AdenoCa, Squamous cell, Large cell,Undifferentiated Ca, BAC

• Non-SCLC

• Mesothelioma

• Sarcoma (chondro-, angio-, etc)

• Mucoepidermoid

• Pleuro-pulmonary blastoma

RB Tumor Suppressor Product

Cell Cycle ArrestRepress transcription (E2F) p105 hypophosphorylated RB

Cellular DifferentiationCo-activate transcription (MyoD)p105 hypophosphorylated RB

Apoptosis p100cl RB

RB functions as a tumor suppressor gene in lung cancer

>90% of neuroendocrine SCLC express mutant or absent RB protein

10% of non-SCLC express mutant or absent RB protein

all mutations analyzed inactivate the RB binding pocket domain

ectopic expression of RB reverses tumorigenicity in vivo

RB/p16/cdk pathway

RB

RBphospho

cell cycle arrest

cell proliferation

CDK:cyclin activation

p16

Inactivation of Only One Componentin the Pathway is Required for Tumorigenesis

SCLC Non-SCLC

RB inactivationp16 inactivationp53 mutationK-ras mutationTelomerase activationMyc over-expressionPTEN mutationsChr 3p allele lossAbsent FHIT proteinElevated BCL2ErbB1/EGFRErbB2/neuEpigenetic silencing of many genes of ? significance

90% 10%5-10% 75%90-100% 50-70%0% 30%90-100% 75%30% 10%10-20% 0-5%100% 70-100%50% 75%80% 10-30%20-40% 20-40%<5% 20-30%

Genetic Alterations in Lung Cancer

SCLC non-SCLCgene

p14/Arf

p53

Ras

p16 Myc

RB

Cdk:Cyclin

PTENErbB

arrestapoptosissenescencecell cycle terminal

differentiation

chromosomalinstability

telomeraseactivation

Phosphatase genes

?? role

Genetic events in lung cancer

Autocrine/Paracrine

Mismatch repair

FHIT

Other 3p genes

Bcl2 activation

SV40 Tag

C-Kit gene

many others

Conclusions

• Extrapolation of adult lung tumors to selected pediatric tumors requires consideration of:

i) cell biology featuresii) genetic featuresiii) molecular pathways targeted by the treatment

• This will require a case-by-case evaluation which may vary depending on the specific treatment

• Since our understanding of molecular pathways is still incomplete, empirical approaches may also have value