Chronic Lupus Erythematosus (aka discoid LE)

Discoid Lupus – much more skin limitied. Very rarely progresses to systemic disease. See post-inflammatory hypopigmentation.

Above: Mucin production – collagen

bundles here are separated by mucin. Test q: Histologic features of Lupus Erythematosus include: interface vacuoles and focal epidermal atrophy Interface Dermatitis w/lichenoid (band-like) inflammation Lichen Planus • Chronic but self-limiting disease • Multiple, symmetric lesions on extremities (especially wrists) • Pruritic, purple, polygonal papules • Oral mucosal involvement common (see right)

– oral lesions have lacy, white pattern. • Dense band-like lymphocytic infiltrate hugs epidermis • Epidermal changes:

– Hyperkeratosis – Wedge-shaped hypergranulosis

• “Saw-toothed” basal layer • Thickening of granular layer • Individual necrotic keratinocytes (circled) Test q: A 40y/o woman goes to her dentist who notes that she has 0.2 to 1.5cm scattered, white, reticulated areas on the buccal mucosa. The woman says that these lesions have been present for one year. She also has some 0.3-cm purple, pruritic papules on each elbow. A biopsy specimen of a skin lesion shows a bandlike infiltrate of lymphocytes at the dermal-epidermal junction as well as degeneration of basal keratinocytes. The most likely diagnosis is: Lichen planus.

Figure: Damage to basal layer of epidermis – can see vacuoles within basal keratinocytes as a result of damage. Can see dramatically thickened basement membrane here.

Perivascular lymphocytes

Above: Lichen Planus – Interface dermatitis, so damage to the basal layer of keratinocytes – due to attack by lymphocytes. Circle – necrotic keratinocytes. See band-like infiltrate of lymphocytes. Thickening of epidermis – increase in granular layer.

Bullous Dermatosis: • Bullae and vesicles are primary clinical manifestations • Bullae = large blisters; vesicles = tiny blisters • Diagnostic categories based on level of split in epidermis

– Subcorneal (beneath SC), intraepidermal or subepidermal • Diseases caused by Ig deposition i.e. autoimmune diseases Pemphigus Vulgaris: • Presents in the 4th-6th decades, M=F • Autoimmune blistering disease

– IgG against desmoglein 3 in desmosomes – Desmosomes hold epithelial cells together – loss of cell

adhesion within the epidermis • Test q: In pemphigus vulgaris, IgG autoantibodies are directed against:

Desmosomes REPEATED x2 • Variants: pemphigus vegetans and foliaceus • Flaccid, fragile bullae • Oral mucosa involvement (typically ruptures before you see it clinically)

Above: In the base of the blister is one layer of the Above: Pemphigus Vulgaris Immunofluoresence epidermis. The rest makes up the roof of the blister. Bullous Pemphigoid: • Generally affects elderly patients • Bullae on extremities, intertriginous areas, abdomen and oral mucosa (1/3 pts) • Autoimmune disease

• IgG against hemidesmosome proteins • Hemidesmosomes bind epidermis to basement membrane

• Subepidermal blistering process – blisters have more strength because of more material in the roof. Blisters are tense and stay intact longer (as compared to fragile blisters of PV, described above). • Tense bullae

Pemphigus vulgaris. • Intraepidermal, suprabasilar blister with “tombstone” basal layer • Mixed dermal inflammatory infiltrate, often with eosinophils • Intraepidermal: looks like this blister is under the whole epidermis, but note the one layer of cells left underneath. The rest makes up the roof of the blister.

Above: Bullous Pemphigoid. Subepidermal Above: Blister contains edema Bullous Pemphigoid: Immunofluorescence. blister without “tombstones” or acantholysis. fluid and eosinophils. IgG bound to hemidesmosome – located in No epidermis in the base of the blister. basement membrane. Dermatitis Herpetiformis • Vesicular dermatosis not bullous • 3rd and 4th decades, M>F • Pruritic, burning vesicles, especially on extensor surfaces of extremities • Strongly associated with celiac disease – everyone w/DH either has Celiac disease or sub-clinical Celiac disease. • Responds to gluten free diet (like celiac) • IgA deposited in dermal papillae of skin

Incredibly itchy – patients will scratch blisters DH Histologic Features- Subepidermal vesicles Neutrophilic microabscess before you ever see them in clinic.

DH Immunofluorescence. IgA deposits recruit in neutrophils.

Infections and Infestations: Dermatophytosis: • AKA: Tinea (capitis – scalp, corporis – body, barbae – beard area, cruris – groin, pedis – foot), “ringworm” • Dermatophytes infect outer keratin layer of skin

Test q: A 35y/o female presents w/small vesicles on extremeties. The rash is extremely pruritic. She also has been diagnosed w/celiac disease. Diagnosis: Dermatitis herpetiformis REPEATED x2 Test q: A person w/dermatitis herpetiformis should avoid what food substance: gluten. Test q: A 35y/o man has had an outbreak of pruritic lesions over the extensor surface of the elbows and knees during the past month/ He has a history of malabsorption that requires him to eat a special diet, but he has had no previous skin problems. On phys exam, the lesions are 0.4-0.7cm vesicles. A 3mm punch biopsy of one of the lesions over the elbow is performed. Microscopic exam of the biopsy specimen shows accumulation of neutrophils at the tips of dermal papillae and formation of small blisters due to separation at the dermo-epidermal junction. Immunofluorescence studies performed on this specimen show granular deposits of IgA localized to tips of dermal papillae. Lab studies show serum anti-gliadin antibodies. Which of the following is the most likely diagnosis? Dermatitis herpetiformis. Test q: Neutrophilic microabscesses and fluffy IgA deposits on basement membrane anchoring febrils are characteristic of: Dermatitis herpetiformis.

Dermatophytosis

Above: Tinea corporis – expanding, annular, erythematous plaque w/elevated, scaly border. Annular because dermatophytes start in a small area and grow outwards = ring. Dermatophyte Infection: Histologic Features: • Hyperkeratosis • Parakeratosis • Neutrophils in keratin • Hyphae in keratin

• Difficult to see on H&E • Organisms grow in the stratum corneum – do not go down into epidermis at all. Test q: Neutrophils in the stratum corneum are a common feature in: Psoriasis and dermatophytosis. Test q: A 25y/o male joins a gym and works out regularly. He develops a pruritic rash on his feet which shows white centers w/a red, scaly border. A diagnostic stain would be: PAS stain. Warts (verrucae): • Benign neoplasms caused by human papillomavirus (HPV)

– >60 subtypes – Certain subsets associated w/squamous cell carcinoma

• Common – Common wart (verruca vulgaris) – Plantar/palmar wart - caused by diff HPV subtypes – Genital wart (condyloma acuminatum) – Flat wart

• Occur at any age • Self-limited Verruca Vulgaris: Histologic Features • Histology similar across all the different subtypes. • Papillomatosis – projections of epidermis • Acanthosis – thickening of epidermis • Tortuous vessels within papillae KEY FEATURE = Koilocytes. Have clear area within cytoplasm – due to viral particles present.

PAS stain demonstrating hyphae

Shows fungal hyphae/spores very clearly – but only in s. corneum.

Molluscum Contagiosum: • Common especially in children • Dome-shaped papules with a central keratin-filled crater • Easily spread through contact • DNA poxvirus • Histologic Features: large, bright pink viral inclusions. • Molluscum body: eosinophilic cytoplasmic inclusion in upper layers of epidermis. Test q: A 35y/o man has noted a bump on his upper trunk for the past 6wk. On phys exam, there is a solitary 0.4cm flesh-colored nodule on the upper trunk. The dome-shaped lesion is umbilicated, and a curd-like material can be expressed from the center. This material is smeared on a slide, and Giemsa stain shows many pink, homogenous, cytoplasmic inclusions. The lesion regresses over the next 2mo. Which of the following infectious agents most likely produced this lesion? Molluscum contagiosum Impetigo: • Common superficial infection • Staphylococcus or streptococcus • Exposed surfaces • Characteristic honey-colored crust • Histologic Feature: Subcorneal pustule • A lot of neutrophils in the stratum corneum – can see gram positive cocci here. Infestations: Scabies (Sarcoptes scabiei)

Above: The scabies mite. Scabies feces. Linear burrows. Scabies like to burrow underneath the stratum corneum. Find them on the penis and web spaces of the fingers.

Figure: Scabies organism underneath the stratum corneum.

Scabies feces underneath?

Herpesvirus infections: • HSV-1

– Cold sores, fever blisters – Oral infection most common – Cutaneous blistering eruption, usually linear

• HSV-2 – Genital herpes

• VZV – varicella zoster – Chicken pox

Figure: Herpes infects keratinocytes – see multinucleated cells (circled one has 10-15 nuclei)

Molecular Basis of Cancer Fri. 09/17/10 Two types of cancer: Heritable cancer (germline mutation) and Sporadic cancer (somatic mutation) Germline / Somatic Mutations:

Basis of Neoplasia: Mutations of: (four major pathways)

• Oncogenes • Tumor suppressor genes • Genes regulating apoptosis • Genes regulating DNA repair

Epigenetic Mechanisms, No Mutations – genes silenced • DNA Methylation (usu on guanine) • Post-translational modification of histones – proteins that wrap

around DNA. PH3, PH2ax are two of the important biomarkers predictive of cancer reoccurring.

Cell Pathway to Malignant Neoplasm: Tumor macrophages – enhance tumor progression

T lymphocytes can promote tumor progression

Sources of Mutation • Environmental Exposure - eg., Asbestos,

Mesothelioma, Aflatoxins, Liver Ca, Chromium, nickel, Lung Ca

• Chemicals - eg., Soot, Scrotum Ca, Azo dyes, Bladder Ca, Chemo Rx, Leukemia

• Irradiation (UV, x-rays, etc.) - eg., Leukemia, Skin Ca • Viruses - eg., Liver Ca, Cervical Ca, Burkitts

Lymphoma

Figure: Germline mutation: born w/one mutated allele and one wild-type allele. During life, you’ll have hits – from viruses, chemicals, other environmental factors – and you will lose the wildtype allele. Called LOH (loss of heterozygosity) uncontrolled proliferation.

Oncogenes • Genes which cause cell transformation • Oncogenes are in our genome • Proto-oncogenes- normal gene which, when mutated or overexpressed, becomes an oncogene • Proto-oncogenes are important for normal growth and development Properties of Oncogenes • Transfection of oncogene into cell culture results in loss of

contact inhibition • Over Expression of oncogene in transgenic mice often

lead to tumor formation Culturing cells in a culture plate: When normal cells hit the edge, they stop dividing. Cell culture plates of oncogenes form hills, valleys, etc. – no loss of contact inhibition.

Figure: If you get an alteration in DNA altered mRNA AA is truncated or shortened non-functioning

protein cell proliferation or blockage of apoptosis Oncogenes • Found in many species • Activated in many cancers • Effect of activation is dominant • Encode a protein involved in signal transduction Mechanisms of Signal Transduction • Involves protein phosphorylation • Kinases

• serine / threonine - most proteins • tyrosine - most growth factors activate signal transduction pathways here

• Phosphatases – involve blockage of dephosphorylation of the turned-on signal

Major Signal Transduction Pathways: Figure: gene overexpressed cell proliferation.

Must hit multiple targets on multiple pathways to enhance treatment/improvement.

Oncoproteins • Components of growth regulatory pathways • Regulate normal cellular proliferation • Growth factors (PDGF-b, FGF, TGFa) • Growth factor receptors (EGF, erbB-2, RET, KIT) • Signal transduction proteins (ras) • Protein kinases (abl) • Nuclear regulatory proteins (myc) • Cyclin and cyclin dependent kinases (Cyclin D) • Apoptosis suppressors (Bcl-2) Oncogenes • Over 100 known • Examples include: sis erbB-2 (HER-2/neu) abl ras myc bcl-2 CdK4 MDM2

Figure: Growth factor stimulates receptor – turns on bridging protein that activates Ras. Ras goes from GDP (inactive state)

to activated GTP, sends signal via MAP kinase pathway to nucleus activates retinoblastoma gene new cell.

Inactivation is blocked in mutant Ras.

Test q: If a protooncogene mutates to an oncogene in an otherwise normal cell, the immediate result would be: a slight quickening of the cell cycle.

Test q: A 70y/o woman reported a 4mo history of a 4kg weight loss and increasing generalized icterus. On phys exam, she is afebrile, and her blood pressure is 130/80mmHg. An abdominal CT shows a 5cm mass in the head of the pancreas. Fine-needle aspiration of the mass is performed. On molecular analysis, the neoplastic cells from the mass show continued activation of cytoplasmic kinases. Which of the following oncogenes is most likely to be involved in this process? RAS (see figure above) Cell Cycle Pathway Cell Cycle with Inhibitors

Figure: Alternative inhibition of proteins that block division. Inhibit G1s checkpoint. Block passage of signals prevents phosphorylation of Rb gene. p57/p27/p21 – block at multiple points.

Mutation of Oncogenes • Point mutation • Chromosomal translocation • Gene amplification* (most important) Oncogenes Activated by Point Mutation • Most extensive in Ras family • Single base substitution in genes • Amino acid changes at positions 12, 13, and 61. • Abnormal activity of guanine nucleotide binding proteins (GTP, GDP) • K ras associated with cancer of lung, colon, and pancreas

Oncogenes Activated by Translocation Common Chromosomal Translocations:

Burkitt Lymphoma: Switch from myc oncogene (goes over to chromosome 14). The 14 Ig gene ends up right above the myc oncogene sends signals to lead to

increased myc protein.

CML: 9:22 translocation. abl goes over to bcr locus – activates tyrosine kinase receptor on outside of cell cascade of protein phosphorylation into the nucleus

proliferation of cells.

Test q: Which of the following malignancies exhibits the chromosomal translocation of cmyc? Chronic Myelogenous Leukemia

Above: Biggest checkpoint is G1s checkpoint. Usually held in check by Rb. If phosphorylated cell division. Have cyclin inhibitors (cyclin d, cdk) – when phosphorylated, the 3 proteins become one and allow phosphorylation of Rb gene. Normally, these 3 are held in check to prevent cell division.

Test q: Which of the following genes is activated by point mutation and is common in lung, colon, and pancreatic carcinomas? Ras. Test q: A child is born w/a single functional copy of a tumor suppressor gene. At the age of 5, the remaining normal allele is lost through mutation. As a result, the ability to control the transition from G1 to S phase in the cell cycle is lost. Which of the following neoplasms is most likely to occur? Retinoblastoma

Chromosome 14/18 translocation: Follicular Lymphoma Solid Tumor Gene Translocation/Fusion:

Test q: Which of the following tumors is associated w/the chromosomal translocation of Bcl-2 (14 to 18)? Follicular lymphoma. REPEATED x3 ETV1 overexpression in prostate cells confers invasiveness. Gene Translocation/gene fusion:

Above: A type of prostate cancer that involves translocation from chromosome 7 to 21. Test q: Which of the following solid tumors has been recently associated w/chromosomal translocation/gene fusion? Prostate.

Amplified Oncogenes in Human Tumors (most common thing that you see) Oncogene Neoplasm • c-myc leukemias, Burkitt’s lymphoma • N-myc neuroblastomas, retinoblastomas, lung

carcinomas • L-myc lung carcinomas • EGF glioblastomas, squamous cell • erbB-2 breast, salivary, and ovarian • RET MEA 2A and B, medullary thyroid Ca • INT-2 breast, bladder, Melanoma • HST breast, bladder, and stomach • ABL chronic myelogenous leukemia • KIT GI stromal tumors( GIST) • WNT hepatocellular Ca • H Ras bladder and kidney carcinoma • K Ras lung, colon, and pancreatic carcinoma • N Ras Melanomas, hematologic malignancies

Above: Chromosome 14/18 translocation occurs when a chromosome goes to divide – the DNA divide – introns are removed, spliced out, and you have a bunch of exons that come together to form new strand. Bcl2 exon on chromosome 18 is abnormally spliced into chromosome 14 follicular lymphoma.

Above: Non small cell lung cancer – involves EGFR (epidermal GF receptor) and Erbb2 receptor – EML-4alk protein waits in the cytosol – fusion protein that activates K-Ras, Raf cell proliferation and prevention of apoptosis

N-myc forming double minutes Br Ca FISH

Early fluorescent in situ hybridization – could visually see in a gene an increased HSR (homogeneous staining region) – increased production of N-myc. Could break off and form small pieces of myc (double minutes). In BrCa RISH figure, can see huge areas of increased staining regions. Can also see small areas of double minutes. Oncogenes - Only one copy (allele) must be mutated for tumor formation - Mutations are dominant Tumor Suppressor Genes (TSG’s) - Genes that are in our genome - Normally, they control cellular growth - Presently 30-40 TSG’s known - Both copies must be knocked out for tumor growth - Mutations are recessive - Ex: p16, p17-18-19 – put brakes on to prevent cells from dividing - Vulnerable sites for DNA damage - Function as barriers against clonal expansion - Hinder growth and metastasis of cells Location of Tumor Suppressor Genes Rb Pathway: - Cell surface (TGFb, cadherins) - Inner plasma membrane (NF1) - Cytoskeleton - Cytosol (APC) - Nucleus (Rb, p53)

Figure: Rb Pathway Familial form – occurs in 35-40%. Spontaneous rate is higher.

If you were born w/one mutant allele, as you go through growth and development, you’ll have a 2nd mutation tumor.

Test q: A child is born w/a single functional copy of a tumor suppressor gene. At the age of 5, the remaining normal allele is lost through mutation. As a result, the ability to control the transition from G1 to S phase in the cell cycle is lost. Which of the following neoplasms is most likely to occur? Retinoblastoma (Other choices: Breast carcinoma, Adenocarcinoma of the colon, Cerebral astrocytoma, or CML) Test q: The tumor suppressor genes Rb and p53 are found in what cellular location? In the nucleus. Test q: The nuclear proteins Rb and p53 are gene products for: Tumor suppressor genes. REPEATED TWICE.

Common Tumor Suppressor Genes: p53 WT-1 RB APC BRCA1 NF-2 NF-1 TGFb

E2F Cell Cycle Pathway

p53 Tumor Suppressor Gene: Mutated in half of all types of cancer Implicated in control of: - Cell cycle pathway - DNA repair and synthesis Test q: Which of the following situations favors tumor angiogenesis? Homozygous deletion of p53. - Cell differentiation - Apoptosis P53 Mutations Leading to Cancer:

Clinical p53 Implications: - Loss of p53 function leads to shortened survival in patients with breast and lung carcinomas - Over expression of p53 is an independent, unfavorable factor

Figure: E2F Cell cycle Pathway E2F also controls cell cycle. Mostly between G1 and S – have inhibitors that block hyperphosphorylation of Rb gene (p15, p16, etc). Also have growth factors constantly stimulating. If hyperphosphorylated, E2F links w/DP1 – leads to transcriptional activation. Phosphorylation prevents division on tumor suppressor side. Br Ca E2F Antibody Staining:

Lot of nuclear staining in the tumor – E2F is localized in the nucleus.

Normally, p53 activates when it’s damaged (virus, radiation, chemicals) – binds to DNA, turns on p21 (tumor suppressor gene) – cell can’t divide (G1 arrest). GADD45 – DNA mismatch repair gene. Repairs cell or pushes it into apoptosis (so it cannot proliferate). Mutant p53 – no DNA repair, no cell cycle arrest proliferation of mutant cells malignant tumor.

P53 Overexpression Prostate Ca: p53 Antibody stain – see in the nucleus.

Hereditary Cancer Syndromes: - Autosomal dominant inheritance - Multiple tumors, multiple organs - Early age of onset of tumors compared to sporadic tumors Hereditary Cancer Syndromes:

• Familial adenomatous polyposis (FAP)-APC • Hereditary nonpolyposis colorectal cancer (HNPCC) • TGFb pathway • Multiple endocrine neoplasia (type 1 and 2) -RET • Neurofibromatosis (type 1 and 2) (NF) • Li-Fraumeni syndrome( p53) • Retinoblastoma (Rb) • Hereditary breast-ovarian cancer (BRCA1) • Wilm's tumor- WT2

Colorectal Cancer - Hereditary non polyposis colorectal cancer (HNPCC) - Familial adenomatous polyposis (FAP) - Sporadic colorectal cancer Familial Adenomatous Polyposis (FAP) - 85% sporadic cases - Chromosomal Instability Specific Genes in the b Catenin/APC (FAP) - APC (LOSS of APC) - K-ras (activation of the oncogene K-ras – the only oncogene that is activated in colon cancer) - DCC (deleted in colon cancer – now SMAD2 and 4) - p53 (loss) B Catenin/APC Pathway in Colorectal Ca

Colorectal Ca Genetic Pathways

Test q: Clinical features of familial adenomatous polyposis (FAP) include which of the following: Loss of APC gene REPEATED x5!!

Test q: Among the genes implicated in colon cancer related to FAP and most cases of sporadic colon cancer, the only known oncogene is: K-ras.

Test q: A 25y/o male is diagnosed w/Familial Adenomatous Polyposis. Which of the following best describes this disease? Inactivation of a suppressor gene

Normally, B catenin and APC link up – when they do, B catenin is broken down and dissolved no proliferation. Mutated or lost APC – B catenin is not broken down goes to nucleus proliferation.

Colon cancer is a progression – Can either have a germline, inherited, or somatic mutation (specifically in the suppressor gene, APC). You lose APC B catenin causes cell to proliferate. Can also have DNA silenced by methylation (usually in guanine). Activation in K-ras leads to carcinoma. There is also loss of additional suppressor genes (DCC, p53).

Hereditary Nonpolyposis Colorectal Cancer - 15% sporadic cases (most go down FAP pathway) - TGFb and SMAD 4 pathway - DNA Mismatch Repair Genes (hMSH2, hMLH1, hPMS1, and hPMS2) - Microsatellite instability Chromosomal instability = breakage of chromosomes. Microsatellite instability = small runs of nucleic acids all throughout DNA. Everyone usually has the same nucleic acid in a row – all adenines, all thymidines, etc. When microsatellites start to become variable instability. Test q: A family history of colon cancer is elicited from a 36y/o male. Based on history, a screening colonoscopy is performed, and the ascending colon is found to contain five polyps from 0.5-2cm in diameter. They are excised and examined microscopically. The 2cm polyp is found to have a focus of adenocarcinoma. Inheritance of which of the following genes is most likely to be involved in the causation of this tumor? DNA mismatch repair Test q: A family history of colon cancer is elicited from a 36y/o male. Based on history, a screening colonoscopy is performed, and the ascending colon is found to contain five polyps from 0.5-2.0cm in diameter. They are excised and examined microscopically. The 2cm polyp is found to have a focus of adenocarcinoma. Inheritance of which of the following genes is most likely to be involved in the causation of this tumor? Inhibitors of apoptosis. Colorectal Ca Genetic Pathways:

Colorectal DNA Mismatch Repair:

Four most common types of errors in MMR: • Left: simple mismatch – adenine linked to guanine (A-G

should not happen). Mismatch repair fixes it.

• Adduct: methylation of a nucleic acid, usually guanine MMR.

• Loop-out: sequence run of a bunch of adenines (common) MMR

• Group of loop-outs: adenine but also guanines too. All are due to mutations in the MMR genes.

Figure: Colorectal Ca Genetic Pathways. DNA is damaged, not repaired correctly mutations. MMR genes are very poorly understood. PMS1, PMS2, MLH1, MSH2 are the big ones. Again – is NOT mutation in one gene – have ~17 mutations in both pathways here for colon cancer.

Clinical Implications in Colorectal Cancer - Definitive clinical tests to diagnose familial forms of FAP and HNPCC – fecal chip test (expensive) - Seven genes--APC in FAP - hMSH2, hMLH1, hPMS1, and hPMS2 in HNPCC are now being tested for germline mutation BRCA1 and BRCA2 - Mutations cause 90% of hereditary Br Ca - Together, both account for only 10% of all breast cancer - These genes not mutated in the majority of sporadic Br Ca BRCA 1 and 2 Gene Mutations BRCA Gene Amino Acid Sequence

There are 12-14 different mutations in BRCA1 and BRCA2. Deletion of 100 amino acids could result in no disease. Deletion of 10 (top) – cancer. So a shortened protein does not necessarily lead to cancer. High Penetrance Mutations - Increase risk of breast cancer as high as eight fold - From 12% for all women to 70-90% for mutation carriers - BRCA1, BRCA2, and p53 are high penetrance mutations Dilemmas of BRCA Testing - Distinguishing true from false negatives - Positive finding may not represent a mutation - Lack of knowledge on which to base management of care - Interpretive problems diminish in high-risk families Clinical Implications in Breast Cancer: BRCA1 and BRCA2 - Both genes responsible for 90% of hereditary breast cancer - Genes play a role in genetic stability - Role in sporadic breast cancer remains uncertain HER-2/Neu - Cell membrane protein - Member of EGF-R family - Transmits signals to the cell nucleus - Over-expressed in some breast, ovarian, and other cancers - 25% of invasive breast carcinomas have increased levels on the neoplastic cell surface HER-2 Receptor Overexpression: Result: a cell membrane receptor that sends a ton of signals to the nucleus for the cell to divide.

Test q: During her yearly physical, a 35y/o woman’s gynocologist notices a mass in her right adnexal area. An ultrasound reveals a mass in her right ovary. The woman’s sister was diagnosed w/breast cancer two years ago. She also has two aunts who were diagnosed w/breast cancer at an early age. Which tumor suppressor gene mutation is responsible for this condition? BRCA2. Test q: A 50y/o woman saw her physician after noticing a mass in the right breast. Physical exam showed a 2cm mass fixed to the underlying tissues and three firm, nontender, lymph nodes palpable in the right axilla. There was no family history of cancer. An excisional breast biopsy was performed, and microscopic exam showed a well-differentiated ductal carcinoma. Over the next 6mo, additional lymph nodes became enlarged, and CT scans showed nodules in the lung, liver and brain. The patient died 9mo after diagnosis. Which of the following molecular abnormalities is most likely to be found in this setting? Amplification of the c-erb B2 (HER2) gene in breast cancer cells REPEATED x5!! (Once, answer was “Amplification of the ERBB2 (HER2) gene”)