Cancer Genetics Flashcards
Describe the following cancer types... Sarcoma Leukemia Lymphoma Carcinoma
Sarcoma- cancer that forms in bone and soft tissues (muscle, fat, blood and lymph vessels, tendons and ligaments)
Leukemia- cancer that begins in the blood forming tissue of the bone marrow
Lymphoma- cancer that begins in the lymphocytes (T and B cells; can be Hodgkins or Non-Hodgkins
Carcinoma- cancer that begins in the epithelial cells that line internal organs (e.g. breast, ovarian, colorectal, prostate, basal cell, renal cell)
Describe the following cancer types... Multiple Myeloma Melanoma Glioma/Glioblastoma Meningioma Astrocytoma
Multiple Myeloma- cancer that begins in the plasma cells (immune cells); abnormal plasma cells build up in the bone marrow and form tumors in bones all throughout the body
Melanoma- cancer that begins in the cells that make pigment (skin melanoma and ocular melanoma)
Glioma- form in the glial cells of the brain/spinal cord (benign); glioblastoma is the malignant form
Meningioma- form in the meninges of the brain
(benign)
Astrocytoma- form in the astrocytes of the brain/spinal cord and are malignant
Describe the following types of tumors…
Germ Cell tumors
Neuroendocrine tumors
Carcinoid tumors
Germ cell tumors- tumors that begin in the cells that give rise to sperm and eggs that can be benign or malignant (e.g. ovarian germ cell tumors vs testicular cancer)
Neuroendocrine tumors- arise in cells that release hormones into the blood; can be benign or malignant (e.g. pancreatic islet cell tumors, medullary thyroid cancer, and pheochromocytomas in adrenal gland or paraganglioma in other locations)
Carcinoid- a type of neuroendocrine tumor that is slow growing and often found in the GI tract that secretes substances like serotonin or prostaglandins which cases carcinoid syndrome
What features are suggestive of hereditary cancer syndromes?
Cancer at earlier than expected ages Cancer in paired organs Multifocal disease (multiple tumors) Rare tumors Multiple close relatives in the same lineage with same or related forms of cancer
What is DCIS?
Ductal Carcinoma in Situ
non-invasive neoplasm of ductal origin (tubes that bring milk from lobules in breast)
May or may not progress to cancer- Comedo type DCIS has a higher chance of becoming invasive- ~30% chance of invasive cancer if left untreated
Treatment options include breast conserving surgery, radiation therapy, with or without tamoxifen
What is LCIS?
Lobular Carcinoma in Situ
pre-malignant lesion that is a marker of breast cancer risk
25-35% risk of invasive breast cancer (not necessarily where you found the LCIS)
subsequent invasive cancers can be ductal (often multi-centric and frequently bilateral)
Treatment options include observation, chemoprevention, or bilateral prophylactic mastectomy
List the risk factors for breast cancer.
aging early menarche (<12 y/o) late menopause (>52) breast density/breast architecture nulliparity (not having children) first child after age 30 estrogen/progesterone use after menopause more than 2-3 alcoholic beverages per week
What are protective factors from breast cancer.
at least for or more hours a week of exercise
breastfeeding
maintaining ideal body weight (especially after menopause- because the more body fat you have the more the fat is converted to hormones via aromatase)
having children prior to the age of 30
What is Borderline Ovarian Cancer?
Ovarian cancer of Low Malignant Potential
comprise 15% of epithelial tumors of the ovary; over 90% survival
less common in BRCA1/2 carriers; BRCA positive patients are more likely to have more aggressive disease
What genes are implicated in increased risk for ovarian cancer?
HBOC- BRCA1, BRCA2, BRIP1, RAD51C, RAD51D
MMR (Lynch Syndrome)- MSH2, MLH1, MSH6, PMS2
What are the risk factors for ovarian cancer?
age post-menopausal hormone replacement therapy infertility nulliparity (not having kids) endometriosis
What factors are protective for ovarian cancer.
oral contraceptives tubal ligation hysterectomy breast feeding pariety (>2 births)
What factors are incorporated into the Gail Model?
age
age at first live birth
age at menarche
number of first degree relatives with breast cancer (MATERNAL side only)
ever had a breast biopsy/number of breast biopsies
presence of atypical hyperplasia
race
What are the limitations of the Gail Model?
Does NOT include... -other cancers (other than breast) -second-degree relatives -paternal history -age at diagnosis in relatives This can lead to underestimation of risk for breast cancer
What are the Claus tables?
family history based breast cancer risk model
looks at age of dx, when FHx is significant
can help determine MRI screens and usually used in insurance
does NOT consider any other risk factors outside fhx and does not always have appropriate risk for every relation (“fudges” using other tables for different relations)
List the most common, high penetrance, AD breast cancer risk conditions/genes?
Hereditary Breast Ovarian Cancer (HBOC)- BRCA1, BRCA2 Li-Fraumeni Syndrome (LFS)- TP53 Cowden Syndrome- PTEN PALB2 Associated Cancer Syndrome- PALB2 Hereditary Diffuse Gastric Cancer- CDH1 Peutz-Jegher Syndrome- STK11
Cancers involving the…
breast (multiple cases of early onset, bilateral, and/or male)
ovaries
prostate (early age, higher Gleason score, metastatic)
pancreas
Melanomas
Hereditary Breast Ovarian Cancer (HBOC)
BRCA1, BRCA2 (function: DNA repair)
High incidence in AJ population with founder mutations (187delAG; 538insC; 617delT)
Note- BRCA1 changes have increased frequency of tumors that are triple negative (ER neg, PR neg, HER2neu neg)
Note- BRCA2 incurs a higher risk of pancreatic cancer than expected (even when compared to individuals with BRCA1 genes)
Cancers involving the... *breast (as early as teens and early 20's)* brain *Adrenocortical tumors (especially in childhood)* Sarcomas (=45) Leukemia *Choroid plexus tumor* Other early onset tumors
Li Fraumeni (LFS)
TP53
7-20% de novo mutations
HIGHLY sensitive to radiation damage (typically recommend total mastectomy rather than lumpectomy + radiation therapy)
Cancers involving the…
thyroid (usually follicular, rarely papillary, NOT medullary; childhood onset/germ cell)
breast
uterine (endometrial)
Trichilemmomas (hair follicle tumors) and papillomatous papules (usually by late 20’s)
Lhermitte-Duclose disease (cerebellar dysplastic gangliocytoma -in brain- presenting typically 30-40’s); may present with hydrocephalus
Macrocephaly
Macular pigmentation of the glans penis
Esophageal glycogenic acanthosis (multiple)
Autism Spectrum Disorder
Fibromas
Lipomas
Hamartomatous intestinal polyps
AVMs or hemangiomas
Cowden Syndrome
PTEN
Cancers involving the…
breast
pancreas
ovaries (unconfirmed)
PALB2 Associated Cancer Syndrome
PALB2
Cancers involving the…
breast
ovaries
pancreas
gastric
small bowel
lung
sex-cord tumors/Sertoli cell tumors
Hamartomatous polyps (multiple - <100- usually stomach to rectum, most commonly in the small intestines/jejunum)
Adenomatous polyps
Mucocutaneous pigmentation (may fade after puberty)
Freckling on lips crossing the vermillion border
Small bowel intussusception, severe abdominal pain, GI bleeding begin at <20 y/o
Peutz-Jegher Syndrome
STK11 (LKB1)
Diagnosed on NCCN clinical criteria (2+ of the following):
-2+ Peutz-Jecher type hamartomatous polyps of the small intestine
-mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia or fingers
-family history of PJS
What is CAPS-5 and who is eligible to participate?
ongoing research study looking at different ways to screen for pancreatic cancer
Inclusion criteria (1+ of the following):
-Hereditary Pancreatitis
- Peutz-Jeghers Syndrome
- Strong family history of pancreatic cancer on one side of the family
- Confirmed germline mutation carrier (BRCA2, CDKN2A, PALB2, BRCA1, HNPCC, PRSS1/2, CTRC) and a family history of pancreatic cancer
What are the recommendations for clinical management/prophylaxes of BRCA Mutation-Positive patients?
Breast screening (start at age 25 y/o)- clinical breast exams (q6 months), self breast exams (q6 months), MRI screening (q12 months)
Breast screening (starting at age 30)- mammograms (q12 months)
Ovarian screening (starting at age 30-35)- CA-125 (q6-12 months), transvaginal US (q6-12 months)
*note that ovarian cancer screening has no evidence of effectiveness
Risk reducing mastectomy
Risk reducing oophorectomy (BRCA1 ideally between 35-40 y/o; BRCA2 ideally between 40-45 y/o) with/without hysterectomy- note that this can reduce breast cancer risk in pre-menopausal women (more for BRCA2 than BRCA1 carriers) but there is still a risk for primary peritoneal carcinoma
Chemoprevention for breast cancer- tamoxifen, raloxifen, aromatase inhibitors (post-menopausal women only)
How is cancer risk in Li-Fraumeni Syndrome managed in adults?
Clinical breast exams (starting at age 20 OR 5-10 years earlier than earliest onset in family) q6 months
Breast MRI with or without mammography (starting at age 20-25) q12 months
Alternating beast MRI AND mammography (starting at age 30-75) q12 months
Consider risk reducing mastectomy
Comprehensive physical exam with high index of suspicion for rare cancers, careful skin and neuro exam
Colonoscopy (starting no later than 25 y/o) q2-3 years
Can offer novel approaches including rapid whole body MRI, abdominal US, and brain MRI
Additional surveillance based on fhx
How is Cowden Syndrome managed?
Clinical breast exams (starting at age 25 or 5-10 years prior to earliest onset) q6 months
Mammogram (starting at age 25) q 12 months
Breast MRI (starting at age 25) q 12 months
Consider risk reducing mastectomy
Consider hysterectomy
Comprehensive physical exam with attention to the thyroid starting at age 18 OR 5 years earlier than earliest cancer case in family
Thyroid US (starting at age 18) q 12 months
Colonoscopy (starting at age 35) q 5-10 years OR more frequently based on symptoms or polyps
Consider dermatology exam q12 months
List examples of PTEN multiple hamartoma syndromes.
Cowden Syndrome (see other flashcard for in-depth) Bannayan-Riley-Ruvacalba- macrocephaly, hamartomatous intestinal polyposis, pigmented macules of glans penis (speckled penis) Proteus Syndrome- connective tissue nevi, asymmetric/disproportionate overgrowth (limbs, hands, feet, skull, vertebrae), lipomas or absence of fat, vascular malformations, facial phenotype/classic dysmorphisms
List the risk factors for colon cancer.
Aging Personal history of colorectal cancer or adenomas Inflammatory bowel disease (Ulcerative colitis- large intestine-, Crohn's disease- small or large intestine, NOT IBS) Family history of colorectal cancer Hereditary colon cancer syndromes Excess alcohol consumption Cigarette smoking Obesity
Multiple colonic polyps and high risk for colon cancer Risk of extracolonic tumors in the... upper GI/duodenum desmoid osteoma (in the jaw) papillary thyroid cancer medulloblastoma (and other brain tumors) hepatoblastoma *Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE; most often bilateral and multiple lesions - >4 highly suggestive)* Supernumerary teeth, epidermoid cysts
Familial Adenomatous Polyposis (FAP) APC gene (chromosome 5q) AD up to 30% de novo most families have a unique mutation DOES have genotype-phenotype correlations
Few colonic adenomas (usually >20 but <100 polyps)
Later onset colorectal cancer (~ age 50)
+/-Upper GI lesions
NO CHRPE
Attenuated Familial Adenomatous Polyposis
APC gene (chromosome 5q)
Associated with mutation in the 5’ and 3’ ends of the gene
How is FAP managed?
Annual colonoscopy on an annual basis (typically more often than that based on polyp findings) starting around age 10-14 y/o until polyposis develops (OR starting at 40 y/o with repeat q5 years in individuals with I1307K AJ founder mutation)
Consideration of colectomy when polyps are no longer manageable with colonoscopy
Annual upper endoscopy
Chemoprevention (Aspirin, Sulindac, others)- can slow growth of polyps/delays need for colectomy
Monitoring for desmoids and other complications
Genetic testing to identify mutation for testing of other family members
Usually at least 15 polyps (typically adenomatous, may be few hyperplastic), but fewer than 100’s of colonic polyps
Average age of presentation is in the 50’s
High risk for colon cancer
Increased risk for duodenal cancer/polyposis
Higher incidence of cancers of the…
ovaries
bladder
skin
sebaceous gland tumors
MUTYH Associated Polyposis (MAP)
MUTYH
AR (carrier frequency is ~1%)
Common mutations in European ancestry- Y165C and G382D
NOTE- carriers may have an increased colon cancer risk (and higher with additional family history)
Colon cancer that is... tumor site in proximal (right sided) colon predominately trend towards early age of onset signet ring mucinous tumor-infiltrating lymphocytes medullary pattern Extracolonic cancers... endometrial stomach ovarian pancreas ureter and renal pelvis (transitional cell ca) biliary tract brain (usually glioblastoma) sebaceous gland adenomas/carcinomas; keratoacanthomas (Muir-Torre Syndrome) carcinoma of the small bowel NOTE- Accelerated rate of progression from normal to polyp to cancer
Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer)
Mismatch repair (MMR) genes- MLH1, MSH2, MSH6, PMS2, EPCAM (mutations in the 3’ end of the gene silence MSH2 via hypermethylation)
AD
Risk for cancer is stratified by gene
*most common genes associated (and higher risk/slightly earlier onset for cancer)
NOTE- about 10-15% of sporadic tumors are due to somatic mutations in MLH1 (promotor methylation); usually in the presence of a BRAF mutation
