Cancer Genetics Flashcards

Question

How is Cowden Syndrome managed?

Answer 1

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

Answer 2

``` 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 ```

Answer 3

``` 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 ```

Answer 4

``` 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 ```

Answer 5

Attenuated Familial Adenomatous Polyposis APC gene (chromosome 5q) Associated with mutation in the 5' and 3' ends of the gene

Answer 6

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

Answer 7

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)

Answer 8

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

Answer 9

Describes individuals who are at elevated risk for colon cancer (the 3, 2, 1 rule) 3 or more relatives with verified colorectal cancer in the family 2 or more generations 1 case a first degree relative of the other two EXCLUDES polyposis (though polyps are not an exclusion) NOTE- this is outdated and now we are more liberal about our testing

Answer 10

Guidelines for tumors that should be tested for IHC/MSI NOTE- increasing number of institutions have universal screening (do NOT follow Revised Bethesda) for all colon tumors and some endometrial tumors

Answer 11

Congenital Tufting Enteropathy compound heterozygous mutations in EPCAM AR rare

Answer 12

Constitutional Mismatch Repair Homozygous MMR family gene deficiency (MSH1, MLH2, MSH6, PMS2, EPCAM AR rare

Answer 13

Rare hereditary syndrome of multiple colorectal adenomas and primary brain tumors Two distinct subtypes- APC mutations associated with medulloblastomas MMR gene family mutations associated with glioblastomas

Answer 14

colonoscopy starting at 20-25 y/o or 2-5 years before earliest diagnosis repeated q1-2 years monitor abnormal uterine bleeding and hysterectomy after childbearing bilateral salpingo-oophorectomy after childbearing some recommend upper endoscopy starting at 30 y/o repeated q3-5 years testing for H. pylori capsule endoscopy, enteroscopy (no data supporting these- case by case) annual urinalysis starting at 30-35 y/o or cystoscopy consider pancreatic screening protocols such as CAPS-5 (IF positive family history of pancreatic cancer) NOTE- any of these may be modified by the gene affected Consideration of prophylactic colectomy for adenomas (not generally recommended) Total abdominal colectomy and not just resection when colon cancer is present (higher risk for secondary colon cancer) Proctocolectomy when rectal cancer is present

Answer 15

Juvenile Polyposis Syndrome BMPR1A, SMAD4 AD Clinical diagnosis is made when >3 juvenile polyps are present

Answer 16

colonoscopy beginning at about age 15 and repeated annually if polyps are found and every 2-3 years if polyps are found upper endoscopy starting at 15 y/o and repeating annually if polyps are found and every 2-3 years if no polyps are found individuals with SMAD4 mutations should be screened for vascular lesions associated with HHT within the first 6 months of life no recommendations at this time for screening for small intestine or pancreas

Answer 17

Hereditary Hemorrhagic Telangiectasia | SMAD4 (this means that it can present +/- Juvenile Polyposis syndrome)

Answer 18

Hereditary Diffuse Gastric Cancer/Lobular Breast Cancer CDH1 gene AD

Answer 19

prophylactic total gastrectomy (usually not until 20 y/o unless very early onset family)- this is because screening is ineffective endoscopic screening with random biopsy for those who are too young or who decline surgery high risk options for breast cancer risk management (high risk breast screening such as mammograms and breast MRI; prophylactic surgery)

Answer 20

von Hippel Lindau Disease VHL AD (90% penetrance but variable expressivity) Good genotype-phenotype correlation

Answer 21

Annual MRI of brain and full spine starting age 10 Ophthalmological exam annually by a retinal specialist starting in early childhood (by age 5 y/o) Annual/semi-annual abdominal MRI/CT starting at age 20 and annual renal US starting at age 10 (renal cell cancers are watched until 3m carcinomas) Biochemical screening for pheochromocytomas starting at age 5

Answer 22

Multiple Endocrine Neoplasia Type 1 MEN1 AD Most sensitive test is checking parathyroid hormone and calcium level (rather than genetic testing IF presents with isolated tumor and no fhx)

Answer 23

MRI every 1-3 years | Annual biochemical analysis for PTH and calcium

Answer 24

Carney Complex 1 (PRKAR1A) Cowden Disease (PTEN) Familial adenomatous polyposis (FAP) Multinodular goiter (14q, Xp22, 3p26)

Answer 25

``` Multiple Endocrine Neoplasia Type 2 RET AD low de novo rate Genotype-phenotype correlation- -MEN2A: risks for medullary thyroid cancer, pheochromocytoma, etc -MEN2B: risks similar to 2A plus other features -FMTC: medullary thyroid cancer only ```

Answer 26

Prophylactic thyroidectomy recommended at time of diagnosis/early childhood Annual screening of plasma metanephrines (starting age depends on mutation)

Answer 27

Hereditary Paraganglioma-Pheochromocytoma Syndrome SDHB, SDHC, SDHD*, SDHA, SDHAF2, MAX, TMEEM127 AD (*tumor risks if inherited paternally)

Answer 28

Begin at age 10- Annual physical exams, including vital signs, BP, and heart rate Annual non-sedated neck to pelvis MRI without contrast Annual neck/thoracic US Annual serum metanephrines and catecholamines Appropriate evaluation of symptoms suggestive of PGL, PCC, or GIST

Answer 29

Birt Hogg Dube FLCN AD- ~85% penetrance

Answer 30

Renal MRI every 1-2 years starting at age 20

Answer 31

``` Hereditary Leiomyomatosis- Renal Cell Cancer Syndrome FH AD thought to be highly penetrant Some genotype-phenotype correlation ```

Answer 32

Annual renal US starting by age 10 Annual abdominal CT or MRI starting at age 20 Uterine fibromas may be so large or difficult that hysterectomy at a young age is needed

Answer 33

Hereditary Papillary Renal Carcinoma Syndrome MET Highly penetrant (~90%) Rare

Answer 34

Annual abdominal CT or MRI starting at age 30 y/o

Answer 35

Familial Atypical Mole Melanoma CDKN2A (>90% of mutations), CDK4 (2-3% of mutations) AD High penetrance

Answer 36

Careful skin exam at least 2 times a year beginning at age 10 Avoid excessive sun exposure and radiation

Answer 37

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) PTCH1 AD ~100% penetrant with variable expressivity

Answer 38

Xeroderma Pigmentosum XP AR

Answer 39

Avoidance of all sun exposure | Frequent dermatologic exams

Answer 40

``` Neurofibromatosis Type 1 NF1 AD ~50% de novo phenotypic variability even within families ```

Answer 41

Neurofibromatosis Type 2 NF2 AD ~50% de novo (~30% mosaic)

Answer 42

von Hippel Lindau (hemangioblastoma; endolymphatic sac tumors) Tuberous Sclerosis Complex (SEGA) Cowden disease (Lhemitte-Duclos) Li Fraumeni Syndrome (brain tumors) Turcot's syndrome (Medulloblastoma; Glioblastoma) Gorlin Syndrome (Medulloblastoma)

Answer 43

Tuberous Sclerosis TSC1, TSC2 AD NOTE- some are due to contiguous gene deletions of TSC2 and PKD1 (which also means that these individuals have ADPKD as well)

Answer 44

Brain MRI with contrast every 1-3 years until age 25 Baseline EEG Renal MRI with contrast and functional studies every 1-3 years; mTOR inhibitors for widespread renal disease Chest CT in adult women every 5-10 years ECHO and EKG until rhabdos resolve Annual ophthalmology and skin exam Consider topical mTOR inhibitors

Answer 45

DICER1 Syndrome (Familial Pleuropulmonary Blastoma) DICER1 AD

Answer 46

Baseline chest CT at 3 to 6 months (or when mutation is found); if normal, then second chest CT at 2.5 to 3 y/o Chest XR every 6 months until age 8 Biannual abdominal US until age 8, then annual US Annual or biannual pelvic US starting in early childhood Thyroid US starting at 8 y/o; if normal, repeat every 3 years

Answer 47

Annual general assessment including complete physical exam and neurological exam US of abdomen and pelvis every 3-4 months Annual brain MRI (with first with contrast, others without if prior was normal and no new symptoms) Annual whole body MRI (for soft tissue and bone sarcomas)

Answer 48

Hereditary Retinoblastoma RB1 AD ~80% de novo; 90% penetrance (though small subset with significantly reduced penetrance)

Answer 49

Familial Wilms' Tumor (spectrum of conditions that include Denys-Drash Syndrome, Frasier Syndrome, or WAGR) WT1 gene (WAGR can also be associated with a microdeletion including both WT1 and PAX6) AD

Answer 50

WT1 associated Familial Wilms' Tumor Beckwith-Weidmann Syndrome Isolated hemi-hypertrophy WAGR

Answer 51

Bloom Syndrome BLM AR Rare (more frequent in the AJ population)

Answer 52

Avoid sun exposure IGG replacement if anemia becomes severe Increased risk of chemo-induced toxicity (when treating malignant tumors)

Answer 53

Fanconi Anemia FANC genes (FANCA most common- 60-70%) as well as some other genes associated with AD breast cancer (PALB2, BRIP1, RAD51C) AR (some are XL) Diagnosed by chromosomal breakage analysis in peripheral blood lymphocytes (of skin fibroblasts to confirm if ambiguous) OR genetic testing

Answer 54

Schwachman Diamond Syndrome SBDS AR NO phenotype-genotype correlations