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Master Boards Review -- Cancer
Terms in this set (106)
Average woman's lifetime risk for breast cancer, median age of diagnosis, most common type and loation for metastasis
12% (1 in 8), 61 years old, Ductal, metastasis sites bone, brain, lung, liver (rarely ovaries)
Most frequent types of breast cancer and concern for hereditary risk
Adenocarcinoma (ductal or lobular), Ductal carcinoma in-situ (DCIS), Lobular carcinoma in-situ (LCIS). Adenocarcinoma (ductal or lobular) and DCIS have concern for hereditary risk
Breast cancer risk factors
Age, genetics, obesity, alcohol use, physical activity, hormones, early menarche, age at first live birth over 25, late age at menopause, breast density, # breast biopsies/findings, radiation exposure
% Sporadic, hereditary and family cluster of breast cancer
70-80% Sporadic, 5-10% Hereditary, 15-20% Family Cluster
Risk of breast cancer for family clusters and hereditary breast cancer (ie HBOC)
20-30% family cluster (about 2x average woman), 50-85% HBOC or other hereditary
Only mode to determin tamoxifen use, personal factors and limited fhx. Women 45+, Caucasian or African American. Accounts for age, ethnicity, fhx breast cancer in maternal 1st degree relatives, age at menses, age at first live birth, # breast biopsies (finding of ductal hyperplasia)
Limited fhx. Up to two 1st/2nd degree relatives w/ invasive breast cancer, age at breast cancer dx for relatives, lineage, pt current age
Breast/ovarian cancer in 1st/2nd degree relatives, lack of cancer in relatives, ages of patient and relatives, ages of cancer dx patient and relatives, cancer histology, age at oophrectomy, BRCA gene test results
Candidate for tamoxifen
5 year risk of breast cancer is over 1.7% (Gail model)
When to have breast MRI screen
Lifetime risk for breast cancer is at or over 20% with fhx based model
Prevalence HBOC general pop and Ashkenazi
1 in 400 to 1 in 500, Ashkenazi 1 in 45
Ovary cancer risk general population, BRCA1, BRCA2, median age of diagnosis
1.4% general pop, 40-60% BRCA1, 20-30% BRCA2, 63 years old
Male breast cancer risk general population, BRCA1, BRCA2
<1% general pop, about 6% BRCA2, above general pop but <6% for BRCA1
Prostate cancer risk general population, BRCA1, BRCA2
15% general population, 20% BRCA2, above general pop BRCA1
Pancreatic cancer risk general population, BRCA1, BRCA2
1.4% general pop, 7% BRCA2, slight increase BRCA1
Histology BRCA1/2 and Tamoxifen use
BRCA1: 75% ER-, 25% ER+; BRCA2: 75% ER+, 25% ER-
Tamoxifen may be more effective in patients with BRCA2 mutations
Screening recommendations HBOC women
Breast: monthly breast exam age 18, clinical breast exams 6-12 mo. Annual mammogram OR MRI age 25-29, both starting at age 30, consider tamoxifen at age 35+, consider proplylactic mastectomy. Ovaries: prophylactic oophorectomy ages 35-40yrs, oral contraceptives for 5 years, if no oophrectomy consider CA-125 and transvaginal US every 6 mo starting age 30yrs
Screening recommendations HBOC men
Breast: mothly breast self-exam starting age 35yrs, clinical breast exams 6-12 mo starting age 35, consider mammogram for baseline age 40, annual mammogram if gynecomastia or parenchymal/glandular breast density is seen on initial mammogram. Prostate: general pop guidelines
Cancer risks after mastectomy and/or oophorectomy
90% reduction bilateral mastectomy, 95% reduction bilateral mastectomy and oophrectomy before 45yrs, 1-4% risk primary peritoneal cancer after oophorectomy, 50% reduction breast cancer with oophrectomy before 45-50yrs
Sensitivity of BRCA1/2 sequencing and del/dup
Sequencing is 97-99%, del/dup is 1-3%
PTEN, AD, Lifetime risk breast cancer 25-50%, thyroid 3-10% (non-medullary), endometrial 25%, urinary tract, kidney (35% RCC), colon slighly higher than general pop, melanoma >5%, macrocephaly, lhermitte-duclos disease, mucocutaneous lesion, lipomas, tongue papules, thyroid nodules/goiter, uterine fibroids, fibrocystic breasts, GI tract harmartomas. Mutations 90% sequencing, 10% del dup. Up to 50% de novo.
PTEN diagnostic criteria
Pathognomonic: trichilemmomas (facial), acral keratoses, papillomatous lesions, mucosal lesions.
Major criteria: breast cancer, epithelial thyroid cancer (non-medullary, esp folicular), macrocephaly, endometrial cancer
Minor criteria: other tyroid lesions, ID, hamartomatous colon polyps, fibrocystic breasts, lipomas, fibromas, GU tumors (esp RCC), GU malformation, uterine fibroids
Monthly breast self exam start 18yrs, clinical breast exam 6-12 months start 25yrs, annual mammogram/MRI start 30-35yrs, consider mastectomy/hysterectomy. Annual physical exam startuing 18 yrs, annual thyroid US starting 18 yrs, colonoscopy starting at 35 yrs then every 5 yrs or sooner, consider renal US starting at 40 yrs repeat every 1-2 yrs.
STK11, AD, lifetime breast cancer risk 45-50%, Screening same as HBOC. Dark pigmented spots on lips/oral mucosa, very characteristic GI polyps. Lifetime CRC risk 39%. Highest risk for pancreatic cancer for all conditions (36%)
Hereditary diffuse gastric cancer
Very rare, high penetrance (67% men, 83% women). Risk for lobular breast cancer (39%)
Hereditary diffuse gastric cancer screening
Intensive endoscopic surveillance starting age 16, every 6 months, total gastrectomy considered age 20, annual mammogram and breast MRI, clinical breast exam every 6 months start age 35. CDH1.
4 moderate risk genes for breast cancer
CHEK2, ATM (Ataxia-talangiectasia), PALB2 (fanconi anemia), BRIP1 (fanconi anemia)
Three main types of polyps
Adenomatous: precancerous but only 10% become cancer. Hyperplastic: usually not considered precancerous, often left sided and small, large right sided polyps likely precancerous. Inflammatory: not considered precancerous, usually results from ulcerative colitis.
Types of serrated polyps
Hyperplastic, sessile serrated polyp (aka sessile serrated adenoma, not cancerous and not adenoma), traditional serrated adenoma (not an adenoma).
Types of hamartomatous polyps
Juvenile, Peutz-Jeghers, Neuromas, Leiomyomas, Lipomas, Angiomas, Lymphangiomas
Freq of epithelia polyps vs hamartomatous polyps
Epithelial polyps 95% (50% adenomatous polyps, 50% hyperplastic polyps), hamartomatous polyps <5%
% causes of CRC
Sporadic 70%, Familial 25-30%, Lynch 2-4%, FAP/MAP <1%, Hamartomatous polyposis <1%
CRC syndromes by polyp type
Adenomatous polyps: FAP, MAP, Lynch. Hamartomatous polyps: Peutz-Jeghers, Juvenile polyposis, Cowden. Misc: serrated polyposis (hypoplastic polyposis)
Lynch syndrome features
Early age CRC (about 45 yrs), few adenomas (nonpolyposis), microsatellite instability in tumors, risk for various extra-colonic cancers, up to 70% lifetime risk CRC, endometrial cancer risk can be almost as high as CRC risk. Endometrial can be most common cancer in LS women.
Genetic cause of lynch syndrome
Germline DNA MMR defects: MLH1 or MSH2 (80-90%), MSH6 (7-10%), PMS2 (<5%). Other genes: EPCAM (1-3%)
Population risk endometrial cancer
Lynch risk CRC and endometrial cancer by gene
MLH1/MSH2 colon 40-80%, endo 25-60%. MSH6 colon 10-22%, endo 16-26%. PMS2 colon 15-20%, endo 15%.
Lynch EPCAM mutations
High risk of CRC, possibly lower risk of endometrial cancer. May have more de novo mutations. Upstream of MSH2.
Lynch syndrome "variant" conditions
Turcot: lynch wil primary brain tumors (glioblastomas). Muir-torre syndrome: lynch with sebaceous gland tumors and/or keratoacanthomas, observed in 28% lynch families and 9.2% lynch individuals
Constitutional MMR Deficiency Sydnrome
Biallelic MMR mutations, AR, childhood onset. Features: hematologic malignancies, brain tumors, lynch syndrome tumors, signs of NF1. Mean age dx 5.5 yrs, mean age lynch tumors 16 yrs.
1: 3+ family members with comfirmed diagnosis of CRC, one of which is a first degree relative of the other two, 2 successive affected generations, 1+ CRC diagnosed under 50yrs, FAP has been excluded.
2: 3+ family members w/ HNPCCC-related cancers, one of whom is a first degree relative of the other two, 2 successive affected generations, 1+ HNPCC-related cancers diagnosed under 50yrs,
3: FAP excluded
CRC < 50 yrs, person with 2 lynch tumors
CRC <60 years w/ MSI histology (signet ring cell, etc)
CRC diagnosed in a pt w/ 1+ FDR w/ lynch tumors (one <50yrs)
CRC diagnosed in a pt w/ 2+ FDR or SDR w/ lynch tumor at any age
100s to 1000s of colonic adenomatous polyps. Penetrance >90% by age 40. 100% CRC in untreated cases. Risk of extra-colonic cancer. Small bowel polyps (adenomas) in duodenum and ampulla in 60-80%, 4-12% risk for duodenal/ampullary malignancy. Gastric polyps (mainly fundic gland polyps) about 90%, low risk of gastic malignancy, but increased. Incrased risk of hepatoblastoma in children. Gene APC, AD, about 25% de novo mutations
FAP cancer risks
Desmoid tumors 10-20%, benign adrenal adenomas or other masses 7-13%, pancreatic cancer 2%, papillary thyroid cancer 1-12%, hepatoblastoma 1-2%, medulloblastoma 1-2%. Screen for hepatoblastoma like BWS/IHH using AFP and abdominal US
FAP with extra-intestinal growths. Desmoid tumors, osteomas, supernumerary teeth, CHRPE (flat, pigmented lesions of the retina not age dependent, multiple or bilateral lesions), soft tissue skin tumors.
FAP and brian tumor. 2/3 of Turcot have APC mutations.
<100 polyps and older age of CRC onset (50s). Average 30 colonic polyps, more proximal in location. CRC 70% risk. Fundic glad polyps and duodenal adenomas similar presentation as classic FAP
FAP colorectal mgmt
Annual colonoscopy start age 10-12 yrs FAP, 18-20 years attenuated FAP. Consider chemoprevention, prophylactic colectomy, subsequent surveillance for rectal, pouch and extracolonic tumors.
FAP extracolonic screening
Duodenal or peri-ampullary: upper GI endoscopy every 1-3 yrs start 25yrs. Annual thyroid exam. Hepatoblastoma: hepatic US, AFP every 3 months start birth to 5yrs
Similar to AFAP phenotype. 15-100 adenomas, multiple serrated polyps may occur. Older age of CRC onset (around 50s), AR.
PJS Diagnostic criteria, risks, gene
Proband meets both:
1: histopathological confirmation of hamartomatous GI polyps.
2: At least two of: small bowel polyposis, family history consistent w/ AD transmission, pigmented macule of buccal mucosa, lips, fingers or toes.
CRC 39%, gastric 29%, pancreatic 36%, breast cancer 54%. Higher ovarian, lung, cervix, uterus, testes, small intestine, esophagus. Gene: STK11. 50% de novo. Del/dup analysis picks up 20-45%.
Juvenile polyposis syndrome
juvenile polyps in colon, colon cancer (40%), gastric cancer (20%), pancreatic or small bowel cancer. SMAD4 (20%) and BMPR1A (20%). 15-22% of pt with SMAD4 mutation will have combined JPS/HHT syndrome. Dx: Any one of the following: >5 polyps of colorectum, multiple juvenile polyps of upper and lower GI tract, any number of juvenile polyps and a fam hx juvenile polyps. Gene: SMAD4, BMPR1A
Hamartomatous polyposis syndromes
Hereditary mixed polyposis syndrome, gorlin's syndrome, tuberous sclerosis, cronkhite canad syndrome, NF1 and MEN II
Serrated polyposis diagnosis
aka hyperplastic polyposis. Any one of: > 20 serrated polyps throuhout colon, >5 serrated polyps proximal to the sigmoid colon 2 of which >10mm, >1 serrated polyps proximal to sigmoid colon in pt w/ >1 1st degree relative w/ serrated polyposis
Risk factors CRC
>4 fold increase: advanced age, country of birth, long standing UC. 2-4 fold increase: prev adenoma or cancer, high red meat diet, pelvic irradiation. 1-2 fold: high fat diet, alcohol, cigarette smoking, obesity, tall stature, cholecystectomy, high sucrose consumption. Risk reduction 20-30%: high veg/fruit diet, high fiber diet, high folate/methionine intake, high calcium intake, hormone replacement. Risk reduction > 60% high physical activity, aspirin/NSAIDs
General pop risk for CRC and average age at dx
5.5% risk, averge age at dx is 67 years
AR cancer syndromes
MAP, ataxia telangiectasia, bloom syndrome, fanconi anemia, nigmegen breakage syndrome, Rothmund-thomson syndrome, werner syndrome, xeroderma pigmentosa
AD with maternal imprinting cancer syndromes
SDHD PGL/PCC syndrome, BWS
XL recessive cancer syndromes
Fanconi anemia B, simpson-golabi-behmel, dyskeratosis congentia
Population lifetime risk of pancreatic cancer, average age onset, average 5-yr survival
1.4%, age of onset 72yrs, 5.6% five-yr survival
Risk factors for pancreatic cancer
male, ancestry (India/caribbean), obesity, smoking, diabetes, H. pylori, 1 relative, APC/HNPCC/BRCA1, LFS/p53.
CF, chronic pancreatitis, 2 relatives, BRCA2, FAMM/P16.
hereditary pancreatitis, 3+ relatives, CDKN2A/STK11, Peutz-Jeghers
Pancreatic screening methods
1 - Tumor markers (blood CA19-9), inexpensive, easy, non-specific.
2 - CT scan / MRCP, non-invasive, sensitive for large lesions, expensive, radiation risks.
3 - Endoscopic ultra sound (EUS), most sensitive, operator dependent, invasive. Consider if risk is >10%
Genetic condition assoc w/ pancreatic cancer only
Hereditary pancreatitis. Pancreatic cancer is rarely the major cancer associated w/ hereditary cancer conditions.
When to consider genetic causes for pancreatitis
Pancreatitis and positive fhx of recurrent acute pancreatitis, idiopathic acute pancreatitis (ICP), or unexplained childhood pancreatitis; unexplained recurrent acute pancreatitis; unexplained childhood pancreatitis; ICP esp if early-onset
Hereditary pancreatitis overview
Age of onset 10-14yrs, 80% overall penetrance, 1-2 bouts pancreatitis per year, 40% lifetime risk for panc cancer, AD. Variable expressivity even w/in families. Dx criteria: At least 2 FDR or 3 SDR over at least 2 generations have recurrent acute pancreatitis or chronic pancreatitis w/o another identifiable cause (EUROPAC criteria); Up to 80% of individuals meeting this criteria will have identifiable mutations in PRSS1
% CFTR mutations found in ICP cases and risk of cancer
13-37% CFTR mutations foud in ICP cases. Compound heterozygotes have 40-80 fold risk, carriers have 3-4 fold risk.
Serine protease inhibitor of Kazal type. 12 fold increase in chronic pancreatitis risk. Mutations found in 20% of ICP cases. Greatly reduced penetrance. No clear functional consequence of mutation, may increase risk in patients w/ 2 CFTR mutations
Pancreatic cancer risks in hereditary cancer syndromes
HBOC (primarily BRCA2) 3-8%; CDKN2A 10-17%; Peutz-Jeghers 36%; Juv polyposis, FAP, Lynch, Ataxia-telangiectasia, CF <5%; Familial pancreatic cancer (PALLD) unclear
Basal cell carcinoma (BCC)
90% occur in sun exposed areas. 5-10% are difficult to treat and damage surrounding skin/cartilage. Rarely life threatening. Most common skin cancer.
Squamous cell carcinoma (SCC)
97-98% are localized. Common skin cancer, not as common as basal cell carcinoma. Cost of care for squamous cell/basal cell carcinoma is 5th highest for Medicare population (huge financial burden)
BCC/SCC risk factors
UV exposure, skin types 1 to 3, male gender, chemical exposures, radiation exposure, burn or scar injuries, immunosuppression due to organ transplant, HPV infection, ulcerating conditions, genetic conditions.
Melanoma population risks by ethnicity
Lifetime risk white 2%, black .09%, asian lowest risk. Staging is standard TNM, w/ Breslow depth to measure tumor size. Major predictors of outcome is depth and ulceration.
Melanoma risk factors
>5 atypical nevi (10), previous cutaneous melanoma (8.6), 100+ nevi (6.9), red hair (3.6), skin type 1 (2.1), history of blistering sunburn (2), blue eyes (1.5).
% heriditary and sporadic melanoma
Sporadic about 90%. Heriditary 6-12%. Of heriditary melanoma, 20-40% are CDKN2A, about 1% are other single genes (CDK4, p14ARF)
CDNK1A. Tumor supressor gene. Penetrance varies according to background risk from sun exposure: 28-91% overall, Europe 58%, US 76%, Australia 91%. Increased risk of pancreatic cancer 11-17% in some families. Family members who test neg for a known mutatioin have greatly decreased melanoma risk, but still above average (about 1.7x higher than general population).
Likelihood of mutation detection
# family members w/ melanoma, muliple primary melanomas, presence of pancreatic cancer. Factors less predictive: early onset, isolated pancreatic cancer, multiple atypical nevi. North america mutation detection rates 5% w/ 2 family members, 11% w/ 3 family members. Rule of 3s: 3 melanoma in famly members of any relation, 3 melanomas in an individual, 3 cancer events (melanoma or pancreatic) in a family. Use rule of 2s for low melanoma incidence areas
Basal cell nevus syndrome
Gorlin syndrome. Multiple BCC, congenital anomalies, palmar pits, jaw keratocysts, medulloblastoma, AD inheritance, 20-30% de novo mutations, PTCH gene
Risk for melanoma in hereditary cancer conditions
BRCA2 is 3-4%, 1-9% for sebaceous neoplasms in Lynch, 6% risk for melanoma in Cowden
Most common primary eye tumor in children. Non-heritable 60-70%, heritable 30-40%. Of heritable: 80% bilateral, 20% unilateral, trilateral is rare. Optic nerve is invaded by whitish tumor.
RB1 gene. AD inheritance. Penetrance >90% but not 100% (two-hit). Rb is a nuclear phosphoprotein that plays a role in cell growth regulation. Loss of both Rb alleles assoc w/ tumor formation. >100 known mutations. Life-long risk increases w/ time. Also at risk for bone/soft tissue sarcomas, brain/nasal cavity cancer, melanoma, lung, GI, bladder bancers. Risk of second cancers increased by radiation.
Childhood kidney cancer arising from embryonic cells. >90% sporadic, unilateral; 5-7% bilateral presumed heritable, 1% familial.
WT1 gene on chr 11. Gonadal dysgenesis, nephropathy, wilms tumor.
Wilms tumor, aniridia, GU abnormality, intellectual disability. 50% risk of developing Wilms tumor, 70% have intellectual disability. Genes: deletion that includes PAX6 (aniridia) and WT1 (Wilms tumor) on chr 11
Prenatal/postnatal overgrowth, distinctive facial gestalt (protruding jaw and tongue, widened nasal bridge, upturned nasal tip), malformations overlap with BWS except distinctive hands and more coarse face. Macrosomia, polydactyly, congenital heart disease, wilms tumor. GPC3 gene, X-linked
Hepatoblastoma prevalence (BWS)
Hepatoblastoma occurs in 1:1,000,000 children. Occurs 1-3% in BWS/IHH pt. >96% of pt w/ HB have elevated AFP.
Rhabdoid predisposition syndrome
AD. INI1/SNF5 (SMARCB1) gene. Renal and extrarenal malignant rhabdoid tumors, choroid plexus carcinomas, central primitive neuroectodermal tumors and medulloblastomas. High penetrance at a young age.
AD. Early onset of bone and soft tissue sarcomas, adrenocortical carcinoma, breast cancer, brain tumors (esp coroid plexus) and other tumors. Multiple primary tumors. Overall lifetime risk of cancer 80-90%. P53 gene. About 20% de novo. Sequencing identified 95% of cases, deletions 1%.
Li-Fraumeni syndrome Chompret diagnostic criteria
1. Proband w/ tumor in LFS spectrum before age 46 AND at least one 1st or 2nd degree relative w/ LFS tumor before age 56 or w/ multiple tumors. 2. Proband w/ multiple tumors, two of which belong to LFS spectrum and first occurred before 46yrs. 3. Pt w/ adrenocortical carcinoma or choroid plexus tumor, irrespective of fhx.
Conditions with increased risk for pheochromocytomas or paragangliomas
MEN1 (RET gene): PCC. VHL: PCC. NF1: PCC. Familial PCC/PGL: PCC and PGL
Familial paraganglioma syndrome
SDHB, SDHC, SDHD, SDHAF2 mutations. Most common in head, neck, chest or abdomen. Also increased risk for GIST. Screen: physical exam, blood pressure check, blood test every 12 months; total MRI every 2 yrs; fu abnormal MRI w/ PET scan.
Von hippel-lindau syndrome
VHL gene. Tumor supressor gene functions as transcription elongation regulator. De novo mutations in 20% of VHL cases. Seq variants 70%, deletions 30%. Mutation detection nearly 100%. Strong genotype-phenotype correlations. Penetrance nearly 100% by 65 years.
Findings: Retinal angiomata, endolymphatic sac tumors, hemangioblastoma (cerebral, spinal cord, renal, pancreatic), hemangiomas (pulmonary, liver), pheochromocytoma, renal cell carcinoma, cysts (renal, pancreatic, epididymal), bilateral papillary cystadenomas of broad ligament, bilateral papillary cystadenomas of epididymis
Most common hereditary risk for RCC
VHL dx criteria
No fhx presents w/ 2 or more:
2+ hemangioblastomas (retina, spine, brain)
1 hemangioblastoma in association w/ visceral manifestation (multiple kidney or pancreatic cysts)
Adrenal or extra adrenal PCC
Less common: endolymphatic sac tumors, papillary cystadenomas or neuroendocrine tumors of pancreas.
Postive fhx with 1 or more:
Retinal angioma, spinal/cerebellar hemangioblastoma, adrena ore extra-adrenal PCC, RCC, multiple renal and pancreatic cysts.
Other testing to establish dx or extent of manifestations: Fundoscopy for retinal angiomas, brain CT/MRI for hemangioblastomas and endolyphatic sac tumors, US/CT/MRI for visceral tumors/cysts
Von hippel-lindau surveillance
Retinal hemangioblastoma: ophthalmological exam starting from birth, full retinal exam beginning at age 2-10yrs. Pheochromocytoma: start at 5yrs, physical exam, blood pressure monitoring, plasma/urine metanephrines, urine catecholamines. Renal, pancreatic, adrenal masses: start 11-16yrs w/ annual abdominal US. CNS & endolymphatic sac tumors: start 15-16, every 12-24 month brain MRI w/ gadolinium.
Multiple endocrine neoplasia types 1 and 2A differences
MEN 1: anterior pituitary, parathyroid, adrenal cortex, pancreatic islets, MEN1 gene. MEN 2A: thyroid C cells, parathyroid, adrenal medulla, RET gene.
Multiple endocrine neoplasia type 1
Susceptibility to endocrine and non-endocrine tumors. Parathyroid adenomas 90%, pancreatic islet cell tumors 30-75%, Pituitary adenomas/prolactinomas 25-60%, carcinoid, gastric enterochromaffin-like tumor, pheochromocytoma, adrenocortical tumor, ependymoma. Most common is hyperparathyroidism. Usually occurs in 20s w/ >95% by 40s. gene: MEN1
Multiple endocrine neoplasia type 2
RET proto-oncogene. Mutated RET gene remains activated. Early onset is sometimes more aggressive. Medullary thyroid carcinoma, pheochromocytoma, dev abnormalities, mucosal neuromas, gangliomneuromatosis. MEN2B: characteristic marfanoid phenotype, megacolon.
MEN2 cancer risks
MEN2A: MTC 95-100% (hallmark), pheochromocytomas 50% risk, PTH adenomas/hyperparathyroidism 15-30% risk. MEN2B: very early onset aggressive MTC, pheochromocytomas, typical physical freatures including marfanoid habitus, mucosal neuromas and intestinal ganglioneuromatosis. Familial MTC: MTC in absence of other assoc tumors
ATM gene. Cerebellar ataxia in infancy. Telangiectasiae begin in sun-exposed areas, 50% have endocrine dysfunction. 1/3 develop cancer. Non-hodgkins lymphoma, leukemia; also gatric cancer, medulloblastoma, basal cell carcinoma, glioma, uterine cancer, breast, pancreas, colon cancer. Other features: neurodegeneration, ataxia, ocular/facial telangiectasia, dysarthria. ATM gene role in DNA repair. 10% will develop cancer, 16.6% risk of breast cancer, double the risk of pancreatic cancer.
BLM gene. IUGR, small jaw, high-pitched voice, skin rashes/lesions, immunodeficiency, infertility, below-average inelligence, DM, pulmonary disease. Cancers: leukemia, lymphoid neoplasms, Wilms tumors, carcinomas of tongue, larynx, lung, esophagus, colon, skin, breast, cervix
RecQ helicase defect leads to DNA replication errors and increased sister-chromatid exchanges. Inheritance AR
13 FANC complementation groups. Bone marrow failure, physical anomalies, cancer risk, high sensitivity to chemo/radiation. Cancer: acute myeloid leukemia (AML), myelodysplastic syndrome, head, neck, skin, GI, genital, and liver tumors. 15 genes including FANCA, FANCB, FANCC, BRCA2, BRIP1, PALB2. AR inheritance
AR. Numerous genes. 1000x risk of cancer at UV exposed sites by 20yrs. Median age of onset of non-melanoma skin cancer <10yrs. Also risk of: glioma, solid tumors of lung, uterus, breast, pancreas, stomach, kidney, etc. Eye abnormalities: ophthalmologic abnormalities, photophobia, severe keratitis of eyelids, pigmented eyelids, loss of lashes. CNS abnormalities: acquired microcephaly, diminished deep tendon reflexes, progressive SNHL, progressive neuromuscular degeneration.
TSC1 and TSC2 genes. Prevalence: 1/5,800
66% de novo mutation rate, variability within families, somatic mosaicism.
Penetrance almost 100%. 80% have renal lesions by age 11.
Mutations identified in 85% of individuals DEFINATE clinical dx. TSC1 found in 31%, TSC2 found in 69%. Deletions in 1-5% of cases.
Some genotype-phenotype correlation: TSC2 tends to be more severe and more often de novo.
TSC clinical findings
Skin: hypomelanomic macules, facial angiofibromas, shagree patches, ungual fibromata.
CNS: subependymal glial nodules 90%, cortical tubers 70%, subependymal gial cell astrocytomas, dev delay 50%, PDD, autism, seizures.
Cardiac: rhabdomyomas 47-67%, arrhythmias
Kidney: angiomyolipomas, cysts, RCC (2nd leading cause of death)
Lungs: lymphangioleiomyomatosis (LAM) 1-6%
Eye: Retinal lesions/hamartomas 75%.
TSC Dx criteria
Definite: 2 major features, or 1 major and 2 minor
Probable: 1 major AND 1 minor
Possible: 1 major OR 2+ minor
Facial angiofibromas, ungual or periungual fibromas, 3+ Hypomelanotic macules, Shagreen patch, retinal nodular hamartomas, Cortical tuber, Subependymal nodule (SEN), Subependymal giant cell astrocytoma (SEGA), Cardiac rhabdomyoma, 1+ Lymphangiomyomatosis, Renal angiomyolipoma
Multiple pits in teeth, Hamartomatous rectal polyps, bone cysts, Cerebral white matter radial migration lines, Gingival fibromas, Nonrenal hamartoma, Retinal achromic patch, "Confetti" skin lesions, multiple renal cysts
FLCN gene. Kidney cancer: average onset 48 years, usually bilateral, multifocal and slow growing. Other features: fibromas, folliculomas, pulmonary cysts/spontaneous phenumothorax. 85-90% detection for individuals meeting dx criteria.
NSGC guidelines for cancer risk assessment
Genetic testing should be offered when it will influence medical management of the patient or other relatives.
Informed consent should include the following:
Purpose of the test and who to test
General info about gene
Possible test results
Technical aspects and accuracy of test
Utilization of test results
Alternatives to genetic testing
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