A. Colorectal Cancer (CRC) Syndromes [1,36,40]

1. Overview of Syndromes
   1. Hereditary Nonpolyposis CRC Syndrome (Lynch Syndrome)
   2. Familial Adenomatous Polyposis (Gardner Syndrome)
   3. Turcot Disease
   4. Cowden Disease
   5. Familial Juvenile Polyposis
   6. Peutz-Jeghers Syndrome
   7. Ruvalcaba-Nyhre-Smith (Bannayan-Zonana) Syndrome
2. Hereditary Nonpolyposis CRC Syndrome (HNPCC) [4,25,30]
   1. Originally called the Lynch Syndrome (included MSH2 mutations only) [10,14]
   2. Responsible for ~6% of all CRC (most common familial syndrome)
   3. Two types; Type I has only colorectal tumors
   4. Type II HNPCC includes extra-colonic tumors, usually endometrial, gastric, ovarian [25,34]
   5. CRC develop age 20-80 and run in families and mostly right sided
   6. Due to mutations in genes which code for DNA mismatch repair proteins
   7. Mutations in five distinct genes have been identified which lead to HNPCC
   8. Inactivation in any of these genes leads to "microsatellite" instability (MSI)
   9. Microsatellites are tandemly repeated stretches of DNA
   10. Most patients with HNPCC meet "Amsterdam" Criteria for disease
   11. Amsterdam Criteria include >2 family members in 2 or more successive generations with colorectal cancer; one is 1° relative; cancer <50 years in 1 person; rule out FAP
   12. Modified Amsterdam Criteria (II) and separate Bethesda Criteria have been developed to aid in identification of patients who should be screened for HNPCC
   13. Amsterdam I Criteria families without mismatch repair deficiency appear not to have an increased risk of cancer [9]
   14. Bethesda criteria mainly identify patients with MLH1 or MSH2 mutations [57]
   15. Bethesda (revised) Guidelines are useful for identifying patients at high risk for HNPCC [33]
   16. Screening for HNPCC in ALL patients with newly diagnosed CRC is cost effective [41]
   17. Prophylactic bilateral salpingo-oophorectomy prevents development of endometrial and ovarian cancer in Lynch syndrome patients [17]
3. Pathogenesis and Evaluation of HNPCC [4,10,30]
   1. Most patients have hMSH2 (chr 2p16; ~45%) or hMLH1 (chr 3p; ~45%) mutations
   2. ~10% have MSH6 mutations; remaining patients have hPMS1 (chr 2q), hPMS2 (chr 7p)
   3. Mutations in these genes confer ~80% lifetime risk of colon cancer (versus ~4% normal)
   4. Males with MSH2 or MLH1 mutations have a higher colon ca risk than females
   5. Presence of at least 2 colon ca cases in a family, or colon ca with endometrial ca, makes HNPCC likely [19,20]
   6. Definitive mutation testing identified in ~25% of HNPCC related persons [30]
   7. Genetic testing of family members is recommended
   8. Evaluation of hMSH2 and hMLH1 gene sequences is most effective initial screen [10]
   9. About 20% of spontaneous colon cancers have microsatellite instability (MSI) [43]
   10. In spontaneous MSI, majority of cases due to mutations in hMLH1
   11. Tumors with MS instability (MSI) are more often right sided [46]
   12. Tumors with MSI appear to have better prognosis and response to adjuvant therapy [46]
   13. Screening programs have been developed for patients with HNPCC [20]
   14. Colonoscopy q1-2 years beginning age 20-30 (age 30 for MSH6 mutations), or 10 years younger than youngest relative diagnosed with syndrome [20]
   15. Endometrial sampling and transvaginal ultrasound of uterus and ovaries (age 30-35 years) and urinalysis with cytology (age ~30) also recommended [20]
4. Familial Adenomatous Polyposis (FAP or FPC) [1]
   1. Also called Bussey-Gardner polyposis and Gardner Syndrome
   2. Deletion or mutation of APC (adenomatous polyposis cancer) gene
   3. APC is located on chromosome 5q21 (prevalence of loss is 1:12,000)
   4. Loss of APC can lead to increased cell proliferation
   5. Associated with multiple cancers of the colon, stomach, pancreas
   6. Autosomal dominant inheritance; ~1% of all colon cancers
   7. Mainly left-sided colorectal cancers develop <40 years (~100% of patients)
   8. Hundreds to 1000s of polyps in the colon
   9. Mutation in APC gene (I1307K) associated with adenomatous polyps in Ashkenazi Jews [50]
   10. Small intestine (usually peri-ampullary, duodenum), may develop adenomatous polyps
   11. Gastric polyps may also develop and can become neoplastic
   12. Dental abnormalities: odontomas, dentigerons cysts, abnormal tooth development
   13. Osteomas, desmoids and extra-GI malignancies
   14. Celecoxib (Celebrex®) but not sulindac reduce polyp numbers in FAP [12,18]
5. Turcot Syndrome
   1. Mutations in the APC gene or in a distinct DNA-mismatch repair gene
   2. Autosomal recessive inheritance
   3. Colonic adenomas usually with brain tumors
   4. Medulloblastoma and glioblastoma is major type of brain tumor
   5. Rare syndrome compared with others
6. Hereditary Hamartomatous Polyposis Syndromes [1,40]
   1. Cowden's Syndrome - PTEN gene mutations
   2. Familial Juvenile Polyposis - SMAD4 (DPC4), BMPRIA, PTEN mutations
   3. Peutz-Jeghers Syndrome - LKB1 (STK11) mutations, abnormal pigmentation
   4. Ruvalcaba-Myhre-Smith Syndrome - PTEN Mutations
7. Other Heritary Cancer Syndromes
   1. Neurofibromatosis (see below)
   2. Basal Cell Nevus Syndrome
   3. Muir Syndrome - multiple skin tumors and benign and malignant GI tract tumors
8. Chemoprevention of Polyps [48,49]
   1. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS) are best studied
   2. Polyp growth is believed to be dependent on cyclo-oxygenase 2 (COX2)
   3. Celecoxib, a COX2 specific inhibitor, reduces polyp generation in dose-dependent manner
   4. Celecoxib, 400mg po bid, for 6 months reduced polyps by 28% [48]
   5. Non-cyclo-oxygenase pathways may also be involved in NSAID effects
   6. Increased folate, calcium, and estrogen intake associated with reduction in polyps [49]

B. Breast Cancer Syndromes [5,51]

1. Mutations in Familial Breast Ca [22]
   1. BRCA1 and BRCA2 account for ~10% of breast ca cases
   2. Rare mutations of BRCA1 or 2 (genomic rearrangements) in ~12% of familial breast ca
   3. Similar clinical outcomes with BRCA1 or 2 mutations versus other breast ca [74]
   4. BRCA1 and/or BRCA2 mutations may also play a role in prostate cancer and colon cancer
   5. CHECK2 mutations in ~5% of non-BRCA1/2 breast ca
   6. TP53 (p53) mutations in ~1% of non-BRCA1/2 breast ca
2. BRCA1 Properties [6]
   1. Large gene on chromosome 17q21
   2. Protein 1863 residues with ring finger, nuclear localization, transactivation domains
   3. BRCA1 and BRCA2 involved in DNA repair systems activated by radiation [59]
   4. Germline mutations increase susceptibility to breast and ovarian cancer
   5. Variety of mutations code for increased cancer risk, especially non-sense type
   6. Abnormal protein associated with increased mitotic rate, reduced tubules, and increased tumor grade [24]
   7. Protein terminating mutations found in familial breast cancer increase cancer risk
   8. ~30% of spontaneous breast and ovarian cancers have reduced BRCA1 expression
   9. Unclear significance of mutations leading to single amino acid changes [31]
3. BRCA1 Mutations and Breast Ca Risk [6,32]
   1. BRCA1 mutations confer an overall risk of breast cancer of 56-87%
   2. BRCA1 mutations confer an overall risk of ovarian cancers of 16-60%
   3. In breast Ca patients with strong family history, 13-45% have BRCA1 mutations [31,32]
   4. In women age <35 yrs with breast cancer, BRCA1 mutations occur in 6-12% [31,32]
   5. In Jewish women, mutation 185delAG is strongly associated with breast Ca <40 yrs [23]
   6. BRCA1 mutations in 3% breast Ca [31,32] and ~1% of ductal carcinoma in situ (DCIS) [3]
   7. Having one first degree relative with breast Ca is not associated with BRCA1 mutations [31,32]
   8. However, in women with breast AND ovarian cancer, >13% have BRCA1 mutations [7]
   9. BRCA1 mutations found more commonly in medullary Ca and fewer ductal Ca [24]
   10. Screening for BRCA1 mutations in the general population is not warrented [31]
   11. African American women have lower incidence of deleterious mutations and higher incidence of sequence variations in BRCA1 and 2 compared with European women [69]
   12. Majority (83%) of BRCA1 breast cancers are estrogen receptor negative [2]
4. BRCA2 [8]
   1. Gene localized to 13q12-q13; codes very large protein of 3418 residues (no homology)
   2. Binds to RAD51, part of the DNA repair system [59]
   3. Involved in 2.5-30.0% patients with young onset, familial breast Ca
   4. Found in 2.4% of DCIS [3]
   5. Mutations in affected persons are deletions (likely tumor suppressor)
   6. Genetics in affected families suggest autosomal dominant inheritance
   7. May play greater role than BRCA1 in male breast cancer and in ovarian cancer [24]
   8. Risk of breast Ca with BRCA2 999del5 mutation is 17% at 50, 37% at 70 years [35]
   9. Majority (76%) of breast ca associated with BRCA2 mutations are ER+ [2]
5. Recommend BRCA1/2 DNA test for women with the following [67,76]
   1. Ashkenazi Jewish women with any first degree relative with breast or ovarian Ca
   2. Two first-degree relatives with breast Ca, one age <50
   3. More than two 1st or 2nd degree relatives with breast Ca
   4. Both breast and ovarian Ca among 1st and 2nd degree relatives
   5. A first degree relative with bilateral breast Ca
   6. Two or more 1st or 2nd degree relatives with ovarian Ca
   7. A 1st or 2nd degree relative with ovarian Ca
   8. A male relative with breast Ca30.
   9. If a woman does not meet one of the above criterion, BRCA1/2 screening not recommended [67]
6. Management of Inherited BRCA1/2 Carriers [29]
   1. Mammography has reduced sensitivy in younger women, but begin at age 25-30 years
   2. MRI (see below) is superior to mammography
   3. Clinical breast exam is essentially useless in detecting cancers in high risk patients
   4. Consider chemoprophylaxis, though side effects are significant
   5. Carriers of BRCA1 or BRCA2 mutations who have children have a 1.7 fold increased risk of developing breast ca before age 40 compared with nulliparous carriers [42]
   6. Prophylactic mastectomy should be considered
   7. Overall, carriers should undergo frequent MRI ± mammographic screening
   8. Family members should be advised to seek counseling and potential testing
7. Magnetic Resonance Imaging (MRI) in BRCA1/2
   1. Screening BRCA1/2 carriers with MRI is superior to mammography, ultrasound, and clinical breast examination [65]
   2. MRI breast ca screening is cost effective in women with BRCA1/2 mutations [70]
8. In male breast cancer, androgen receptor appears to contribute
9. In clinical setting, BRCA testing in family members is in high demand [47]
10. Prophylactic Mastectomy [6,45,47,55]
    1. Consideration for women with BRCA1 or BRCA2 mutations [15]
    2. Confer a survival benefit, and reduce new breast cancers by >90% (up to 100%)
11. Prophylactic Bilateral Salpingo-Oopherectomy [6,7,8]
    1. Reduces risk of ovarian cancer >80%
    2. Reduces risk of breast cancer >50%
    3. Recommended for women with BRCA1 or BRCA2 mutations
12. Tamoxifen [68]
    1. Reduced risk of breast ca in contralateral breast in BRAC1/2+ cancers [54]
    2. Reduced incidence of ER+ breast cancer in healthy women with BRCA2 mutations 62% [2]
    3. No effect on incidence of ER+ breast cancer in healthy women with BRCA1 mutations [2]

C. Ovarian Cancer Syndromes [5]

1. BRCA1 and BRCA2 mutations both increase risk for ovarian cancer
2. BRCA1185delAG is common germline mutation in Israeli patients and may confer early onset ovarian cancer
3. Ovarian tumors with germline mutations of BRCA1 are associated with a better clinical course than ovarian cancers with sporadic mutations [44]
4. BRCA2 mutations linked to ~3%, and BRCA1 to ~6%, of all ovarian cancers
5. Unclear whether oral contraceptive use reduces risk of ovarian cancer in women with pathogenic BRCA1 or BRCA2 mutations [37,56]
6. Increasing parity reduces risk of familial ovarian cancer in BRCA1 or BRCA2 carriers [56]

D. Li-Fraumeni Syndrome [51]

1. Characteristics of Li-Fraumeni Syndrome
   1. Childhood occurrance of various malignancies
   2. Females who survive until puberty are at risk for early onset breast cancer
2. Etiology
   1. Mutation of the p53 gene on chromosome 17p13.1 is most common cause
   2. Rarely caused by mutatios in CHK2 (protein kinase) which phosphorylates p53
   3. CHK2 also phosphorylates and activates BRCA1 (see above)
3. Role p53 [51]
   1. Most important checkpoint control gene
   2. Normal p53 "Senses" DNA damage in cell and causes cell cycle arrest
   3. Normal p53 is a transcription factor which regulates gene expression
   4. Functionally, normal gene is a tumor suppressor
4. Mutated p53
   1. Germline mutations cause Li-Fraumeni Syndrome
   2. Somatic mutations found in >50% of human tumors
   3. Inherited as autosomal dominant trait with high penetrance

E. Retinoblastoma (Rb) Mutations

1. Rb gene on chromosome 13q14
   1. Protein is 105kD and plays a role in cell cycle regulation
   2. Functionally, normal gene is a tumor suppressor
   3. Normal protein important in retinal and bone growth
2. Major Diseases Associated with Rb Mutations
   1. Retinoblastoma - unilateral or bilateral
   2. Osteosarcoma
   3. Retinoblastoma Syndrome
3. Inherited dysfunction of single Rb allele
   1. Relatively high likelihood of second allele inactivation in several cells around same time
   2. This apparently leads to poorly controlled cell growth
   3. Tumors arise in multiple foci within retina
   4. ~10% of carriers of germ-line mutations do not develop retinoblastoma
   5. All patients are at risk for osteosarcomas
4. Sporadic Initial Mutations of Rb Gene
   1. Double Rb inactivation in the same cell required for tumor initiation
   2. Very unusual event leading to unilateral disease
   3. No increased risk of secondary tumors

F. Wilms' Tumor [61]

1. WT1 gene on chromosome 11p13
   1. Zinc finger type transcription factor
   2. Functionally, normal gene is a tumor suppressor
2. Characteristics of Wilms' Tumor (Nephroblastoma)
   1. Familial and Sporadic Cases, ~1/10,000 children
   2. Several different loci on chromosome 11 linked to gene
   3. Gene on 11p13 codes for 345 residue zinc finger protein; probable tumor suppressor
   4. The 11p13 gene expressed in kidney and urogenital precursors (WAGR)
3. Developmental Syndrome with Wilms' Tumors Common
   1. Called "WAGR"
   2. Wilms' tumor with aniridia, genitourinary malformations and retardation
   3. Aniridia gene Pax6 in close proximity with Wilms' Suppressor gene WT1
4. WT2 gene found on chrom 11p15
   1. Associated with Beckwith-Wiedemann Syndrome
   2. This syndrome has macroglossia, organomegaly, hyperinsulinemic hypoglycemia

G. Neurofibromatosis (NF) [13,26]

1. Clinical diseases and genetic abnormalities correlate nicely
   1. Two types of NF have been identified
   2. Both types are autosomal dominant disorders
   3. Both have increased benign and malignant tumors at increased frequency
   4. NF Type 1 previously called Von Recklinghausen's NF
2. NF Type 1 Disease [21,66]
   1. Over 60 distinct mutations in NF1 gene on chr 17q11 lead to NF Type 1
   2. NF1 protein is called neurofibromin and includes is a GTP activating protein (GAP) domain
   3. Neurofibromin is involved in signalling and cell cycle
   4. Neurofibromin mainly expressed in neurons, Schwann cells, glial cells
   5. Protein behaves like a tumor suppressor, regulates RAS signalling
   6. Molecular testing to detect many of mutations is now available
   7. Occurs in about 1:3500 persons
   8. Schwannomas or other types of nerve cell tumors; plexiform neurofibromas
   9. Cafe-au-lait spots: usually 6 or more
   10. Freckling in axilla or groin
   11. Optic glioma and/or benign iris hamartomas
   12. Bony Lesion: dysplasia of sphenoid bone, of a long bone, or of vertebral bodies
   13. Increased incidence of juvenile acute myelomonocytic leukemia (AMML) [27]
   14. Pheochromocytoma in <10%
   15. Ras inhibitors are being investigated
   16. Simvastatin (Zocor®) in children with NF1 did not improve cognitive function in 12 weeks [77]
3. NF Type 2 Disease [21]
   1. Mutations in NF2 gene on chr 22q lead to NF Type 2
   2. NF2 protein is a called merlin, related to other cytoskeletal proteins
   3. These related proteins include ezrin, moesin, and radixin
   4. Schwannoma: bilateral vestibular are most common, may be unilateral
   5. Meningioma and/or glioma
   6. Juvenile cataracts
   7. Must have combination of the above signs/symptoms
   8. Occurs in ~1 in 40,000 births, population prevalance 1 in 210,000 population

H. Multiple Endocrine Neoplasia (MEN)

1. Mutations in the c-RET gene on chromosome 10 found in all MEN
2. Neoplastic Associations of Ret Mutations [28]
   1. Hemangiomas
   2. Renal Cell Carcinoma
   3. Pheochromocytoma
   4. Von Hippel-Lindau (VHL) Disease
3. Genetics of MEN1
   1. Mutations in gene called menin is found in MEN1
   2. Menin is a tumor suppressor gene
4. Genetics of MEN2
   1. MEN 2 arises from mutations of the RET gene on chromosome 10
   2. MEN-2B is usually caused by germ-line mutations in the RET gene
   3. MEN-2A may be caused by non-germ-line mutations in the RET gene
   4. Some families have mutations of von Hippel-Lindau gene and may not have MEN 2
   5. Deletions in the RET oncogene appear to cause Hirschsprung's Disease
5. Measurements of plasma normetanephrine and metanephrine are useful for screening for pheochromocytoma in these patients [39]

I. Von Hippel-Lindau Disease [11,60,71]

1. Autosomal dominant inheritance with germline mutations in one copy of VHL Gene
2. Occurs in 1 in 36,000-39,000 live births
3. VHL Tumor Suppressor Gene and Protein [72]
   1. Located on chromosome 3p25-26
   2. VHL is a E3 (ubiquitin ligase) enzyme involved in protein degradation
   3. Normal VHL protein targets degradation of elongin, a translational control factor
   4. Normal VHL also blocks expression of hypoxia induced genes including HIF-1a
   5. All patients with VHL disease have one germline inactivating VHL allele
4. Tumorigenesis
   1. Tumors only arise in cells that have deleted or mutated second VHL allele
   2. Mutated VHL protein cannot degrade elongin, leading to abnormal protein translation
   3. In addition, mutated VHL cannot block expression of hypoxia induced genes
   4. Some c-ret mutations (see above) are associated with VHL Disease
5. Characteristics of Von Hippel-Lindau Disease
   1. Rare, multisystem neoplastic disorder
   2. Benign and malignant neoplasms occur
   3. Retinal Angiomas
   4. Brain and Spinal Cord Hemangioblastomas - nonmetastasizing vascular tumors, often retinal; major cause of death in VHL
   5. Renal Cysts and Renal Cell Carcinomas (RCC is major cause of death in VHL disease)
   6. Neuroendocrine Tumors: pheochromocytomas (~20%), islet cell tumors
   7. Pancreatic and Epididymal Cysts and Cystadenomas
   8. Endolymphatic (Temporal Bone) Sac Tumors
6. Endolymphatic Sac Tumors [11,73]
   1. Hearing loss in 95%, primarily due to microscopic tumors in endolymphatic sac/duct
   2. Tinnitus 92%
   3. Vertigo or disequilibrium 62%
   4. Aural fullness 29%
   5. Facial paresis 8%
   6. Hemorrhage can also occur due to the tumors, causing acute hearing loss [73]
7. Screening and Evaluation
   1. Ophthalmoscopy annually beginning in infancy
   2. Measurements of plasma normetanephrine (but less so of metanephrine) are useful for screening for pheochromocytoma in patients with VHL [39]
   3. Begin measuring plasma or 24 hour urinary metanephrines annually, begin at age 2 years
   4. MRI of craniospinal axis annually at 11 years of age
   5. CT and MRI of internal auditory canals at onset of symptoms
   6. Abdominal Ultrasound: annually, begin age 8
   7. Abdominal CT: annually, begin age 18 or earlier if clinically indicated
   8. MRI as clinically needed
8. Early detection and surgical resection is most effective therapy in general

J. Ataxia-Telangiectasia (ATM) [52,53]

1. Rare autosomal recessive disorder
   1. Carriers represent ~1.5% of population
   2. Disease frequency <1:10,000
   3. Median lifespan 20 years in homozygotes
   4. Lifespan ~7 years shorter in heterozytoges
2. Defective DNA Repair [51]
   1. Mutation on ATM gene on chromosome 11q22-23
   2. ATM gene codes for DNA repair protein involved in mitogenic signal transduction
   3. Also involved in meiotic recombination and control of cell cycle
   4. One domain is homologous to radiation repair genes RAD3 and MEC1
   5. Other domain is homologous to a phosphatidylinositol-3-kinase (DNA dependent kinase)
   6. Altered cell signalling and DNA repair appears to be result of abnormal gene product
3. Symptoms
   1. Ataxia due to cerebellar Purkinje fiber degeneration
   2. Neuromuscular degeneration, progression to wheelchair requirements, usually by age 10
   3. Dilation of capillary vessels, shows up on skin (telangiectasias)
   4. Immune abnormalities
4. Role in Neoplasia
   1. Role in development of B cell (B-CLL) and prolymphocytic T cell leukemias
   2. Abnormal expression of ATM gene found in nearly 50% of chronic B cell leukemias
   3. Increased risk of other cancers including breast cancer (3-5X in some studies)
   4. ATM gene product can phosphorylate and thereby activate BRCA1 protein
   5. Mutant ATM is probably unable to phosphorylate key regulatory proteins
   6. Hypersensitivity to radiation exposure
   7. ATM gene may also play a role in telomere maintenance [62]

H. Familial Melanoma [63]

1. About 10% of melanoma associated with family history
2. Hereditary melanoma (high risk alleles) represents ~1% of all melanomas overall
   1. True hereditary melanoma due to mutations in CDKN2A and CDK4
   2. CDK is cyclin dependent kinase involved in cell cycle regulation
   3. CDKN2A on chromosome 9p21 codes for 16K protein called p16
   4. p16 blocks CDK 4/6 complex from phosphorylating Rb protein (see above)
   5. Phosphorylation of Rb protein leads to expression of E2F transcription factors
   6. E2F transcription factors drive G1 to S phase transition of cell cycle
   7. p16 loss leads to hyperphosphorylation of Rb protein and allows cell cycle progression
3. Carney Complex [63,64]
   1. Symptoms as above for NAME or LAMB also including adrenal abnormalities
   2. ~50% of cases due to mutations in PRKAR1 alpha gene on chromosome 17q2
   3. PRKAR1a encodes regulatory subunit of R1alpha of cAMP-dependent protein kinase A

I. Hereditary Diffuse Gastric Cancer Syndrome [75]

1. Due to E-cadherin (CDH1) mutations
2. ~2% of gastric cancers associated with this mutation
3. Diffuse (rather than focal) gastric cancer of signet rignt type occurs
4. Increased risk (~45% lifetime) of breast cancer, usually lobular form

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