Cancer Genetics Flashcards
1
Q
Six Features of Cancer Cells
A
- independence of external growth signals
- insensitive to anti-growth signals
- ability to avoid apoptosis
- ability to replicate indefinitely
- ability to trigger angiogenesis
and vascularize - ability to invade tissues and establish secondary tumors
2
Q
t(8;14)(q24;q22)
A
Burkitt’s lymphoma; MYC gene translocated next to immunoglobulin gene
3
Q
t(9;22)
A
Philadelphia chromosome; BCR-ABL fusion oncogene causing chronic myeloid leukemia
4
Q
Four Classes of Cancer Regulatory Genes
A
- protooncogenes/oncogenes
- tumor suppressor genes
- apoptosis regulation genes
- DNA repair genes
5
Q
Oncogenes
A
- “too much gas”
- GoF mutation that is dominant at cellular level and promotes uncontrolled cell growth
- Examples: Her2, BCR-ABL, RAS family
6
Q
Tumor Suppressor Genes
A
- “no brakes”
- LoF mutation that is recessive at cellular level and leads to loss of cell division control
- Examples: RB1, BRCA1/2, NF1/2, etc
7
Q
Apoptosis Regulation Genes
A
- “energizer bunny”
- damaged cell does not undergo programmed cell death
- Examples: TP53
8
Q
DNA Repair Genes
A
- “no quality control”
- enzymes lose function to repair DNA appropriately
- seen in both heterozygous and homozygous states
- Examples: ATM/ataxia telangiectasia, NBN/Nijmegen breakage, Bloom, Fanconi anemia
9
Q
Population Risk - Prostate Cancer
A
14%
10
Q
Population Risk - Breast Cancer
A
12-13%; <1% in males
11
Q
Population Risk - Colorectal Cancer
A
4-5%
12
Q
Population Risk - Pancreatic Cancer
A
1.5%
13
Q
Population Risk - Ovarian Cancer
A
1%
14
Q
Population Risk - Uterine Cancer
A
3%
15
Q
Cancer Risk Factors
A
- age
- tobacco
- diet
- alcohol consumption
- occupational exposures
- hereditary factors
- radiation
- virus exposure
- chronic conditions (Crohn’s, celiac)
16
Q
Colorectal Cancer Risk Factors
A
- diet
- family history
- alcohol
- cigarettes
- chronic disease
- history of polyps
- older age
17
Q
Hallmarks of Hereditary Cancer
A
- cancer diagnosed at an early age (<50; premenopausal)
- multiple close relatives with same or related cancers
- 2+ primary cancer diagnoses in same individual
- certain rare cancers or tumors
- other features associated with hereditary cancer syndromes
18
Q
Limitations to Assessing Hereditary Cancer Risk
A
- small family size/limited family structure
- incomplete family history
- inability to document diagnoses
19
Q
Limited Family Structure
A
fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage
20
Q
Uninformative Negative
A
- negative result in context of undocumented familial pathogenic variant that cannot rule out a hereditary predisposition
- risk based on personal and family history
21
Q
True Negative
A
- negative result in context of a documented and identifiable familial pathogenic variant
- risk is population risk
22
Q
Multi-Gene Panel Testing
A
- benefits: higher mutation detection rate, may reduce uninformative negative results, increased number of patients benefit from risk-reducing options, more cost and time effective than single gene, may reveal more than 1 pathogenic variant
- limitations: increased chance to find a VUS, variant classifications may differ across labs, limited data regarding cancer risk for some genes, lack of clear guidelines for medical management of mutation carriers for some genes
23
Q
Polygenic Risk Scores
A
- combines risk contribution of multiple SNPs to generate a single risk estimate that is more comprehensive than risk estimate obtained from any individual SNPs
- performance improved when combined with family history or additional clinical features
24
Q
Breast Anatomy
A
- 15-20 lobules that produce milk in lactating women
- fat (1/3 of breast) not considered part of breast tissue
- stroma is fibrous connective tissue
- lymphatic system tries to flush out cancer cells when present
25
Breast Cancer Risk Factors
- age: 1/3 breast cancers in women >50y
- alcohol use: 2+ drinks per week increase estrogen levels in body
- benign breast conditions
- atypical breast cells (hyperplasia)
- ethnicity: white women more likely to get it; non-white women more likely to die from it
- personal history and family history
- hormones: menarche <12y, menopause >55y, ERT, age at first live birth >30y, no pregnancy, no breast-feeding, postmenopausal obesity, prolonged HRT use >5y
26
Benign Breast Lesions
- cyst: fluid-filled sac; complex cysts should be biopsied
- fibroadenoma: smooth, round lumps that move easily with breast tissue; size may fluctuate with menstrual cycle
- microcalcifications: specks of calcium on mammogram; 20% associated with malignant tumor
27
LCIS
not cancer but 7-11x more likely to develop invasive breast cancer
28
DCIS
- noninvasive, preductal stage 0 breast cancer
| - 1/3 turn into invasive cancer
29
IDC
- 80% of all breast cancer diagnoses
- originated in epithelial cells of milk duct and spread through duct walls to surrounding tissues
- types: tubular, medullary (BRCA1), mucinous, colloid, papillary, cribriform
30
ILC
- 10% of all breast cancer diagnoses
- originated in lobules and spread through lobule walls to surrounding tissues
- CDH1/diffuse gastric cancer
31
Inflammatory Breast Cancer
- 1% of all breast cancer diagnoses
| - high-grade, aggressive cancer
32
Phyllodes Tumor
- "leaf like"
- originates from stromal cells and may be benign or malignant
- malignant reported in LFS
33
Paget's Disease of the Nipple
- cancer cells collect around nipple causing scaly, red, itchy nipple/areola
- 97% associated with cancer elsewhere in breast
34
Breast Cancer Screening - Average Risk
- 25-29y: clinical encounter every 1-3y, breast awareness
| - 40y+: annual clinical encounter, annual screening mammo, breast awareness
35
Women at Increased Risk for Breast Cancer
- prior history of breast cancer
- women with lifetime risk >20% as defined by models largely based on family history
- patients who received RT <30y
- 5-year invasive breast cancer risk >1.7% in women >35y
- women who have lifetime risk >20% based on history of LCIS or ADH/ALH
- pedigree suggestive of known genetic predisposition
36
Breast Cancer Screening - Lifetime Risk >20%
- clinical encounter every 6-12m
- annual screening mammo, which begins 10y prior to youngest diagnosis but not before 30y
- recommend annual breast MRI, which begins 10y prior to youngest diagnosis but not before 25y
- recommend risk-reducing strategies
- breast awareness
37
Mammogram
- low dose x-ray picture of breast
- can detect tumors before palpable
- less informative in dense breasts
38
BI-RADS
- breast density levels
- 40% of women have dense breasts
- BI-RADS 4-6 require biopsy or treatment
39
Tomosynthesis
3D mammogram
40
Breast MRI
- uses a powerful magnetic field linked to computer and injection of gadolinium dye for contrast
- can find things mammo can't
- false positives can lead to unnecessary biopsy
41
Breast Ultrasound
- helps distinguish between fluid-filled cysts from solid tumors
- offered to women with dense breasts
- suitable for pregnant women
- least sensitive and specific
42
Biopsy
- incisional: takes small sample from mass for analysis
- excisional: removes entire mass
- core: removal of tissue using wide needle
- fine-needle aspiration: removal of tissue using thin needle
- if malignancy detected, biopsy sentinel lymph node
43
Cancer Staging
```
T = size of tumor
N = lymph node involvement
M = metastasis to distant sites
ER = estrogen receptor status
PR = progesterone receptor status
Her2 = her2/neu status
G = cancer grade
```
44
OncotypeDx
- 21 gene panel (16 cancer related, 5 reference) performed on breast tumor typically after surgery for ER+, her2-, LN- breast cancers (stage I)
- predicts likelihood of recurrence and likely benefit of addition of adjuvant systemic chemotherapy to adjuvant endocrine therapy
45
Lumpectomy
partial mastectomy or breast-conserving surgery
46
Mastectomy
- modified radical: removes breast, most/all lymph nodes, lining over chest muscles
- radical: also removes pectoral muscles
- total/simple: leaves behind lymph nodes and muscles
- double: both breasts
- skin sparing: for immediate breast reconstruction
- nipple sparing: nipple and areola left intact
47
Breast Reconstruction
- implant reconstruction: saline, silicone gel, or combo
| - autologous/flap reconstruction: tissue transplanted from another part of body
48
Radiation
targets remaining breast tissue, neighboring lymph nodes, chest wall via external beams or surgically implanted seeds
49
Chemotherapy
post-op systemic therapy or neoadjuvant therapy (treat tumor before surgery)
50
Hormonal Therapy
- ER/PR+: tamoxifen, aromatase inhibitor (good for postmenopausal women)
- Her2+: Herceptin, Perjecta
51
PARP Inhibitor
- biological therapy that prevents PARP from repairing double-stranded breaks
- BRCA genes repair DNA through homologous recombination while PARP repairs through base excision repair
52
Candidates for Breast Cancer Counseling
- early age of onset
- multiple relatives with same/related cancer
- multiple promaries
- AJ ancestry
- unusual presentation/rare cancer
- pathology (TNBC)
- known pathogenic variant, including those uncovered on tumor testing
53
Gail Model
- only used for women 35-85y
- estimates risk of developing invasive breast cancer over next 5 years and up to age 90
- uses personal medical and reproductive history along with history of breast cancer in 1st degree relatives
- validated for many ethnicities
- should not be used for women with hereditary cancer syndrome, extensive family history beyond first degree relatives, received radiation, previous history of breast cancer
- can underestimate hereditary risk of breask cancer
- 5y risk >1.7% indicates qualification for tamoxifen
54
Tyrer-Cuzick Model
- used for women 20-85y without a personal history of breast cancer
- estimates 10y and lifetime risk for cancer as well as BRCA risk
- based on UK population, so not as accurate for non-white populations
- adjusts for negative BRCA results, can include cousins, adjusts for AJ ancestry
- incorporates menarche, parity, age of first child, age at menopause, use of HRT, atypical hyperplasia, LCIS, premenopausal height, postmenopausal BMI
- places emphasis on biopsy history which may inflate risks, no inclusion of male prostate or pancreatic cancers
55
Claus Model
- statistical model used to calculate cumulative breast cancer risk based on family history (only factor considered)
- incorporates age at diagnosis, cumulative risk by age, paternal relatives, second degree relatives
- best for moderate risk patients, may underestimate risk in families with 3+ affected relatives, and does not take into account lifestyle factors
56
Myriad Tables
- two tables, one for AJ and one for non-AJ individuals based on personal history, family history/degree of relationship to breast or ovarian cancers
- predicts BRCA1/2 mutations
57
BRCAPro
- predicts BRCA1/2 mutations and breast and ovarian cancer risks based on BRCA1/2 risks
- includes unaffected family members to modify risk, male breast cancers, age of diagnosis
- includes adjustment based on pathological features/biomarkers of patient's cancer, genetic testing results, history of oophorectomy, risks of other BRCA-associated cancers, race, penetrance estimates
58
Pen II Model
- pretest probability of BRCA1/2
- does not predict breast cancer risk
- one lineage at a time, does not combine maternal and paternal history
- accounts for prostate and pancreatic cancer
59
BOADICEA
- accounts for current age/age of death, year of birth (cohort effect), age of diagnosis, occurrence/lack of for survivors, genetic testing results, half sibs, male breast cancer, pancreatic cancer, prostate cancer, AJ ancestry, genes other than BRCA1/2
- often requires info not available, does not account for non-genetic factors, does not adjust for pathology, does not include previous oophorectomy, underestimates mutation detection rate, "research use only"
60
Cleveland Clinic PTEN Calculator
calculates risk for having PTEN mutation
61
AJ Founder Mutations
c. 68_69delAG or 187delAG
c. 5266dupC or 5382insC
c. 5946delT or 6174delT
62
PALB2
- 17-58% breast cancer risk
- risk for pancreatic cancer, male breast cancer, Fanconi anemia
- screening: annual mammo, consider breast MRI with contrast at 30y
63
CHEK2
- 23-48% (variant specific) breast cancer risk
- risk for CRC, male breast cancer
- screening: annual mammo, consider breast MRI with contrast at 40y
64
ATM
- 17-52% breast cancer risk
- risk for pancreatic, prostate, maybe ovarian cancers, ataxia telangiectasia
- screening: annual mammo, consider breast MRI with contrast at 40y
65
NBN
- up to 30% breast cancer risk
- risk for prostate cancer, Nijmegen breakage syndrome
- screening: annual mammo, consider breast MRI with contrast at 40y
66
NF1
- 8.4% breast cancer risk to age 50 compared with gen pop of 1.9%
- risk for neurofibromas, GIST, malignant peripheral nerve sheath tumors
- screening: annual mammo at 30y, consider breast MRI with contrast 30-50y
67
BARD1
- potentially increased breast cancer risk
68
BRCA1 Cancer Risks
- breast: 50-85%
- second breast primary: 13-20%
- ovarian: 20-44%
- male breast: 1-2%
- prostate: elevated
- pancreatic: elevated
69
BRCA2 Cancer Risks
- breast: 40-70%
- second breast primary: 8-12%
- ovarian: 15-27%
- male breast: 7%
- prostate: 20%
- pancreatic: 2-7%
- melanoma: elevated
70
Mutation Positive Management Recommendations - Breast Cancer
- increased surveillance: breast MRI with contrast 25-29y, annual mammo + breast MRI 30-75y
- prophylactic surgery: risk-reducing mastectomy, BSO (35-40y for BRCA1, 40-45y in BRCA2)
- chemoprevention: tamoxifen (ER+, BRCA2, premenopausal), aromatase inhibitors (postmenopausal)
- PARP inhibitors
71
Gynecologic Anatomy
- ovary: produces oocytes
- fallopian tube: transports oocytes to site of fertilization
- uterus: promotes implantation of fertilized egg in uterine wall, otherwise menstruation occurs
- FSH, LH, estrogen, and progesterone produced to maintain reproductive cycles and promote bone density
- peritoneum: serous membrane lining abdominal cavity and surrounding organs
- lymphatic system: drainage system that can enable metastasis of cancer cells
- 95% of uterine cancers are endometrial
72
Risk Factors for Uterine Cancer
- age >50y
- endometrial hyperplasia
- estrogen exposure: estrogen-only HRT, early menstruation, late menopause, never being pregnant, obesity (6x higher risk), diabetes, tamoxifen in postmenopausal women
- previous pelvic radiation
- family history in FDR
- hereditary cancer syndrome
- Caucasian ethnicity
- cigarettes are protective
73
Risk Factors for Ovarian Cancer
- family history in FDR (5% lifetime risk)
- hereditary cancer syndrome
- age (rare <40y)
- obesity
- estrogen-only HRT after menopause
- North American, Northern European, or AJ heritage
- pregnancy, breastfeeding, oral contraceptives protective
74
Risk Factors for Vaginal Cancer
- age
- HPV
- smoking
- cervical cancer
- previous radiation
- diethystilbestrol (DES) exposure
75
Risk Factors for Cervical Cancer
- age (late teens - mid 30's)
- HPV, herpes
- smoking
- immune system deficiency
- DES exposure
- socioeconomic factors
76
Noncancerous Uterine Lesions
- fibroids/leiomyomas: benign tumors in uterine muscle
- benign polyps
- endometriosis: endometrial tissue found outside of uterus
- endometrial hyperplasia: increased number of cells and glandular structures in uterine lining
77
Types of Uterine Cancer
- endometrial cancer/adenocarcinoma (85-95%): type I have endometrioid histology and associated with PTEN, type II have non-endometrioid histology and have poorer prognosis
- sarcoma (<5%): leiomyosarcoma, endometrial stromal sarcoma
78
Types of Ovarian Cancer
- epithelial (majority): benign, borderline, malignant (85-90% of malignant ovarian tumors; serous, endometrioid, clear cell, mucinous)
- germ cell (benign): develops in egg-producing cells of ovaries; 10-29y
- stromal: connective tissue tumors; associated with PJS
- cyst
79
Signs/Symptoms of Uterine Cancer
- unusual vaginal bleeding/discharge
- pelvic pain
- pain during intercourse
- difficult/painful urination- abnormal Pap
80
Diagnosis of Uterine Cancer
- physical exam of pelvis
- medical history
- endometrial biopsy
- dilation and curettage
- imaging: hysteroscopy, transvaginal u/s, CT, MRI
81
Treatment of Uterine Cancer
- surgery: vaginal hysterectomy, TAH, total laparoscopic hysterectomy
- radiation, chemotherapy, hormone therapy/biological therapy
82
Signs/Symptoms of Ovarian Cancer
- pain, swelling, pressure in abdomen/pelvis
- irregular/heavy vaginal bleeding, especially after menopause
- vaginal discharge
- lump in pelvic area
- GI problems
- ascites
83
Diagnosis of Ovarian Cancer
- physical exam of pelvis
- medical history
- CA-125 assay
- biopsy or paracentesis (removal of ascites fluid)
- imaging: transvaginal or abdominal u/s, CT, PET, MRI, chest x-ray
84
Favorable Prognostic Factors for Ovarian Cancer
- younger age
- cell type other than mucinous or clear cell
- grade 1 tumor/early disease
- absence of ascites
- lower disease volume before surgical debulking
- smaller residual tumor after primary cytoreductive surgery
- BRCA carrier (platinum based chemo, PARP)
85
Treatment of Ovarian Cancer
- surgery: salpingo-oophorectomy, hysterectomy, lymphadenectomy/lymph node dissection, omentectomy, cytoreductive/debulking surgery
- chemotherapy, targeted therapy, radiation, immunotherapy, clinical trial
- oncofertility preservation
86
Risk Factors for Prostate Cancer
- age >65y
- race/ethnicity: black men have a higher risk and tends to be more aggressive
- family history: risk is 2-3x high in men with affected FDR
- hereditary cancer syndrome (BRCA2)
87
Prostate Cancer Screening
digital rectal exam or PSA blood test starting at 45y
88
Gleason Score
- used to grade prostate cancer
- score assigned from 3-5 based on two locations and added together
- scores 7+ concerning and warrant genetic testing
89
Treatment of Prostate Cancer
- watchful waiting/surveillance
- radiation
- surgery
90
Testicular Cancer
- typically germ cell tumors
- lifetime risk <1%
- average age at diagnosis is 33y
- risk factors: age (20-45y), cryptorchidism, personal/family history, race (more common in white men), HIV
- no screening
- treatment includes radiation, chemo, surgery
91
BRIP1
- 5.8% ovarian cancer risk
- risk for Fanconi anemia
- consider RRSO 45-50y
92
RAD51C
- 6.7% ovarian cancer risk
- risk for Fanconi anemia
- consider RRSO 45-50y
93
RAD51D
- 14.8% ovarian cancer risk
| - consider RRSO 45-50y
94
Colon Anatomy
cecum (right-sided) -> ascending colon -> hepatic flexure -> transverse colon -> splenic flexure -> descending colon (left-sided) -> sigmoid colon -> rectum -> anus
95
Screening Options for CRC
- colonoscopy: gold standard; prep required, procedure done under anesthesia
- fecal occult blood test: noninvasive/inexpensive/private; positive result indicates cancer already present
- CTC colonoscopy (virtual): prep required, gas inserted through rectal tube; needs to be followed up with normal colonoscopy if suspicious findings present
- flexible sigmoidoscopy
96
Screening for CRC - Average Risk
- starting at age 50
- every 10y if no polyps found
- FOBT yearly
- CTC colonoscopy every 5y
- flexible sigmoidoscopy every 5-10y
97
Screening for CRC - Increased Risk
- 1+ FDR with CRC: colonoscopy beginning at age 40y or 10y prior to youngest diagnosis; repeat every 5y if negative
- 1+ SDR with CRC <50: colonoscopy beginning at age 50y; repeat every 5-10y if negative
- FDR with advanced adenomas: colonoscopy beginning at 40y or at age of onset of adenoma; repeat every 5-10y if negative
98
MSI
- accounts for 15% of cases of CRC (85% due to chromosomal instability)
- short, repetitive DNA sequences found throughout tumor genome that are prone to mutations leading to frameshifts
- cancers with MSI tend to be right-sided (sporadic are left-sided), have higher numbers of lymphocytes, improved survivability
99
IHC
looks for presence/absence of MLH1, MSH2, MSH6, and PMS2 proteins on tumor tissue
100
MLH1 Promoter Methylation
hypermethylation pathway that involves CpG islands and tends to be sporadic
101
BRAF
- V600E mutation seen in 8-11% of all CRC tumors and 80% of all MLH1-deficient tumors
- presence indicates sporadic MSI CRC and excludes diagnosis of Lynch
102
CRC Prediction Models
- MMRPro, MMRPredict, PREMM5
| - consider testing for Lynch syndrome if predicted risk score >5% on prediction model
103
Types of Colon Polyps
- pedunculated tubular adenoma (FAP)
- hamartoma (PJS, JPS)
- hyperplastic/serrated adenoma (SPS)
- inflammatory (celiac, Crohn's, IBS)
104
Detection of Polyps
- colonoscopy (if >10 adenomatous polyps over lifetime, genetic evaluation necessary)
- rectal bleeding
- anemia on CBC
- diarrhea/constipation/"change in bowel habits"
105
MLH1/MSH2 Cancer Risks
- colon: 52-82%
- endometrium: 25-60%
- ovarian: 11-20% for MLH1, 15-24% for MSH2
- prostate: 30%
- stomach: 6-13%
- other cancer risks: hepatobiliary tract, urinary tract, small bowel, brain/CNS, sebaceous neoplasms, pancreas
106
MSH6 Cancer Risks
- colon: 10-22%
- endometrium: 16-26%
- prostate: 30%
- stomach: 3% or less
107
PMS2 Cancer Risks
- colon: 15-20%
- endometrium: 15%
- CMMRD
108
Hereditary Breast Cancer Syndromes
- BRCA1/2
- PALB2, CHEK2, ATM, NBN, NF1, BARD1
- Li Fraumeni Syndrome
- Hereditary Diffuse Gastric Cancer Syndrome
- PTEN/Cowden
- PJS
109
Hereditary GYN Cancer Syndromes
- BRCA1/2
- Lynch Syndrome
- BRIP1, RAD51C, RAD51D
- PJS
- PTEN/Cowden
- HLRCC
110
Hereditary CRC Syndromes
- Lynch Syndrome
- FAP
- AFAP
- MUTYH-Associated Polyposis
- MSH3-Associated Polyposis (FAP4)
- GREM1
- NTHL1-Associated Polyposis
- Polymerase Proofreading Associated Polyposis
- PTEN/Cowden
- PJS
- JPS
- Serrated Polyposis Syndrome
111
Hereditary Neuroendocrine Cancer Syndromes
- MEN1
- MEN2 (A, B, FMTC)
- MEN4
- Hereditary Paraganglioma/Pheochromocytoma Syndrome
- von Hippel Lindau
112
Hereditary Renal Cancer Syndromes
- von Hippel Lindau
- Birt-Hogg-Dube
- HLRCC
- Hereditary Papillary Renal Carcinoma
113
Hereditary Dermatologic Cancer Syndromes
- Familial Atypical Multiple Mole Melanoma
- Nevoid Basal Cell Carcinoma/Gorlin
- Xeroderma Pigmentosum
114
Hereditary CNS Cancer Syndromes
- NF1
- NF2
- Tuberous Sclerosis
115
Hereditary Pediatric Cancer Syndromes
- 65% of pediatric cancers in general are leukemias, lymphomas, and brain/CNS tumors
- Li Fraumeni Syndrome
- Hereditary Retinoblastoma
- Hereditary Neuroblastoma
- Fanconi anemia
- DICER1 Syndrome
- Gorlin Syndrome
- Hereditary Predisposition to AML/ALL
- Tuberous sclerosis
- FAP
- MEN2
- DNA instability syndromes: Bloom, CMMRD, ataxia telangiectasia, xeroderma pigmentosum, NBS, Diamond-Blackfan anemia, dyskeratosis congenita
116
Testing Criteria for Breast, Ovarian, Prostate and Pancreatic Cancers
- blood relative with a known P/LP variant
- meet criteria and previous limited testing
- personal history of breast cancer <45y, 46-50y with limited fhx/second primary/1+ close relative with related cancer, <60y with TNBC, any age with AJ ancestry, any age with 1+ close relative with related cancer (breast <50y), any age with 3+ breast cancer diagnoses in patient/close relatives, male breast cancer at any age
- epithelial ovarian cancer at any age
- exocrine pancreatic cancer at any age
- metastatic or intraductal prostate cancer at any age
- Gleason 7+ and AJ ancestry, or 1+ close relative with related cancer (breast <50y), or 2+ close relatives with breast/prostate cancer
- mutation identified on tumor testing
- affected/unaffected individual with FDR/SDR meeting criteria
- affected/unaffected individual who does not meet criteria but has probability >5% for BRCA1/2 mutation
117
Testing for LFS
- Classic Criteria: individual diagnosed <45y with sarcoma, FDR diagnosed <45y with cancer, and additional FDR/SDR in same lineage with cancer <45y or sarcoma at any age
- Chompret Criteria: individual with LFS tumor <46y and 1 FDR/SDR with LFS tumor <56y or multiple primaries at any age; individual with multiple tumors belonging to LFS spectrum with initial tumor <46y; individual with ACC or choroid plexus carcinoma or rhabdomyosarcoma at any age; breast cancer <31y
- known P/LP variant
- mutation identified on tumor testing
118
Testing for Cowden/PTEN
- known P/LP variant
- personal history of Bannayan-Riley-Ruvalcaba
- meeting clinical diagnostic criteria: Lhermitte-Duclos, ASD + macrocephaly, 2+ trichilemmomas, 2+ major criteria (w/ macrocephaly), 3 major criteria (w/o macrocephaly), 1 major and 3+ minor criteria, 4+ minor criteria
- mutation identified on tumor testing
119
Testing for Lynch Syndrome
- known P/LP variant
- personal history of CRC/endometrial at any age with positive IHC/MSI; CRC/endometrial cancer <50y, or synchronous/metachronous LS-related cancer, or 1+ FDR/SDR with LS cancer <50y, or 2+ FDR/SDR with LS cancer at any age; CRC tumor with MSI-H histology
- family history of 1+ FDR with CRC/endometrial cancer <50y; 1+ FDR with CRC/endometrial cancer and another LS cancer; 2+ FDR/SDR with LS cancer with one <50y; 3+ FDR/SDR with LS cancer at any age
- 5% + risk of having MMR mutation based on models
- meeting Amsterdam II or Bethesda guidelines
120
Amsterdam II (3-2-1 rule)
- 3+ relatives with LS-associated cancers (1 must be FDR of other two)
- at least 2 successive generations affected
- at least 1 diagnosed <50y
- FAP excluded
121
Bethesda
- CRC <50y
- synchronous or metachronous LS cancer at any age
- CRC with MSI-H histology <60y
- CRC and 1+ FDR with LS cancer <50y
- CRC and 2+ FDR/SDR with LS cancer at any age
122
Testing for Adenomatous Polyposis
- personal history of 20+ cumulative adenomas
- known P/LP variant
- consider testing if personal history of desmoid tumor, hepatoblastoma, cribriform-morular variant of papillary thyroid cancer, CHRPE, criteria met for SPS, 11-20 cumulative adenomas
123
Testing for Peutz-Jeghers Syndrome
- clinical diagnosis made when individual has 2+ of: 2+ PJ-type hamartomatous polyps, mucocutaneous pigmentation, family history of PJS
124
Testing for Juvenile Polyposis Syndrome
- clinical diagnosis made when individual has 1 of: 5+ juvenile polyps, multiple juvenile polyps throughout GI tract, any juvenile polyps when there's a family history of JPS
- genetic testing recommended
- if known SMAD4 variant, genetic testing should be performed within first 6mos of life due to HHT risk
125
Testing for Serrated Polyposis Syndrome
- RNF43 gene; otherwise no causative gene identifiable
126
Individuals Eligible for Screening for Pancreatic Cancer
- known P/LP variants in ATM, BRCA1/2, CDKN2A, MLH1, MSH2, MSH6, EPCAM, PALB2, STK11, TP53 and family history of pancreatic cancer in FDR/SDR from same side of family as germline variant
- family history of exocrine pancreatic cancer in 2+ FDR from same side of family
- family history of exocrine pancreatic cancer in 3+ FDR/SDR from same side of family
127
Screening Methods for Pancreatic Cancer
- contrast-enhanced MRI/magnetic resonance cholangiopancreatography (MRCP)
- endoscopic ultrasound
- usually done under research conditions
128
Pancreatic Cancer Screening - STK11
screening starting 30-35y or 10y prior to youngest diagnosis
129
Pancreatic Cancer Screening - CDKN2A
screening starting 40y or 10y prior to youngest diagnosis
130
Pancreatic Cancer Screening - Mutation in Another Susceptibility Gene
- screening starting 50y or 10y prior to youngest diagnosis for individuals with exocrine pancreatic cancer in 1+ FDR/SDR from same side of family as germline variant
- not recommended in absence of family history
