Cancer syndromes Flashcards
What features on a FH should make you suspicious for HBOC
breast ca dx before the age of 50
male breast ca
ovarian ca
triple negative breast cancer histology
multiple primary breast cancers in either one or both breasts
combination of pancreatic cancer and/or prostate ca with breast and/or ovarian ca
AJ ancestry
two or more relatives with breast ca, one dx at or before 50yo
three or more relatives with breast ca at any age
FM with a known BRCA1/BRCA2 variant
What are the most common AJ PVs in BRCA1/BRCA2
BRCA1 c.68_69delAG
BRCA1 c.5266dupC
BRCA2 c.5946delT
What testing should be ordered for HBOC
multigene panel with BRCA1/BRCA2 with sequence analysis and del dup concurrently
for AJ ancestry, targeted analysis to start which account for 99% of all PVs identified
10-15% of variants are genomic rearrangements, make sure this testing is also ordered
If there is a known BRCA1/2 PV in a family, when is it still ok to order more testing other than the targeted testing
- individuals of AJ descent who may consider also testing for the three founder variants in addition to the familial variant
- individuals with known BRCA1/2 PV on one side of the family with characteristics of HBOC or another inherited cancer syndrome on the other side of the family should consider multigene panel testing which will also pick up the familial variant
What proportion of HBOC is made of BRCA1 PVs and BRCA2 PVs
BRCA1: 66%
BRCA2: 34%
What cancers are you at risk for if you have a BRCA1 PV and what is the lifetime risk
Breast: 50-70% by 70yo
Contralateral breast: 20-30% w/in 10yrs; 40-50% w/in 20yrs
Male breast: 1-2%
Ovarian: 39-44%
Prostate: 29% by 85yo
Pancreatic: 1-3%
What cancers are you at risk for if you have a BRCA2 PV and what is the lifetime risk
Breast: 45-69%
Contralateral breast: 20-30% w/in 10yrs; 40-50% w/in 20yrs
Male breast: 6-8%
Ovarian: 11-17%
Prostate: 60% by 85yo
Pancreatic: 3-5% by 70
elevated risk for melanoma of the skin and eye
What is the histology of tumors associated with HBOC
Triple negative breast cancer
BRCA2 tumors tend to be ER/PR +
serous adenocarcinomas of the fallopian tubes (rather than the ovaries)
male breast cancer tends to be high grade, hormone receptor + with lymph node metastases
BRCA1/2 among the most common known genetic causes of hereditary pancreatic ductal adenocarcinoma
How is breast and ovarian cancer tx if you have HBOC
Consider bilateral mastectomy as a primary sx tx of breast cancer bc of elevated rate of ipsilateral and contralateral breast cancer
PARP inhibitors given their role in DNA repair could lead to lethality of tumor cells (also called olaparib, which can also be used for ovarian ca tx)
How should you prevent cancer if you have HBOC
Consider prophylactic bilateral mastectomy
chemoprevention w tamoxifen reduces the risk for breast cancer by ~60% (higher rates of endometrial cancer and thromboembolic episodes though)
breast feed for a cumulative total or more than one year to reduce risk of breast cancer
consider prophylactic salpingo-oophorectomy which leads to a 80% reduction in ovarian cancer mortality
50% reduction in risk of ovarian ca associated with oral contraceptive use
What surveillance is recommended for women with HBOC
monthly self breast exam, CBE q6-12mos beginning @25yo, mammogram starting @30yo, breast MRI @25yo or earlier if cancer was dx in family member before 30yo
no screening for ovarian cancer
skin exam w derm
MRCP/EUS in asymptomatic ppl with a FH of pancreatic cancer and based on mutation status
What surveillance is recommended for men with HBOC
monthly self breast exam @35yo, CBE @35yo
serum PSA and digital rectal exam @40yo
skin exam w derm
MRCP/EUS in asymptomatic ppl with a FH of pancreatic cancer and based on mutation status
Is HBOC testing recommended for minors
No, bc surveillance is not recommended to start until 25yo
What is the mechanism of dz for HBOC
BRCA1 colocalized with BRCA2 and RAD51 at sites of DNA damage and activates RAD51 mediated homologous recombination repair of DNA ds breaks
LOF
How is the dx of Lynch syndrome established
in a proband with a heterozygous PV or deletion
recommended to start with a multigene panel that includes MLH1, MSH2, MSH6, and PMS2 as well as EPCAM deletion analysis AND DNA methylation studies of MLH1 promoter since it can be caused by constitutional inactivation of MLH1 by methylation of its promoter (usually in all tissues and is most often simplex)
Not often recommended by can also do serial single gene testing based on IHC results indicating that LOF of a particular MMR gene is most likely but this correlation is not 100%
What proportion of Lynch syndrome is attributed to PVs in which genes
MLH1: 15-40%
MSH2: 20-40%
MSH6: 12-35%
PMS2: 5-25%
EPCAM: <10%
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6+, PMS2+
MSI: MSS
Sporadic cancer
cancer due to other hereditary cancer syndrome
no further lynch testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6+, PMS2+
MSI: MSI High
sporadic cancer
Germline MMR gene PV
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
MSI: MSI high
sporadic cancer
germline MMR gene PV
IHC
if IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
sporadic cancer
germline MLH1 PV
germline PMS2 PV (rare)
targeted BRAF and/or MLH1 promoter methylation testing on tumor tissue
If BRAF/MLH1 methylation is normal, germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
BRAF V600E: Pos
OR
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
BRAF V600E: Neg
MLH1 promotor methylation: Pos
sporadic cancer
germline MLHI PV (rare)
Constitutional MLH1 epimutation
If early onset cancer or significant FH of cancer: germline MMR gene testing
If not, no additional testing
For early onset only: constitutional MLH1 epimutation testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
BRAF V600E: Neg
MLH1 promotor methylation: Neg
Germline MLH1 PV
Germline PMS2 PV (rare)
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2-, MSH6-, PMS2+
Germline MSH2/EPCAM PV
Germline MSH6 PV (rare)
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6+, PMS2-
Germline PMS2 PV
Germline MLH1 PV (rare)
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2-, MSH6+, PMS2+
Germline MSH2/EPCAM PV
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6-, PMS2+
Germline MSH6 PV
Germline MSH2/EPCAM PV
sporadic cancer with tx effect
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
If applicable, consider MSI analysis or repeat IHC on nontreated tumor
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2+
Sporadic cancer: MLH1 promotor methylation or somatic MLH1 or PMS2 PV
Germline MLH1 PV
Germline PMS2 PV
Targeted BRAF and/or MLH1 promoter methylation testing on tumor tissue
If BRAF and MLH1 methylation normal: germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2-, MSH6-, PMS2-
Germline MMR gene PV
Sporadic cancer
Targeted BRAF and/or MLH1 promoter methylation testing AND germline MMR gene testing or paired germline/tumor tissue MMR gene testing (often incl MLH1 methylation testing)
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
What cancer types are you at risk for if you are a female with a PV in MLH1
Any (78%)
CRC (44%)
Endometrium (35%)
Ovary (11%)
Stomach (8%)
Small bowel (8%)
Ureter, kidney (3%)
Urinary bladder (3%)
Brain (2%)
Breast (11%)
What cancer types are you at risk for if you are a male with a PV in MLH1
Any (64%)
CRC (53%)
Stomach (16%)
Small bowel (16%)
Ureter, kidney (4%)
Urinary bladder (5%)
Prostate (7%)
Brain (1%)
What cancer types are you at risk for if you are a female with a PV in MSH2
Any (77%)
CRC (42%)
Endometrium (46%)
Ovary (17%)
Stomach (10%)
Small bowel (10%)
Ureter, kidney (13%)
Urinary bladder (7%)
Brain (2%)
Breast (13%)
What cancer types are you at risk for if you are a male with a PV in MSH2
Any (71%)
CRC (46%)
Stomach (16%)
Small bowel (16%)
Ureter, kidney (16%)
Urinary bladder (9%)
Prostate (16%)
Brain (4%)
What cancer types are you at risk for if you are a female with a PV in MSH6
Any (62%)
CRC (20%)
Endometrium (41%)
Ovary (11%)
Stomach (2%)
Small bowel (2%)
Ureter, kidney (6%)
Urinary bladder (1%)
Brain (1%)
Breast (11%)
What cancer types are you at risk for if you are a male with a PV in MSH6
Any (28%)
CRC (12%)
Stomach (4%)
Small bowel (4%)
Ureter, kidney (2%)
Urinary bladder (4%)
Prostate (5%)
Brain (2%)
What cancer types are you at risk for if you are a female or male with a PV in PMS2
Any (22%)
CRC (3%)
Endometrium (13%)
Ovary (3%)
Stomach (4%)
Small bowel (4%)
Prostate (5%)
Breast (8%)
What cancer types are you at risk for if you are a female or male with a del in EPCAM
CRC: 75%
Endometrium: 12%
What histology is consistent with Lynch syndrome
CRCs with MSI tend to have better prognosis than MSS tumors, potentially reflecting active anti-tumor immune response; risk of metachronous CRC can be as high as 43% for those with MLH1/MSH2 PVs
endometrial cancers with MSI show better prognosis
ovarian cancer is typically of endometrioid histologic subtype
gastric cancers tend to present as intestinal-type adenocarcinoma, located to the duodenum and jejunum
urinary tract cancers are transitional carcinomas of the ureter, renal pelvis, and kidney
brain: glioblastoma makes up more than half; then astrocytoma (22%), oligodendroglioma (9%)
sebaceous neoplasm: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas (all are typically MSI high)
What are the features of Muir Torre syndrome
describes individuals presenting with the combination of sebaceous neoplasms of the skin and one or more visceral malignancies, commonly those seen in lynch syndrome
Is an uncommon variant OF lynch syndrome
What are the features of Turcot syndrome
individuals presenting with CRC or one or more colorectal adenomas in addition to tumors of the CNS caused by PVs in one of the MMR genes or an APC PV
APC PVs are more commonly associated with medulloblastoma; PVs in MMR genes are commonly associated with glioblastoma
What are the features of constitutional mismatch repair deficiency
rare childhood cancer predisposition syndrome caused by biallelic PVs in MLH1, MSH2, MSH6, or PMS2
have CRC or cancer of the small intestine prior to the second decade of life (colonic adenomas were the most frequent finding, cutaneous phenotype similar to NF1, nearly all with cafe au lait macules; hematologic cancers and brain tumors)
What is the genotype/phenotype seen in pts with Lynch syndrome
risk for extracolonic cancers is dependent on the size of the del. 3’ EPCAM deletions have been shown to confer a lower risk for extracolonic cancers, whereas deletions that extend into MSH2 confer extracolonic cancer risks similar to intragenic MSH2 PV
Describe the difference between the molecular differences of sporadic CRC and lynch syndrome associated CRC
sporadic MMR deficient tumors commonly occur in older females; show lack of MLH1 protein expression due to MLH1 promoter methylation and are strongly associated with the CpG island methylator phenotype and serrated route of carcinogenesis
BRAF-related: Somatic BRAF PVs occur in 15% of all CRC and, in rare instances, may be identified in tumor tissue from individuals with Lynch. Prevalence of BRAF PVs in MSI-high CRCs also increased with age; BRAF testing is cost-inefficient for screening in those with MSI-high CRCs dx before 50yo
Somatic MLH1 promoter methylation: 10-15% of CRCs are MSI high or MMR deficient due to somatic methylation of the promoter region of MLH1 that silences gene expression in the tumor tissue, rather than due to Lynch (more effective than BRAF testing); individuals in whom a Lynch syndrome associated germline PV is not identified and who have somatic MLH1 promoter methylation are likely to have sporadic cancer
What is the management for pts with Lynch syndrome
CRC: colonoscopy beginning at 20-25yo or 2-5yrs before earliest CRC dx in family
Endometrial cancer: educate females about symptoms (abnormal uterine bleeding, postmenopausal bleeding); eval of symptoms including endometrial bx q1-2yrs; screening should begin between 30-35yo
Ovarian cancer: educate females about symptoms (pelvic/abdominal pain, bloating, difficulty eating, urinary frequency)
Gastric and duodenal cancers: consider upper endoscopy beginning at 40yo q3-5yrs for those with FH of gastric cancer and Asian ancestry
Distal small bowel: consider capsule endoscopy and small bowel enterography in symptomatic individuals
Urinary tract cancers (renal pelvis, ureter, and/or bladder): consider urine cytology to identify microscopic hematuria in those with a FH beginning between 30-35yo
Pancreatic cancer: consider EUS/MRCP at 50yo in those with a FH
What are the tx options for pts with Lynch syndrome
adenomas of colon: complete endoscopic polypectomy w f/u colonoscopy q1-2yrs
CRC: segmental or extended colonic resection; for those with rectal adenocarcinoma, proctectomy or total proctocolectomy is indicated
other tumors: management as in general population
prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed
prophylactic colectomy is generally not recommended since screening is effective
aspirin therapy has been shown to decrease the risk of CRC
Why may a parent with Lynch not have cancer
incomplete penetrance, variable age of cancer development, cancer risk reduction from screening or prophylactic sx, or early death
What is the molecular pathogenesis of Lynch syndrome
PVs in genes involved in the MMR pathway which functions to identify and remove single-nucleotide mismatches or insertions and deletion loops
germline dels with EPCAM, which is not an MMR gene, can disrupt the MMR pathway by inactivating the adjacent MMR gene, MSH2, even though MSH2 itself has not been mutated
What are some laboratory considerations for Lynch syndrome
EPCAM: only large dels that include the last exon of EPCAM are causative of Lynch; other EPCAM variants are NOT associated with Lynch
MLH1: most instances of MLH1 promoter methylation are simplex, but a few families w inherited hypermethylation have been reported; MLH1 promoter methylation is not detectable by either sequence analysis or dup/del analysis of MLH1
PMS2: molecular analysis is more complex due to the presence of multiple pseudogenes; Long range PCR, cDNA sequencing, or specific solutions to NGS testing can help distinguish between the pseudogenes and PVs
How is the dx of Li Fraumeni syndrome established
proband who meets ALL THREE classic LFS criteria AND/OR has a germline PV in TP53
Classic criteria
1. proband with sarcoma before age 45
2. first degree relative with any cancer dx before 45
3. first or second degree relative with any cancer before 45yo or a sarcoma dx at any age
How are germline and somatic PVs in TP53 distinguished? How can they be acquired somatically?
Identification of low-level mosaicism for TP53 in leukocytes is suggestive of a postzygotic PV due to clonal hematopoiesis of indeterminate potential related to aging, cytotoxic txs, underlying hematologic malignancy or premalignancy, or circulating tumor cells
Evals include:
analysis of cultured skin fibroblasts for identified TP53 PV
molecular genetic testing of all offspring to determine if the TP53 PV was transmitted
molecular genetic testing of other FMs to determine if the TP53 PV is segregating with cancer in the family
What is the name of the criteria for Li Fraumeni syndrome
Chompret criteria; 30% will have a TP53 PV
What cancers is someone with Li Fraumeni at risk for
lifetime cancer risk for men is 70%; women is 90%
Five main types: adrenocortical carcinomas (6-13% before age 5), breast cancer (27-31%, most common cancer in women with TP53 PV, occurs prior to menopause), central nervous system tumors (9-14% of cancers typically before 40yo), osteosarcomas (3-16% by 30yo), soft-tissue sarcomas (17-27%, most common LFS cancer in children)
avg onset of first cancer in men is ~17yo; for women it is ~13yo although when including breast cancer it is 28yo
~50% risk of developing a second cancer 10yo after first dx
What are the common histologies associated with Li Fraumeni syndrome
Breast: triple positive; more likely to be ductal and have malignant phyllodes tumors
CNS tumors: glioblastomas and astrocytomas are the most common type; medulloblastomas are typically the sonic hedgehog subtype and display chromothripsos (numerous clustered chromosome rearrangements occurring in malignant cells)
Soft-tissue sarcomas: rhabdomyosarcomas and other soft-tissue sarcomas; rhabdomyosarcomas often before 5yo and are often nonalveolar tumors with diffuse anaplasia
leukemias/lymphomas: in 2-4%, usually primary and secondary leukemias, especially ALL, AML, and myelodysplastic syndrome; ALL often exhibits a low hypodiploid state with 32-39 chroms
What needs to be considered for pregnant women with a fetus at risk for a TP53 mutation
the pregnant mother of a fetus heterozygous for a pat inherited TP53 PV is at risk for choriocarcinoma or another gestational trophoblastic disease (occurrence of cancer in the placental tissue that can spread to other tissues)
What are genotype-phenotype correlations in Li Fraumeni syndrome
individuals with LFS who carry dominant negative PVs (mutated p53 protein interferes with the function of the wild type p53 protein)
TP53 founder variant p.Arg337His common in southern Brazil is associated with a high risk of childhood onset ACC, up to 55%; mat inheritance of p.Arg337His was identified in 72% of individuals, suggesting preferential selection
What genetic modifiers exist for Li Fraumeni syndrome
p.Arg72 polymorphism: higher levels of p53 degradation and earlier onset of first cancer
MDM2 c.14+309T>G: higher levels of p53 degradation and earlier onset of first cancer
microRNA R-605 variant: ten year accelerated mean age of tumor onset
16bp dup polymorphism in intron 3 (PIN3): appears to be protective, older ages of first cancer dx
shortened telomere length: accelerated tumor development (anticipation) in families
How are cancers in Li Fraumeni tx/managed
radiation therapy is avoided if possible to reduce the risk of secondary malignancies. however, tx efficacy should be prioritized above concerns regarding risk of subsequent malignancies (radiation may be needed to provide best chance of cure)
women encouraged to consider bilateral mastectomy to reduce risk of developing second primary breast cancer
adults should have colonoscopies
avoid sun, tobacco, other carcinogens
What is the recommended surveillance for Li Fraumeni
All cancers: complete physical exam (q3-4mo birth to 18yo; q6mo >18yo), whole body MRI annually for all ages
ACC: u/s of abdomen and pelvis q3-4mo birth to 18yo; serum total testosterone, dehydroepiandrosterone sulfate and androstenedione if u/s is unsatisfactory
Breast ca: CBE (q6-12mo from 20-25yo), Breast MRI (annually, 20-30yo); Mammogram (30-75yo)
CNS tumors: neurologic exam and brain MRI annually for all ages
upper endoscopy and colonoscopy q2-5yrs starting at 25yo
annual dermatologic exam starting at 18yo
sarcomas: whole body MRI/ u/s of abdomen and pelvis
Should children be tested for TP53 PVs if they have a FH
YES it is recommended that predictive testing be offered to individuals at birth (via cord blood) or soon after birth
special consideration should be given to education of the children and their parents prior to genetic testing and older children and adolescents should be given the option of assenting to the test
What is the molecular pathogenesis of TP53 and special lab considerations
encodes p53 which has been termed the guardian of the genome since it is involved with DNA replication/repair, epigenetic patterning of the genome, cell cycle arrest, apoptosis, etc. PVs ultimately lead to genomic instability and malignant transformation. It is the most frequently mutated gene in human cancer
TP53 missense variants are the variants most commonly identified and tumors and they present challenges in germline interpretation
How is Cowden syndrome dx via a scoring system
takes into account phenotype and age at dx has been developed
in adults, clinical threshold score of 10 or more leads to recommendation for referral to genetics
In children, macrocephaly and one or more of the following leads to the consideration of PHTS:
autism or DD
dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling
vascular features (arteriovenous malformations or hemangiomas)
gastrointestinal polyps
pediatric-onset thyroid cancer or germ cells
What are pathognomonic features of Cowden syndrome
Adult Lhermitte-Duclos dz (presence of a cerebellar dysplastic gangliocytoma)
mucocutaneus lesions: facial trichilemmomas, acral keratoses, papillomatous lesions, mucosal lesions
How is a clinical dx of Cowden syndrome made
If an individual meets any ONE of the following criteria:
Pathognomonic mucocutaneous lesions including one of the following:
Six or more facial papules, of which three or more must be trichilemmomas
Cutaneous facial papules and oral mucosal papillomatosis
Oral mucosal papillomatosis and acral keratoses
Six or more palmoplantar keratoses
Two or more major criteria
One major and three or more minor criteria
Four or more minor criteria
Major criteria
Breast cancer
Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer
Macrocephaly (occipital frontal circumference ≥97th percentile)
Endometrial carcinoma
Minor criteria
Other thyroid lesions (e.g., adenoma, multinodular goiter)
Intellectual disability (IQ ≤75)
Hamartomatous intestinal polyps
Fibrocystic disease of the breast
Lipomas
Fibromas
Genitourinary tumors (especially renal cell carcinoma)
Genitourinary malformation
Uterine fibroids
How is the dx of Cowden syndrome established in a family
other relatives are considered to have a clinical diagnosis of CS if they meet any one of the following criteria:
A pathognomonic criterion
Any one major criterion with or without minor criteria
Two minor criteria
History of Bannayan-Riley-Ruvalcaba syndrome
What molecular testing should you order for PTEN
sequence analysis then del dup
also perform sequence analysis of the PTEN promoter region for variants that decrease PTEN gene expression (10%)
What is Cowden syndrome
a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium; renal cell carcinoma and colorectal carcinoma present too
What is Bannayan-Riley-Ruvalcaba syndrome
congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis
What is PTEN-related Proteus syndrome
complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues
Describe the features associated with Cowden syndrome
90% have some clinical feature by late 20s, by the 4th decade, 99% of individuals develop the mucocutaneous features as well as acral and plantar keratoses; usually have macrocephaly and dolichocephaly
harmartomatous and mixed GI polyps that confer a risk for CRC
high risk for breast, thyroid, renal, and endometrial cancers, risk for multifocal and bilateral cancer increased; 7-fold increase risk of developing a second primary malignant neoplasm
What are the histologic features associated with Cowden syndrome
glycogenic acanthosis (in colon, small mounds of glycogen stores) have a high likelihood of finding a PTEN PV
breast: 67% risk of benign breast dz; 85% lifetime risk for female breast ca with 50% penetrance by 50yo
thyroid dz: benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas up to 75% of individuals; lifetime risk for epithelial thyroid ca is ~35%, onset at 37yo (FOLLICULAR HISTOLOGY)
endometrial: benign uterine fibroids are common; lifetime risk for endometrial cancer is ~28% starting at late 30s-40s
GI neoplasias: 90% are found to have polyps (ganglioneuromatous polyps, hamartomatous, and juvenile polyps); lifetime CRC is 9% starting at late 30s
RCC: estimated to be 35% by 20s w the predominant histology being papillary RCC
lifetime risk for cutaneous melanoma is ~6%
rare CNS tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos dz) may be pathognomonic
What are the common features associated with Bannayan-Riley-Ruvalcaba syndrome
in addition to the features of CS, high birth weight, DD, ID, myopathic process in proximal muscles, joint hyperextensibility, pectus excavatum, scoliosis
have same cancer risks of CS
GI polyps may be occasionally be associated with intussusception but rectal bleeding and oozing of “serum” is more common; these polyps NOT believed to increase risk for CRC
What are the common features associated with PTEN related Proteus syndrome
progressive segmental or patchy overgrowth of diverse tissues of all germ layers affecting the skeleton, skin, adipose tissue, and CNS
develops and progresses rapidly beginning in the toddler period causing severe overgrowth and disfigurement
striking predisposition to DVT and pulmonary embolism
What genetic modifiers exist for Cowden syndrome
germline KLLN epimutation: ~30% of individuals with CS do NOT have a PTEN PV and have a germline KLLN methylation epimutation resulting in downregulation of KLLN; have a greater prevalence of breast and RCC than do those with a germline PV
susceptibility genes: individuals without PTEN PVs harbor germline variants in SDHB and SDHD in 10% of persons with CS; ~10% are found to harbor a germline PIK3CA or AKT1 PVs; ~3%-6% have germline heterozygous SEC23B PVs, which are particularly associated with thyroid carcinoma and enhanced ribosome biogenesis
What is the recommended surveillance for pts with PTEN Hamartoma Tumor syndrome
annual comprehensive physical exam at 18yo or 5yrs before youngest age of dx
breast: @18, SBE; @25, CBE q6-12mo; @30-35, annual mammogram with consideration of breast MRI; discuss mastectomy as needed
thyroid u/s: starting at age of dx, annual thyroid u/s
kidney: @40, consider renal u/s q1-2yrs
endometrium: consider ca screening @35yo; consider endometrial bx screening q1-2yrs; transvaginal u/s in postmenopausal women as needed; discuss hysterectomy on completion of childbearing
colon: @35, colonoscopy q5yrs
dermatologic: annual exam
developmental: consider psychomotor assessment in children, brain MRI if symptomatic, eval for early intervention
What is the recommended cancer tx for Cowden/Bannayan-Riley-Ruvalcaba syndrome
mucocutaneous lesions: observation, removal only if malignancy is suspected
DD: support services, early intervention
breast dz/neoplasia: refer to breast specialist
thyroid dz: u/s, perform total thyroidectomy if suspicious for malignancy
endometrial dz: multiple fibroids are tx w total abdominal hysterectomy
Should minors be tested for PTEN if there is a FH
YES
given the possible early dz presentation in individuals with BRRS and PTEN-related proteus syndrome
What is the de novo rate for Cowden/Proteus syndrome
10-44%/ virtually all
What is the molecular pathogenesis for PTEN
downregulates the PIK3/AKT pathway
nearly 40% of PVs are in exon 5 which encodes the phosphate core motif
~76% of germline PVs in PTEN predict truncated protein, haploinsufficiency, or dysfunctional protein; many missense variants are functional null and act as dominant negatives
PTEN has a highly homologous pseudogene on chrom 9
What are the cancer risks associated with a heterozygous ATM PV
breast (20-30%), 4% for second breast cancer w/out bilateral mastectomy (annual breast MRI @30-35, start mammo @40- insufficient evidence for risk reducing mastectomy)
pancreatic (5-10%) (screen if FH)
ovarian (2-3%)
When should a dx of APC-associated polyposis be suspected
any of the following:
multiple CR adenomatous polyps (at least 10-20 cumulative)
FH of the above, known APC PV, and/or extracolonic features of APC-associated polyposis conditions
hepatoblastoma
multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
desmoid tumor
cribriform-morular variant of papillary thyroid cancer
others: early onset CRC w few to no adenomatous polyps, dental abnormalities, osteomas, odontomas, epidermoid cysts, duodenal adenomas and cancer, gastric fundic gland polyposis, gastric cancer, pancreatic cancer, small bowel carcinoma, and/or medulloblastoma
How is the dx of APC-associated polyposis established
heterozygous PV in APC
classic FAP: > or =100 CR adenomas OR multiple but less than 100 adenomas and a relative with confirmed classic FAP
attenuated FAP: relative with confirmed AFAP AND/OR <100 CR adenomas OR >100 CR adenomas at an advanced age (>40yo)
GAPPS: PV in promotor 1B of APC AND: gastric polyps restricted to the body and fundus, >100 polyps in the proximal stomach or >30 polyps in a first degree relative w GAPPS; predominantly fundic gland polyps and some gastric adenomas; no evidence of CR or duodenal polyposis
What molecular testing should be ordered for someone with suspected APC-associated polyposis
single gene testing with del/dup; del/dup should also include the analysis of APC regulatory regions (promoter 1B) if APC PV is not identified with initial testing
~20% of simplex cases are somatic mosaic for an APC PV
What clinical features are associated with classic FAP
adenomas by 2nd-3rd decade w avg age of dx at 16yo
by 35yo, 95% of affected individuals have polyps which rapidly increase in number
100s-1000s typically observed
93% w CRC by 50yo
inter and intrafamilial phenotypic variability common
What clinical features are associated with AFAP
Characterized by fewer CR polyps (avg ~30) but a significant risk for CRC
< or = 100 CR adenomas at > or = 25yo
occur more proximally in the colon than FAP
avg age of CRC dx is 50yo
cumulative risk for CRC by 80yo is 70%
What extra-colonic features can be present in pts with FAP
small bowel, duodenal cancer (adenocarcinoma/carcinoma, 4-8%)
pancreas (adenocarcinoma, ~1%)
thyroid (papillary w cribriform pattern, 1-12%; female to male ratio of 80:1)
CNS (usually medulloblastoma, ~1%)
Liver (hepatoblastoma, ~2%; 750-7500x higher than general pop, majority before 3yo)
stomach (adenocarcinoma, ~1.3% in West but higher in Asian cultures)
non-malignant findings
osteomas (60-80%): bony growths typically on skull and mandible
dental anomalies (30-75%): unerupted teeth, congenital absence of one or more teeth, supernumerary teeth
CHRPE(80%): discrete, flat, pigmented lesions of the retina; isolated ones can be seen in the general population
benign cutaneous lesions
desmoid tumors (10-30%): clonal proliferations of myofibroblasts but do not metastasize. 65% are in the abdomen/abdominal wall which can compress organs or complicate abdominal sx
adrenal masses: 2-4x more prevalent than general pop