Download Pediatric cancers and inherited risks

PEDIATRIC CANCERS
AND INHERITED RISKS
Anne Heun, MS, CGC
John Stoddard Cancer Center
Blank Children’s Hospital
November 6, 2015
• Some classic hereditary cancer predisposition syndromes
have implications for both adults AND children
• Some syndromes in children have direct implications for
adult relatives
• Recessive syndrome in child  parents carry mutations that lead to
increased cancer risks
Syndromes
• DICER1 syndrome
• HLRCC
• Von Hippel-Lindau
• FAP
• Li-Fraumeni syndrome
• Peutz-Jeghers syndrome
• Ataxia-telangiectasia
• CMMRD syndrome
• Fanconi anemia
Genetic Testing in Minors
• Generally do not test minors for conditions in which
cancers have onset in adulthood
• Will test minors if there are implications for cancer risks or
screening in childhood
Case Example
• Woman treated for Sertoli-Leydig cell tumor at age 17
• Participated in International OTST Registry through
University of Minnesota
• Through study, she was found to have a DICER1 mutation
while pregnant with her third child in 2013
Case Example
• Children tested for DICER1 mutation, including her infant
son
• He was found to have mutation, as was her older son; daughter did
not carry mutation
• Screening in asymptomatic three month old showed 8 cm
mass in lung
• Pleuropulmonary blastoma
• Successfully removed
• If untreated, survival rate 40%
Case Example
• “He’ll still have to be monitored, but Andrew has
recovered beautifully... “He’s been super normal,” she
said. “I was able to return to work on schedule in February
and he was in day care. His scar is becoming almost
invisible. I don’t know how he is going to pick up chicks.”
DICER1 syndrome
• Recently described tumor suppressor gene
• Inherited from parent in 80%, de novo 20%
• Autosomal dominant
• Increased risks of various rare tumors, both benign and
malignant
• Penetrance unknown
DICER1 syndrome
< Age 6
• Pleuropulmonary
blastoma
• Cystic nephroma (benign)
• Pituitary blastoma
• Pineoblastoma
Age 6-40
• Ciliary body
•
•
•
•
medulloepithelioma (CBME)
Botryoid-type embryonal
rhabdomyosarcoma (ERMS)
of the cervix
Nasal chondromesenchymal
hamartoma (NCMH)
(benign)
Ovarian sex cord-stromal
tumors (OSCST)
Multinodular goiter
DICER1 syndrome: Screening
• No guidelines yet
• PPB: Baseline chest CT to evaluate for lung cysts or tumors in
a patient of any age
• most critical age group for chest CT is children under 3 yr.
• CN: In a patient of any age, especially those younger than 4
yr., annual abdominal examination and monitoring for
abdominal pain, swelling, or hematuria
• Thyroid physical examination in a patient of any age
• Pituitary blastoma: Brain MRI for persons with signs of
cortisol excess
• Pineoblastoma: Brain MRI for persons with signs of increased
intracranial pressure such as headache, full fontanel, vomiting,
and lethargy, or other neurologic defects including upgaze
paralysis and nystagmus
DICER1 syndrome: Screening
• Ovarian stromal tumors: Examination of all females of any
age for signs and symptoms of precocious puberty or
virilization, masses in the abdomen or pelvis
• Imaging: abdominal-pelvic US examination, MRI, or CT
• Laboratory testing: serum markers AFP, beta-HCG, LDH, inhibin A and
B, estradiol, testosterone, CA125, and serum electrolytes including
calcium
• CBME: Evaluation of young children for ciliary body
medulloepithelioma including measurement of visual acuity
• Botryoid ERMS: In infants, children, and young adults, when
signs/symptoms of hematuria or abnormal vaginal bleeding are
present, endoscopic evaluation of the bladder or direct
visualization of the cervix, respectively
• NCMH: In infants, children, adolescents, and adults: Review of
systems including respiratory and feeding difficulties,
rhinorrhea, epistaxis, visual disturbances, and otitis media
HLRCC
• Hereditary Leiomyomatosis and Renal Cell Cancer
syndrome
• Due to autosomal dominant mutations in FH
• Autosomal recessive mutations in FH lead to fumarate hydratase
deficiency
• Incidence: ~300 families in literature, but underdiagnosed
• Increased risk for renal cancer and leiomyomas
HLRCC
HLRCC
• Cutaneous leiomyomas: found in 76% of patients
• Uterine leiomyomas: diagnosed age 18-52 years
• Irregular or heavy menstruation and pelvic pain
• Leads to early hysterectomy
• Renal tumors: 10-16% lifetime risk
• Type 2 papillary renal cancer (characteristic histopathology)
• Tubulo-papillary renal cell carcinoma
• Collecting duct renal cell carcinomas
• Typically unilateral and solitary
• Kidney cancer diagnosed as young as 11 yr, median 44 yr
HLRCC: Age Distribution
HLRCC: Screening
• Kidneys: annual abdominal MRI beginning at age 8
• Baseline CT
• Renal cancers aggressive, with poor long-term survival; need
immediate intervention
• Skin: Full skin examination every 1-2 years, beginning at
age 1 (or ASAP)
• Uterus: Annual gynecologic exam, beginning at age 21
Von Hippel-Lindau syndrome
• VHL gene
• Autosomal dominant mutations
• 80% inherited, 20% de novo
• Incidence 1:32,000
• Affects various organ systems
• Almost all individuals who have a pathogenic variant
in VHL are symptomatic by age 65 years
VHL: Tumor Risks
• Within and
between
families, the
presentation can
be very different
VHL: Pheochromocytomas
• Paraganglioma of the
adrenal gland
• Neuroendocrine tumor, starts in
medulla of adrenal gland
• Secretes catecholamines
• Including norepinephrine and
epinephrine
• High blood pressure
• “fight or flight” response
• Palpitations
• Anxiety
• Headaches
• Diaphoresis
VHL: Screening Starting at Age 1
• Annual exam for neurologic symptoms, vision problems or
hearing disturbance, signs of nystagmus, strabismus, or
white pupils
• Annual blood pressure monitoring
• Annual ophthalmology evaluation with indirect
ophthalmoscope for retinal angiomas
VHL: Screening Starting at Age 5
• Annual blood or urinary fractionated metanephrines
starting at age 5 yr for pheochromocytomas
• And before any surgery
• Audiology assessment every 2-3 years
• Thin-slice MRI with contrast of the internal auditory canal
in those with repeated ear infections
VHL: Screening Starting at Age 16
• Annual abdominal ultrasound
• MRI scan of the abdomen (kidney, pancreas, adrenal
glands) every 2 years
• Watch lesions closely until they reach the size of 3 cm, which then
necessitates removal
• MRI of the brain and total spine every 2 years
McC kindred,1998
This pedigree is of the McCoy family,
descendants of the Hatfield-McCoy
feud…
Could pheochromocytomas have
fueled the feud?
Familial Adenomatous Polyposis
• APC gene
• Autosomal dominant
• 20-25% de novo, 75-80% inherited from parent
• Incidence: 1:25,000 – 1:30,000
• 1% of all colon cancers
• Characterized by GI polyps
• 100s – 1000s in colon
• Duodenum
• Ampulla of Vater
FAP: Risks
FAP: Other Features
FAP: Management
• Annual colonoscopies beginning at age 10 yr.
• Prophylactic removal of colon
• Can occur in childhood
Case Example
• 3 yr. old girl with headaches
• Diagnosed with glioma
• Family history of maternal great grandmother with breast
cancer in her 20s and grandfather with prostate cancer
Case Example
• After her diagnosis, her mother was diagnosed with
breast cancer in her mid-20s
• Genetic testing revealed mutation in TP53, consistent with
Li-Fraumeni syndrome
• She was also found to carry TP53 mutation
Li-Fraumeni syndrome
• Mutations in TP53
• Autosomal dominant
• 7-20% de novo, 80-93% inherited
• Incidence: 1:20,000
• Could be as high as 1:5000
• Variable penetrance
• Characterized by very high lifetime risks of cancer
• Nearly 100% for women
• 73% for men
Li-Fraumeni syndrome: Risks
• Core Cancers:
• Breast
• Brain
• Sarcoma – both soft tissue and bone
• Adrenocortical Carcinoma
• Other cancers also occur in excess
• 50% risk by age 30, 90% by age 60
• Median age of diagnosis of cancer 25
• Individuals at risk for multiple primaries
Li-Fraumeni syndrome: Screening
Peutz-Jeghers syndrome
• Mutations in STK11
• Incidence: 1:25,000 – 1:280,000
• 45% de novo, 55% inherited
• Characterized by:
• Increased cancer risks
• Mucocutaneous pigmentation
• Small bowel intussusceptions
• Hamartomatous polyps
PJS: Risks and Screening
• Also consider prophylactic surgeries
Childhood-onset Conditions with
Implications for Adults
• Some conditions in childhood have direct, albeit different,
implications for risks in adult carriers
• Typically autosomal recessive conditions in which carriers
also have increased risks
Ataxia-Telangiectasia
• Recessive disorder due to mutations in ATM
• Incidence: 1:40,000 – 1:100,000
• Primary immunodeficiency disease
• Characterized by
• Neurological problems (particularly of balance) - ataxia
• Recurrence sinus and respiratory infections
• Dilated blood vessels in eyes and on surface of skin – telangiectasias
• Sensitivity to radiation
• Normal intelligence but motor delays
• Increased cancer risks – leukemias and lymphomas
• Patients with A-T typically use wheelchairs by the teenage
years
• Generally fatal to patients by the time they reach their twenties
Ataxia-Telangiectasia: Risks
• Approximately 20% of A-T patients develop cancer
• 100-fold risk increase for lymphoid tumors
• 37-fold risk increase for any cancer
• Liver
• Leukemia
• Larynx
• Stomach
• Parotid gland
• Brain
• Breast
• Ovary
• Skin
• No official screening protocol, just monitor for early signs
of cancer
ATM Heterozygotes
• Approximately 1% of population are carriers
• Case-control studies have suggested a link between
the ATM gene and increased breast cancer risk
• 2-4 fold risk increase
• Other potential risks? Pancreatic cancer, others?
• NCCN recommends increased breast cancer screening
for ATM carriers
• Annual breast MRI and annual mammogram beginning at age 30
• Alternate every 6 months
CMMRD syndrome
• Constitutional Mismatch Repair Deficiency syndrome
• Biallelic mutations in PMS2 or MSH2
• Less commonly in other Lynch syndrome genes MLH1, MSH6,
EPCAM
• VERY high risks of cancer
• No specific estimates of risk
CMMRD: Clinical Features & Risks
• Hematologic Malignancies
• Primarily lymphoid
• Brain tumors
• Childhood-onset colon cancers and polyposis
• Other cancers reported: rhabdomyosarcoma, embryonic
tumors
• Lynch syndrome cancers
• Skin findings
• Café au lait macules
• Can resemble neurofibromatosis type I
CMMRD: Screening
Lynch syndrome: Risks
Lynch syndrome: Screening
• Colonoscopies every 1-2 years
• Beginning at age 25-30
• Gynecologic cancer screening
• Consider TH-BSO after childbearing is complete
• Upper endoscopy and small bowel screening?
• Annual physical exam
• Annual urinalysis
• Consider family-specific screening
Fanconi Anemia
• Due to biallelic mutations in 17 different genes
• Including BRCA2, PALB2, and others
• Physical changes
• Short stature, abnormalities of the skin, arms, head, eyes, kidneys,
and ears
• Developmental disabilities
• Increased cancer risks
• Median age of death 30 yr
Fanconi Anemia: Risks
• Bone marrow failure – 98% by age 40
• Myelodysplastic syndromes
• Most develop AML
• Older patients are extremely likely to develop head and
neck, esophageal, gastrointestinal, vulvar and anal
cancers
• Treatment challenging since chemotherapy and radiation have
increased risks of toxicity in FA patients
Fanconi Anemia: Screening
• For increased risk of malignancy:
• The majority of solid tumors develop after the first or second
decade of life
• Prompt and aggressive workup for any symptoms suggestive of a
malignancy should be pursued
• Detection and surgical removal of early-stage cancers remains the
mainstay of therapy
• Annual gynecologic examination and Pap smears,
beginning at menarche or by age 16 yr.
• Frequent dental and oropharyngeal examinations,
including nasolaryngoscopy starting at age 10 yr., or
within the first year after stem cell transplantation
• Annual esophageal endoscopy may be considered
DNA repair
BRCA2
BRCA2: Screening
• Women:
• Breast cancer screening with imaging beginning at age 25
• Consider Tamoxifen
• Consider bilateral mastecomies
• Ovarian cancer screening? At age 30-35
• Recommend prophylactic BSO at age 35-40
• Men:
• Begin prostate screening at age 40 with annual PSA + DRE
• Begin breast cancer screening at age 35 with annual clinical breast
exam, monthly breast self-exam
• Men and Women:
• Consider pancreatic cancer screening and melanoma screening
PALB2
• Increased risks of:
• Breast cancer – 38-50% lifetime, dependent upon family history
• Pancreatic cancer – magnitude unknown
• Male breast cancer – magnitude unknown
• Breast cancer more likely to be triple negative than with
sporadic cancers
• Breast cancer risk management
• Consider bilateral mastectomies
• Beginning at age 30, alternate annual breast MRI with annual
mammogram
Fanconi Anemia pathway
• Other genes: heterozygous mutation risks still not well
understood
• Theorized due to Fanconi anemia pathway
Are there others?
• Certainly
• NBN (Nijmegen breakage syndrome), BLM (Bloom syndrome)
• Cowden syndrome, Juvenile polyposis syndrome
• But, for some genes, biallelic mutations are lethal during
embryonic development
• BRCA1
Summary
• Some tumors in children can be indicative of a hereditary
predisposition to cancer that may also affect adults
• Some recessive conditions in children lead to risks in
“carrier” adults
Questions?
Anne Heun, MS, CGC
[email protected]
(515)241-4232