Cancer Final Exam COMPLETE

Familial atypical multiple mole melanoma syndrome (FAMM)

CDKN2A

melanoma and pancreatic

certain variants can incr brain ca risk

Gorlin Syndrome

PTCH1, SUFU

BCC (90%), medulloblastoma (SUFU)

jaw keratocysts (PTCH1)

falx calcification, palmar/plantar pits, ovarian and cardiac fibromas, skeletal anomalies

PTCH1 more common

Birt-Hogg-Dube

FLCN

RCC

fibrofoliculomas, pulmonary cysts, spontaneous pneumothorax

Muir Torre

MLH1, MSH2

CRC, endometrial, ovarian, stomach, other lynch

sebaceous adenomas, keratocanthomas

dx Lynch + sebaceous neoplasm

Xeroderma Pigmentosum

AR

XPA, XPC, POLH, DDB2, ERCC1-5

100% penetrance

skin ca in first decade (65%)

acute sun sensitivity

sunlight-induced ocular involvement

neurodegeneration

Carney Complex

PRKAR1A

blue nevi, cardiac myxomas, gonadal tumors, thyroid nodules, pituitary, schwannomass

Rothmund-Thompson

RECQL4, ANAPC1

osteosarcoma, skin ca, 2ndary lymphoma

sun sensitivity

skeletal, teeth, poor growth, sparse hair, juvenile cataracts

MBD4

AR

uveal melanoma, MDS/AML, CRC

CDK4

melanoma

74% risk by 50

MITF

melanoma

BCC

most common skin ca

sun exposed areas

slow growing, rarely spread

SCC

2nd common skin ca

sun exposure

low risk, can be aggressive

melanoma

malignant melanocytes (deepest layer of skin)

MEN1

MEN1 gene

20+ types of endocrine tumors

hyperparathyroidism (100%)

facial angiofibromas

MEN2A

RET gene

medullary thyroid, pheos

hyperparathyroidism (more mild than MEN1)

70-80% MEN2

thyroidectomy recc

MEN2B

RET

medullary thyroid, pheos, ganglioneuromas of GI tract

marfanoid habitus (no cardiac)

mucosal neuromas (lips and tongue)

100% MTC risk

thyroidectomy

Familial MTC

RET

thyroidectomy

MEN4

CDKN1B

parathyroid, pituitary, endocrine of GEP tract

consider if MEN1 neg

Von Hippel Lindau

VHL

hemangioblastomas (esp CNS, ped onset), renal (adult onset), pheos, pancreatic, endolymphatic sac

renal and pancreatic cysts

testing finds variant in 90-100% clinical criteria

Familial Isolated Pituitary Adenoma

AIP

pituitary neuroendocrine tumors

reduced penetrance

onset in 20s

BAP1-TPDS

BAP1

melanoma (uveal, cutaneous, ped onset), mesothelioma, kidney

Hereditary Papillary Renal Cell Cancer

MET

renal papillary type 1

near 100% ca risk

adult onset in 30s

HLRCC/Reed's Syndrome

FH

papillary type 2 kidney (more aggressive)(10-15%)

leiomyomas (skin fibromas), uterine fibroids (90% in women)

Birt-Hogg-Dube

FLCN

renal ca

lung cysts, spontaneous pneumothorax, fibrofolliculomas

PTEN Hamartoma syndrome

breast, endometrial, thyroid, colorectal, kidney

TSC

TSC1, TSC2

kidney angiomyolipoma

cortical tubers, cardiac rhabdos, facial angiofibromas

MITF

cutaneous melanoma, kidney?

CHEK2

breast

maybe thyroid, kidney?

Pituitary

regulates growth, development, metabolism, reproductive function

mostly benign tumors (can secrete or not)

Thyroid

control metabolism

produce calcitonin (reg calcium)

Papillary thyroid ca

80-90%

good prognosis

medullary thyroid ca

1-5%

very aggressive, high mets potential

parathyroid

releases PTH to control calcium

symptoms: osteoporosis, kidney stones, fatigue

adrenal

produce corticosteroids

on top of kidneys

secrete epinephrine and norepinephrine

symptoms: high bp, rapid heart rate, sweating,weight gain

what percent of adult kidney ca are hereditary

3-8%

RET gene

oncogene

all MEN2

hemangioblastoma

non-malignant vascular tumors

mostly in brain/spine

paragangliomas

grow in peripheral nervous system

AKA extra-adrenal pheos

can secrete or not

pheos

pgls confined to adrenal medulla

secrete catecholamines

high hereditary risk

PCC/PGL genes

SDHA, SDHB, SDHC, SDHD, MAX, TMEM127

Bone Marrow Failure Syndromes

Diverse group of disorder characterized by bone marrow failure, usually with ≥1 extra hematopoietic abnormalities (RBCs, WBCs, platelets, etc)

Diamond Blackfan Anemia genes and inheritance

Dominant - 22 genes

X-linked - GATA1 and TSR2

Diamond Blackfan Anemia features

Macrocytic anemia beginning 1st yr of life

Congenital anomalies (heart, GU)

Growth deficiency

Increased risk of AML, MDS, osteosarcoma

The severe form of Diamond Blackfan Anemia causes...

hydrops and fetal demise

Shwachman Diamond Syndrome gene and inheritance

Recessive - DNAJC21, EFL1, SBDS

Dominant - SRP54

Shwachman Diamond Syndrome features

Pancreatic insufficiency with malnutrition

Growth deficiency

Anemia with neutropenia

Increased risk of AML and MDS

Chromosome instability syndromes usually have what inheritance pattern?

Auto recessive

Chromosome instabiliy can lead what medical problems

Immunodeficiency

BMF

Cancer

Neurological decline

Growth issues

Developmental abnormalities signs of chromosome instability disorders

IUGR, SGA, short stature, microcephaly, dysmorphic features

Photosensitivity signs of chromosome instability disorders

Photophobia, skin sensitivity, easy blistering/sunburns

Skin abnormalities signs of chromosome instability disorders

Young onset of sun damage, pigmentation abnormalities

Immunodeficiencies signs of chromosome instability disorders

Frequent infections, laboratory confirmed

Dyskeratosis congenita features

Impaired telomere maintenance resulting in short/very short telomeres (<1st percentile)

High risk for BMF, MDS, AML

Increased risk of squamous cell tumors of H/N and cervix

Development of pulmonary fibrosis

Dyskeratosis congenita classic triad

Lacy reticular pigmentation of upper chest and/or neck

Dysplastic nails

Oral leukoplakia

What is oral leukoplakia?

accumulation of WBC in the cheek, tongue, gums that cannot be scraped off

Gold standard test for dyskeratosis congenita

Flow-FISH for telomere length

Dyskeratosis congenita genes and inheritance and molecular testing

80% will have pathogenic variants in 16 genes

DKC1 (20-25%), TINF2 (12-20%), TERC (5-10%), TERT (1-7%)

All inheritance patterns

Dyskeratosis congenita cancer screening

Annual physical exam/ROS

CBC every 6 mo

Consider annual bone marrow exam

Annual skin exams starting at 5y

Annual nasolaryngoscopy starting at 10y (for H/N cancers)

Annual gynecologic exam starting at 18y or after becoming sexually active (whichever is first)

Tx of dyskeratosis congenita

HCST

Individualized cancer treatment

Prevention for dyskeratosis congenita

Radiation avoidance (if RT needed, shorter interval/lower dose of radiation)

Sun protection

HPV vaccination

Fanconi Anemia features

Growth deficiency (65%)

Abnormal skin pigmentation (40%)

Skeletal malformations (45%)

Microcephaly (20-25%)

GU anomalies (20-25%)

Ocular manifestations (15%)

Progressive BMF withing first decade, 90% by 40y

Increased risk for malignancy

Fanconia anemia growth deficiency manifestations

Prenatal/postnatal short stature

Fanconia anemia skin pigmentation manifestations

Hypopigmentaiton

Cafe au lait macules

Fanconia anemia skeletal manifestations

Upper/lower limbs:

Hypoplastic thumb

Bifid thumb

Hypoplastic radius

Syndactyly

Polydactyly

Fanconia anemia GU manifestations

Kidney anomalies

Uterine anomalies in females

Reduced fertility in males

Fanconia anemia ocular manifestations

Microphthalmia

Cataracts

Ptosis

Fanconi anemia endocrine manifestations

Hypothyroidism

Diabetes

Hyperglycemia/impaired glucose tolerance

Insulin resistance

Fanconi anemia hearing loss type

Conductive due to middle-ear bony anomalies

Cancer risks in Fanconi Anemia

MDS, AML, SCC of H/N and GU tract, skin cancers

When to suspect Fanconi Anemia in cancer clinic

Patient presents with:

BMF

AML in presence of short stature, microcephaly, other congenital anomalies

SCC of H/N or GU tract with neg HPV titers

When to suspect Fanconi Anemia in general genetic/inpatient clinic

Patient presents with:

Radial ray abnormalities

VACTRL

Microcephaly or short stature with other congenital anomalies

Family hx suggestive of HBOC

Gold standard testing for fanconia anemia

Chromosome breakage of lymphocytes using DEB (diepoxybutane)

Fanconi anemia genes and inheritance and molecular testing

>95% will have pathogenic variants in one of 23 genes

FANCA (60-70%), FANCC (14%), FANCG (10%)

Most are auto recessive

FANCB is X-linked

Few reported de novo RAD51 variants causing auto dom FA

Consideration for sample selection with FA

Somatic reversions can cause false negatives in blood

If clinical suspicion is high, test skin fibroblast

Fanconi Anemia heterozygous risk genes

BRCA2, BRIP1, PALB2, RAD51C

Inc risk for BOPP cancers

Fanconi Anemia cancer screening

Annual bone marrow exam

CBC every 3-4 months

ENT eval at 10y for H/N malignancies

Annual gyn eval starting at 13y

Annual skin exam

Tx of Fanconi Anemia

Surgical resection of solid tumors (especially if they dont respond well to tumors)

HSCT (only curative therapy for heme manifestations)

Prevention for Fanconi Anemia

Radiation avoidance

Sun protection

HPV vaccination

Ataxia telangiectasia features

Progressive cerebellar ataxia in childhood (onset 1-4y)

Gait and truncal ataxia (causes lack of coordination, difficulty walking straight, poor balance)

Slurred speech

Oculomotor apraxia (inability to move eyes horizontally, abnormal and uncontrolled eye movements)

Telangiectasias mostly in eyes by age 5y (dont cause irritation or vision problems)

Ataxia telangiectasia associated cancer risks

Increased cancer risk of 25% lifetime risk

Children (Lymphomas: B-cell NHL and HL; Leukemias: T-cell ALL)

Adults (several types of solid tumors)

What are patients with ataxia telangiectasia extremely susceptible to?

Ionizing radiation

Ataxia telangiectasia gene and inheritance

Gene: ATM

Inheritance: Auto rec

Heterozygous risk for solid tumors

Ataxia telangiectasia cancer screening

Annual ROS/physical exam

Annual skin exam

Breast MRI starting at 25y

Abdominal US in adulthood

Ataxia telangiectasia cancer tx

Individualized, dose-adjusted protocols

Avoid radiation tx if homozygous

Prevention for ataxia telangiectasia

Radiation avoidance

Sun protection

Bloom Syndrome features

Severe pre/postnatal growth deficiency

Immunodeficiency

Sensitivity to sunlight (butterfly rash on face)

Insulin resistance

Increased risk for cancers

Bloom Syndrome cancer risks

Most cancers dx prior to 40y (avg 20-30y)

Hematologic malignancies (26%) - lymphoma > leukemia

Solid tumors: Skin, CRC, Oropharyngeal, breast, Wilms (rare)

Life expectancy of individuals with Bloom syndrome

30-40s

Cancer most common cause of death

Bloom syndrome cancer risk considerations

Sensitive to common chemos and RT

Reduce dose and short course of chemo, RT should be avoided

When to suspect Bloom Syndrome

Individuals very small for their age with sparse adipose tissue and normal intelligence

Lymphoma work-ups

Sun sensitivity with rash

Bloom Syndrome cytogenetic testing

Sister chromatid exchange

Bloom Syndrome gene and inheritance and molecular testing

Gene: BLM gene

Inheritance: Auto rec

Very rare, increased freq in AJ population

Bloom Syndrome cancer screening

Annual ROS/physical exam

Yearly colonoscopy starting at 10-12y (colon polyp risk in homozygotes only)

Breast MRI starting at 18y

Some guidelines may recommend WBMRI

Prevention for Bloom Syndrome

Radiation avoidance

Sun protection

HPV vaccination

Nijmengen Breakage Syndrome features

Progressive microcephaly

Growth deficiency

Recurrent respiratory infections (pneumonia/bronchitis)

Increased risk for cancer

Premature ovarian failure

Developmental delay (early milestones met, but decline to mild/moderate delay)

Cancer risk in Nijmegen Breakage Syndrome

40% risk of cancer by 20y

Most common is lymphoma

Solid tumors (most by 15y) : Medulloblastoma, glioma, rhabdomyosarcoma, ovarian germ cell tumor

Nijmegen Breakage Syndrome gene and inheritance

Gene: NBN

Inheritance: AR

Nijmegen Breakage Syndrome cancer screening

Annual ROS/physical exam

NO imaging or screening for solid tumors

Nijmegen Breakage Syndrome cancer tx

Protocols adapted to individual tolerance

Prevention for Nijmegen Breakage Syndrome

Radiation avoidance

Sun protection

HPV vaccination