Cancer Genetics

What gene is affected in LFS and what is the mode of inheritance?

TP53, autosomal dominant

LFS penetrance

One of the highest of all syndromes:

• men: <70% lifetime risk

• women: >90% lifetime risk

TP53 variants

• loss of tumor suppressor function

• acquisition of dominant negative/GOF effects

• 7-20% de novo

• difficult to distinguish germline from neoplastic DNA

characteristic cancers in LFS

• breast

• sarcomas

• brain

• adrenal gland

• bones

clinical features of LFS

• highly penetrant

• early age of onset

  • men: 17 yrs

  • women: 28 yrs (breast cancer), 13 yrs (excluding)

• excess of multiple primary cancers (40-49% risk of developing second primary)

  • radiation and chemotherapy can increase risk

Classic LFS criteria

NEED ALL:

• proband with sarcoma <45 yrs

• 1st degree relative with any cancer <45 yrs

• 1st/2nd degree relative with any cancer <45 yrs, or sarcoma at any age

  • this doesn’t cover all those who have variant

Chompret LFS criteria

• proband with a tumor in LFS spectrum diagnosed <46 yrs AND 1 or more 1st/2nd degree relative with an LFS tumor at <56yrs or with multiple cancers

NCCN Guidelines: LFS

• an individual diagnosed at age <45 yrs with a sarcoma

• 1st degree relative diagnosed at age <45 yrs with cancer

• another 1st/2nd degree relative with cancer <45 yrs or sarcoma

surveillance for LFS

• start physical screening every 3 to 4 months from birth to 18y/o

  • every 6 months >18y/o

• whole body MRI annually

somatic TP53 variants

• somatic variants can be found in germline testing

• from: mosaicism, age, blood malignancy, aberrant clonal expansion

• confirm with testing of different tissue needed

causes of DNA damage

• ionizing radiation

• UV radiation

• chemical

• spontaneous damage

Bloom Syndrome

• AR, caused by mutations in BLM

• prenatal and postnatal growth deficiency with normal body proportion

• butterfly rash

• immune deficiency, risk of diabetes, decreased fertility

BLM helicase

• dissolves HJs during HR

• rescues stalled replication forks, unwinds, and separates tangled strands

• resects dsDNA

Bloom Syndrome management

• cancer surveillance (small and large intestine, skin, lymphoma, AML)

• full body MRIs

• annual colonoscopy, skin exams, and breast MRIs

Fanconi anemia

• AR, for most (FANCA, BRIP1, BRCA2, etc.)

• AD for RAD51

• X-linked for FANCB

• aplastic anemia and/or bone marrow failure

epidemiology of FA

• extremely rare, 2.5 to 5 mil cases

• carrier frequency: 1 in 180

FA subtypes

• BRCA2: early onset leukemia, solid tumors, 97% chance of cancer by age 4

• PALB2: solid tumors

• FANCG: severe bone marrow failure, higher risk of leukemia

FA management

• low dose androgens

• hematopoietic stem cell transplant

• regular screening for solid tumors

• upper GI endoscopy

somatic

mutation that occurs after conception, not inherited, not passed on

germline

mutation that is present in the egg or sperm, inherited and passed on, in every cell of the body

passenger mutations

mutations that arose as the cancer developed, does not necessarily lead to progression

driver mutations

mutations that likely drove progression of the tumor, often seen recurrently

proto-oncogene

genes that control the normal growth and survival of cells

activated oncogenes

mutations in proto-oncogenes that cause excessive levels of activity

tumor suppressor genes

negatively regulate cell growth or maintain genome integrity, typically mutations are loss of function

Knudson’s Two-Hit Hypothesis

• Two mutations in each allele of a TS gene

• with germline mutation, mutational threshold is lowered

TP53

involved in cell cycle control, apoptosis initiation, maintenance of genome integrity (mutated or lost in over 50% of tumors)

loss of heterozygosity

loss of one parent allele, with only a single allele expressed for a given gene, commonly seen as the inactivating mutation for TS genes

base excision repair (BER)

removal of abnormal bases (MUTYH-polyposis, colorectal cancer)

nucleotide excision repair (NER)

removal of thymine dimers and large chemical adducts (XP, xeroderma pigmentosum)

postreplication repair

removal of DS breaks by HR or NHEJ (NBN, BLM, BRCA1/2)

mismatch repair (MMR)

corrects mismatched bases (MSH and MLH, Lynch syndrome)

Gardner syndrome

A subtype of FAP that includes extra-colonic manifestations such as osteomas and dental abnormalities

Turcot syndrome

A genetic syndrome associated with FAP and brain tumors

Serrated polyposis syndrome

Characterized by serrated polyps in the colon, increasing colorectal cancer risk

• serrated polyps have slightly higher risk of transforming into cancer

Lifetime cancer risk for PJS

Patients have a lifetime risk of cancer as high as 83%, including gastrointestinal and breast cancers.

adenomatous polyposis syndromes

FAP, AFAP, Gardner syndrome, TS2, GAPPS, MAP, serrated polyposis

hamartomatous polyposis syndromes

Peutz-Jeghers syndrome, familial juvenile polyposis

Familial adenomatous polyposis (FAP)

Mutations in APC, development of <100 polyps in the colon and rectum

FAP risks

up to 100% chance of CRC if untreated; stomach, small intestine, pancreas, biliary tract, hepatoblastoma, thyroid

FAP onset

mid-teens, usually multiple polyps by 35

FAP non-cancerous findings

congenital hypertrophy of retinal pigment epithelium (CHRPE), osteomas, extra/missing teeth, desmoid tumors, skin changes, adrenal masses

FAP management

annual colonoscopy starting at 10-15, surgery once poly burden is too much, upper endoscopy at 20-25, baseline thyroid exam, abdominal palpation

Attenuated familial adenomatous polyposis (AFAP)

A variant of FAP characterized by fewer polyps and later onset of colorectal cancer.

AFAP management

screening in late teens, colectomy with increased polyp burden, upper endoscopy, baseline thyroid

Peutz-Jeghers syndrome (PJS)

AD: mutations in STK11

• lead to gastrointestinal polyps and mucocutaneous pigmentation.

PJS clinical symptoms

dark skin freckling (mucosal areas), PJS polyps, adenomas

PJS risks

as high as 83% lifetime risk

• GI, breast, cervical, uterine, pancreatic, lung, benign ovarian tumors

PJS surveillance (pediatric)

upper endoscopy and colonoscopy (8-10), annual testicular exam (10), small bowel visualization (8-10)

PJS surveillance (adults)

mammogram at 30, colonscopy at 18, upper endoscopy at 18, pancreatic screening at 30-35

breast medical management - HBOC

annual clinical exam starting at 25, 25-29 annual MRI, 30-75 annual mammogram, potential risk reducing mastectomy

ovarian medical management - HBOC

recommended risk reducing salpingo-oophorectomy between 35-40y/o

prostate cancer management - HBOC

prostate cancer screening at age 40

pancreatic cancer management - HBOC

screening beginning at 50 y/o or 10 years younger than earliest diagnosis, consider annual MRI or endoscopic ultrasound

melanoma management - HBOC

for BRCA2, annual skin exam

HBOC medicinal management

PARP inhibitors

fanconi anemia

AR genetic condition with early onset that causes bone marrow failure, physical abnormalities, organ defects, and increased risk for cancer

FA physical abnormalities

• hypopigmentation or cafe au lait

• malformed thumbs or forearms

• short stature

• malformed kidneys

• OTDs

• microcephaly

FA cancer risks

high risk AML, tumors of head, neck, skin, GI, GU

triple negative breast cancers

estrogen/progesterone receptor and HER2/Neu negative, more prevalent in BRCA1 related cancer

Lynch related genes and inheritance

• autosomal dominant

• MLH1

• MSH2

• MSH6

• PMS2

• EPCAM

LS associated cancers

most to least common:

• colorectal

• endometrial

• ovarian

• gastric/small bowel

• pancreatic cancer

• prostate

• brain

• skin

mechanism for LS

tumors with signs of mismatch repair deficiency and high microsatellite instability

LS details

• >90% lifetime risk to develop colorectal or other Lynch associated

• diagnosed 10-15 yrs younger than gen population

• polyps develop at younger age with each having a greater chance to transform

• CRC in transverse and ascending colon

MLH1

• 15-40% of all LS cases

• forms complex with PMS2 protein to repair DNA mismatches

• most LOF, 10-20% deletions

• colonoscopy starting 20-25 yrs

MSH2

• 20-40% all LS cases

• forms heterodimer with MSH6 or MSH3 to identify mismatches

• most LOF, 20-40% deletion of 1+ exon

EPCAM

• <10% LS cases

• mutations result in hypermethylation and silencing of downstream MSH2

MSH6

• 12-35% of all LS

• forms heterodimer with MSH2 to identify mismatches

• lower risk of CRC and later age of onset compared to MLH1 and MSH2

• colonoscopy starting 30-35 y/o

PMS2

• 5-25% of LS cases

• forms complex with MLH1 to repair DNA mismatches

• lower risk of CRC compared to MLH1 and MSH2

• lowest risk for any LS cancer, but earlier age of onset

variant phenotypes

• Muir-Torre:

  • sebaceous neoplasms and 1+ internal cancer (MSH2 typically)

• Turcot syndrome:

  • CRC or adenoma with CNS tumor

Constitutional MMR deficiency

• individuals with biallelic pathogenic variants in MLH1, MSH2, MSH6, and PMS2

• colon or small bowel cancer at <20 yrs

• hematologic cancer, brain cancer, and cafe au lait

NCCN breast cancer testing criteria for affected individual (excluding family history considerations)

-diagnosis at 50 y/o or younger

-guide treatment (PARPi)

-triple negative breast cancer

-multiple primary breast cancers

-lobular breast cancer with phx/fhx of diffuse gastric cancer

-male breast cancer

-AJ ancestry

NCCN breast cancer testing criteria for affected individual (family history considerations)

one or more close relatives with:

-breast cancer at or before age 50

-male breast cancer

-ovarian, pancreatic, or prostate cancer

OR

three or more diagnoses of breast and/or prostate cancer in the same side of the family (includes patient with breast cancer)

NCCN breast cancer testing criteria for unaffected individual with family history of cancer only

having a first or second degree relative who does meet criteria

NCCN ovarian cancer testing criteria for affected individuals

personal history of epithelial ovarian cancer at any age

NCCN ovarian cancer testing criteria for unaffected individuals

having a first or second degree relative with epithelial ovarian cancer

NCCN pancreatic cancer testing criteria for affected individuals

personal history of exocrine pancreatic cancer

NCCN pancreatic cancer testing criteria for unaffected individuals

having a first degree relative with exocrine pancreatic cancer

NCCN prostate cancer testing criteria for affected individuals (family history excluded)

-metastatic

-AJ ancestry

NCCN prostate cancer testing criteria for affected individuals (based on family history)

one or more close relative with

-breast cancer at or before age 50

-triple negative breast cancer

-male breast cancer

-ovarian or pancreatic cancer

OR

three or more blood relative with prostate and/or breast cancer on the same side of the family including the patient with prostate cancer

NCCN prostate cancer testing criteria for unaffected individuals

having a first-degree relative who meets NCCN criteria

NCCN Lynch syndrome testing criteria for affected individual with any LS-related cancer (personal and family characteristics)

-tumor with MMR deficiency

-diagnosed before 50 y/o

-phx of an additional LS-related cancer (2 LS-cancers in total)

-one first- or second-degree relative with LS-related cancer dx < 50

-two or more first- or second-degree relatives with LS-related cancer any age

NCCN Lynch syndrome testing criteria for unaffected individual (based on Fhx only)

*relatives have to be from the same side of the family

-one or more first-degree relatives with CRC or endometrial cancer dx < 50 y/o

-one or more first-degree relatives with CRC or endometrial cancer and another LS-related cancer

-2+ FDR or SDR with LS-related cancer, including at least 1 dx < 50y

-3+ FDR or SDR with LS-related cancers

HDGC testing criteria for affected individual

-dx < 50 y/o

-Maori ethnicity

-phx or fhx of CL/P

-phx lobular breast cancer dx < 70

-bilateral lobular breast cancer (don't need to have had DGC)

HDGC testing criteria for unaffected individual

Fhx of:

-2+ cases of gastric cancer in a family with at least one DGC

-1+ case of DGC at any age and 1 case of lobular breast ca < 70 y/o in another family member

-2+ cases of locular breast ca < 50 y/o

Classic Li-Fraumeni criteria

must meet all three:

-proband dx < 45 y/o with sarcoma

-FDR dx < 45 y/o with any cancer

-additional FDR or SDR on the same side dx with cancer < 45 or a sarcoma at any age

HBOC breast cancer surveillance

-clinical breast exam every 6-12 months starting at 25 y

-annual mammogram and breast MRI ages 30-75 y

-optional risk-reducing mastectomy

HDGC screening and management recommendations

-prophylactic total gastrectomy with prior baseline endoscopy

-if not doing gastrectomy, perform upper endoscopy with random biopsies every 6-12 months

When should colonoscopies start for individuals with Lynch syndrome?

can start as early as 20 years old depending on the gene OR 2-5 years prior to earliest CRC in family

Li Fraumeni

Bone, brain, blood, breast cancers

Hereditary diffuse gastric cancer

diffuse gastric/signet ring cancer + lobular breast cancer

MEN1

3 P's: parathyroid, pancreas, pituitary neuroendocrine tumors

-Hyperparathyroidism

-skin findings: CALMS, inguinal or genital freckling, neurofibromas, Lisch nodules

-neurodevelopmental disabilities

MEN1 vs. MEN4 phenotype differences

MEN4 has lower penetrance and later ages at diagnosis

Nevoid basal cell carcinoma syndrome (Gorlin-Goltz)

-numerous BCC

-palmar pits

-odontogenic keratocysts in the jaw

-skeletal abnormalities

Cowden syndrome

-Mucocutaneous lesions (trichilimmomas, papillomas of face, acral keratosis)

-Macrocephaly

-Hamartomas

Muir-Torre syndrome

-uncommon Lynch variant phenotype

-Sebaceous neoplasms

Peutz-Jeghers syndrome

-Pigmented mucotaneous macules

-polyps in GI tract

-adenomas in GI tract

Birt-Hogg-Dube

-Skin (Fibrofolliculomas, Angiofibromas, Acrochordons)

-Lung cysts and spontaneous pneumothorax

-Renal cell carcinoma

NF1, NF2

-Neurofibroma

-Cafe-au-lait, axillary or inguinal freckling

MEN2

-Medullary thyroid carcinoma

-pheochromocytoma

-hyperparathyroidism