Hereditary Cancer Syndromes (Breast + CRC Focused)

Mostly Breast/ovarian, CRC cancer syndromes and genes

Lynch syndrome

Colorectal, Endometrial, Ovarian

Renal pevlis, bladder, gastric, pancreas, prostate

MMR genes - MLH1, MSH2, EPCAM, MSH6, and PMS2.

MSI/MMR-D Testing

Associated with LS. Tests for microsatellite instability and mismatch repair deficiencies in tumors. Uses IHC and PCR

MLH1

15-40% if cases. MMR forms protein with M+PMS2 = LOF - High risk CRC and EC

MSH2 and EPCAM

20-40% of cases and <10% respectively, EPCAM is upstream of MSH2 and silences it

Highest risk for Ovarian and Prostate

MSH6

12-35% of LS, DNA MMR, LOF, lower risk CRC and less stringent requirements for management and surveillance

PMS2

5-25%. Lower risk, other genes can take its place

CRC 8-20% and EC 13-26% (lowest chances)

Associated Variant Phenotypes with LS

Muir Torre syndrome - sebaceous neoplasms of the skin (MSH2)

Turcot syndrome - CRC or adenoma with CNS tumor

Constitutional MMR deficiency - (similar to FA)

Hereditary Diffuse Gastric Cancers (HDGC)

CHD1

AD, Codes for E-cadherin, LOF, cell-cell adhesion

Signet Ring Cancer

CDH1 ~ HDGC

Gastric Cancers (70% men) (56% women)

Lobular Breast Cancer - 42%

Cleft palate and CTNNA1 associations

HDGC / CDH1

Polyposis and Non-polyposis syndromes

Types of CRC syndromes

100+s of polyps each having their own risk for developing into cancer

Polyposis syndromes - FAP, JPS, MAP-MYH associated polyposis, PJS

Individuals with Polyps have a higher risk of each developing into cancer (but not 100s of them occurring)

Non-Polyposis syndromes, Lynch

Familial Adenomatous Polyposis Syndrome

APC gene - 100+ adenomatous colon polyps, avg age to develop is mid teens, ~100% risk for CRC

Cancers associated with FAP

CRC, stomach, small intestine, pancreas, biliary tract, papillary thyroid, medulloblastoma, hepatoblastoma (kids)

Desmoid Tumors

Osteomas (bony haw growths), extra, missing, unerupted teeth, desmoid tumors, CHRPE (retinal issues), skin changes, adrenal masses

FAP Other Findings

Attenuated FAP

APC still, less polyps (30), Later onset 50-55, 70% lifetime risk, duodenal polyps, gastric polyps, papillary thyroid

Hamartomatous polyposis syndromes

PJS and JPS

Peutz-Jeghers Syndrome (PJS)

STK11, AD, significant interfamilial variability, high penetrance

Dark skin freckling around mouth (melanosis), eyes, nostrils, fingers (childhood, can disappear), multiple polyps in the GI tract (jejunum, ilium, dueodenum), adenomas (lower malignancy but can cause other symptoms)

PJS Findings

PJS Cancers

CrC (39%), Stomach (29%), small bowel (13%), breast, (32-54%), Ovarian (21% - benign tumors), uterine, pancreas, testicular, lung

Childhood considerations - stomach bleeding, iron deficiency anemia, small intestine issues, SCTAT, Sertoli cell tumors

TNM

Tumor size (1-4)

Lymph node status (N1-3)

Metastasis (M0-none, M1-met)

CRC uses this staging

Adenomatous Polyposis Syndromes

FAP, AFAP, (gardner, turcot, GAPPS) - part of the FAP spectrum

Breast Cancer Screening Guidelines - AVG Risk

NCCN - annual mammo @40

ACS - annula mammo @45-54, biennial 55+

ACOG and USPTF have similar recs

Tyrer-Cuzick, BRCAPRO, CanRisk

Can use with affected and unaffefcted patients, included in NCCN

ATM

AD (AR risk for Ataxia Telangiectasia)

Breast - 21-24%

Ovarian 2-3, Pancreatic 5-10, Prostate and CRC increased

CHEK2

AD, multiple variants, phen/gene correlation

frameshift and nonsense 27%, some missense same, some missense less risk

23-27% BC

some increased risk for prostate, kidney, colon, thyroid (more evidence needed)

CHEK2

Genes associated with Fanconi Anemia

FANCs for BRCA-ing my PALB2, its RAD! Also BRIP1

PALB2

AD (AR - Fanconi Anemia)

Breast - 32-53%

Ovarian - 3-5%

Pancreatic 2-5%

increased risk for male BC,

BARD1

AD - just breast, 17-30%

BRIP1

AD, (AR - Fanconi Anemia) Ovarian - 5-15%, breast unknown

NF1

AD, Breast - 20-40%

Brain tumors (childhood), leukemia, GIST, pheo, optic nerve gliomas, etc

Cafe au lait spots, inguinal or genital freckling, neurofibromas, optic gliomas, Lisch nodules, skeletal anomalies, ND differences (ASD, ADHD, etc.)

NF1 Findings

Cowden syndrorme

PTEN

PTEN Cancer risks

Breast 40-60%

Thyroid - 37%

EC/uterine - 28%

CRC and melanoma increased

Breast 40-60%

EC/uterine - 28%

Thyroid - 37%

also macrocephaly, ASD, ID, other associations

CRC and melanoma increased

Cowden syndrome

RAD51C

AD (AR - FA)

Breast - 20%, Ovarian 10-15%

RAD51D

AD, (AR-FA)

20% Breast and 10-20% ovarian

Peutz-Jeghers syndrome

Breast - 32-54%, Pancreatic >15%, Ovarian neoplasms, Colon - 39%, small intestine, pancreas, SCTAT, lung, testes

Li-Fraumeni syndrome

AD, TP53, 4 B’s

CHIP - Clonal hematopoiesis of indeterminante potential

TP53 - LFS - sometimes a + TP53 result can be due to a somatic mutation in stem cells

Suspected Mutation due to CHIP when VAF <30%

If worried about CHIP

Risk Factors: Older age, male, previous heme cancer, can be a precursor for leukemia

If patient + for TP53, evaluate family history, take skin samples, maybe test additional tissue source

Hereditary Breast and Ovarian Cancer (HBOC)

BRCA1 and BRCA2

TS genes with AD inheritance but incomplete penetrance

BRCA1

Breast: 60-72%

Male BC : 0.2-12%

Ovarian: 39-58%

Pancreatic: <5%

Prostate: 7-26%

Biallelic - homozygous = death/incompatible with life

BRCA2

Breast: 55-69%

Male Breast 1.8-71%

Ovarian: 13-29%

Pancreatic: 5-10%

Prostate: 19-61%

Melanoma Increased risk

Homozygous biallelic = Fanconi Anemia

PARPi

PARP inhibitor = blocks cancer cells from being able to repair themselves

BRCA nutations rely on PARP pathway to repair DNA, so PARPi inhibits those cells from doing so