Risk Assessment in Cancer Genetics

Question 1

what are the steps to a cancer risk assessment?

Answer 1

assess FHx and personal Hx, choose risk assessment model, interpret risk and choose management (high, moderate, avg)

Question 2

what types of things are taken into account for a brca risk assessment?

Answer 2

age at menarche, age @ 1st birth, length of breastfeeding, age at menopause, any HRT

Hx of radiation therapy, benign breast disease, oophorectomy, BMI

diet, alcohol, smoking, exerecise

FHx (brca specific)

Question 3

what risk factors have the highest risk for brca?

Answer 3

radiation for hodgkins (5.2), benign breast disease (1.9-11), FHx (1.8-200)

Question 4

what biopsy findings are associated with increased risks for brca?

Answer 4

proliferative w/o atypia (slightly increased)

atypia (moderately increased)

carcinoma in situ (high risk)

Question 5

how does having atypical hyperplasia impact their risk for brca?

Answer 5

w/o FHx nrca: 20-25% cumulative lifetime risk

w/ FHx brca: 40% lifetime risk

3.5-5x gen pop

Question 6

how does having LCIS impact their risk for brca?

Answer 6

future marker for brca

7-11x gen pop risk

Subsequent invasive cancer usually ductal

Question 7

how does having DCIS impact their risk for brca?

Answer 7

non-invasive neoplasm of ductal origin

30% chance of becoming invasive if not treated

comedo type DCIS has higher risk of transformation

tx: breast-conserving surgery, radiation, tamoxifen

Question 8

what are some risk models for future brca risks?

Answer 8

Gail, Clause Tables, Tyrer-Cuzick (IBIS), BCSC, BOADICEA, BRCAPRO

Question 9

What doe Gail incorporate and not incorporate to its risk assessment? limitations?

Answer 9

in: current age, reproductive hx; biopsy hx; FHx in up to 2 FDRs

don’t: other cancers, 2ndDRs, >2 relatives, relatives’ age of dx

underestimates risk for Black women, Hispanic women born out of US, poorer discrimination in Hispanic women vs. NHW

Question 10

What doe Claus Tables incorporate and not incorporate to its risk assessment? limitations?

how do we adjust risks?

Answer 10

FHx-only model for future brca risk

in: female maternal and paternal FDRs and SDRs; age of onset of realtives’ cancer; provides cumulative risks to age 80; max of 2 relative considered
limits: not for families with known hereditary risks, limited FHx combos
risks: conditional probability [(new risk-original)/(1-original risk)]

Question 11

what are features consistent with hereditary brca?

Answer 11

multiple case of early onset brca

multiple primary cancers including brca

AJ heritage
Ovca w/ FHx of brca or ovca

Brca and ovca in the same person

male brca

Question 12

What individuals are most likely to have a BRCA1/2 mutation (>15%)?

Answer 12

AJ woman with ovca
woman with bilateral brca
woman with TNBrca

others:
woman with ovca (Non AJ)
at least 2 relatives with brca
woman with brca dx <35y (10%)

Question 13

are DCIS and LCIS considered invasive cancer in hereditary risk models?

Answer 13

only DCIS is, not LCIS

Question 14

what are the features of the Myriad Prevalence tables? limitations?

Answer 14

feat: proband may or may not have brca or ovca, considered age of dx <50y or >50y, considers brca in at least 1 affected relative only if dx <50y, considerd ovca in at least one relative any age, includes AJ ancestry, easy to use
limits: limited consideration of family structure, early age of brca onset

Question 15

what are the features of PENN II?

Answer 15

used only for a priori risk of BRCA1/2 variant

FHx only: inlcudes relative up to 3rdDR, includes brca, ovca, panc, and prostate; includes one side of FHx at a time

Question 16

what are the features of Tyrer-Cuzick? limitations?

Answer 16

proband must be unaffected, includes reproductive factors and BMI

limits: designed for individuals unaffected by brca, overestimates risk in women with atypical ductal hyperplasia

incorporates many factors -> personal Hx, reproductive/hormonal hx, FHx, personal and FHx of genetic testing

Question 17

what are the features of BOADICEA? limitations?

Answer 17

feat: proband may or may not have brca or ovca; considers exact age at brca and ovca; includes all FDR and SDR w/ and w/o cancer; includes AJ ancestry
limits: requires computer software, time-consuming to enter data; incorporate only FDR and SDR (may need to change proband to best capture risk)

Question 18

what are the features of BRCAPRO? limitations?

Answer 18

feat: proband may or may not have brca or ovca; considers exact age @ brca and ovca dx; considers prior genetic testing in family; considers oophorectomy; inlcudes al FDR and SDR w/ or w/o cancer; includes AJ ancestry
limits: requires conlimits: requires computer software, time-consuming to enter data; incorporate only FDR and SDR (may need to change proband to best capture risk), may overestimate risk in bilateral brca, may perform better in Whit epopulation

Question 19

what is the general population risk for colon cancer? PHx of CRC? inflammatory bowel disease? Lynch mutation? FAP?

Answer 19

6%
15-20%
15-40%
60-80%
>95%

Question 20

what criteria are used to stratify crc risk? how are they different?

Answer 20

Bethesda (high sensitivity, low specificity): most ppl have at least one criteria, but most don’t have Lynch

Amsterdam II: for people with or w/o PHx of CRC (difficult with small families)

Question 21

What risk models predict the chance of Lynch syndrome mutations?

Answer 21

MMRpro

MMRpredict

PREMM5