Focus on Genetics and Gastrointestinal Cancers - PowerPoint Presentation

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Focus on Genetics and Gastrointestinal Cancers

Jamin

Morrison, MD

Hematology / Medical OncologySlide3

OverviewCancer “genetics” in the news

Gastrointestinal cancer genetic syndromes

Lynch Syndrome & recommendations

Translating cancer genetics to the bedsideSlide4

https://

www.nytimes.com

/2017/02/28/well/live/

colon-and-rectal-cancers-rising-in-young-people.html?action

=

click&contentCollection

=

Well&module

=

RelatedCoverage&region

=

Marginalia&pgtype

=articleSlide5

https://

www.cnn.com

/2017/02/28/health/colon-cancer-rectal-cancer-risk-young-people-study/

index.htmlSlide6

Incidence rate ratios by birth cohort for colon and rectal cancer

Siegel

et al

.,

J Natl Cancer Inst

. 2017 Aug 1;109(8). Slide7

The Majority of Colorectal Cancers Do

Not

Have an Identifiable Germline MutationSlide8

GI Cancer syndromes

Cowden syndrome

MUTYH

-associated polyposis

Hereditary pancreatic cancer

Peutz-Jeghers syndromeFamilial adenomatous polyposis (FAP)Serrated polyopsis

syndrome

Hereditary gastric cancer

Lynch

syndromeSlide9

FAP (familial adenomatous polyposis)

Autosomal dominant

Gene:

APC

High frequency (30%) of

de novo mutationsNon-malignant features:100-1000 colorectal adenomas, gastric and duodenal adenomatous polyposis, congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, osteomas, dental abnormalities,

desmoid

tumors

Oncology Letters

. 13: 1499-1408, 2017.Slide10

FAP (familial adenomatous polyposis)

https://

library.med.utah.edu

/

WebPath

/GIHTML/GI143.htmlSlide11

FAP (familial adenomatous polyposis)

Petersen et al.,

Gastro

100, 1658 1991Slide12

FAP (familial adenomatous polyposis)

Site of disease

Lifetime risk (%)

Colon

100

Duodenum/

periampullary

4-12

Stomach

<1

Pancreas

2

Thyroid

1-2

Liver (

hepatoblastoma

)

1-2

CNS (

medulloblastoma

)

<1

Oncology Letters

. 13: 1499-1408, 2017.Slide13

AFAP (Attenuated FAP)Autosomal dominant

Gene:

APC

Non-malignant features:

<100 colonic adenomas (0-100)

Upper GI polyposis similar to FAPOther non-malignant features are rare in AFAP

Oncology Letters

. 13: 1499-1408, 2017.Slide14

AFAP (attenuated FAP)

Site of disease

Lifetime risk (%)

Colon

70

Duodenum/

periampullary

4-12

Thyroid

1-2

Oncology Letters

. 13: 1499-1408, 2017.Slide15

AFAP (attenuated FAP)

FAP:

Site of disease

Lifetime risk (%)

Colon

70

Duodenum/

periampullary

4-12

Thyroid

1-2

Site of disease

Lifetime risk (%)

Colon

100

Duodenum/

periampullary

4-12

Thyroid

1-2

Oncology Letters

. 13: 1499-1408, 2017.Slide16

PJS (Peutz—Jeghers syndrome)

Autosomal dominant

Gene:

STK11

Non-malignant features:

Mucocutaneous pigmentations

Gastrointestinal

hamartomatous

(

Peutz-Jegher

) polyps

Oncology Letters

. 13: 1499-1408, 2017.Slide17

PJS (Peutz—Jeghers syndrome)

https://step2.medbullets.com/gastrointestinal/120177/

peutz

-

jeghers

-syndromeSlide18

PJS (Peutz—Jeghers syndrome)

Site of disease

Lifetime risk (%)

Breast

54

Colon

39

Pancreas

11-36

Stomach

29

Ovary

21

Lung

15

Small bowel

13

Uterine/cervix

9

Testicle

<1

Oncology Letters

. 13: 1499-1408, 2017.Slide19

JPS (juvenile polyposis syndrome)

Autosomal dominant

Genes:

SMAD4

: associated with colon (39% lifetime risk)

BMPR1A: associated with stomach, pancreas, small bowel (21% lifetime risk)Non-malignant features:Gastrointestinal

hamartomatous

(juvenile) polyps

Features of HHT congenital defects

Oncology Letters

. 13: 1499-1408, 2017.Slide20

Hereditary Diffuse Gastric Cancer

1994: family with 8 related members with gastric cancer at early ages (31-65 years), over 4 generations, with autosomal dominant transmission

Diffuse gastric cancer, with multiple isolated nests of signet ring cells

“

Linitus

plastica” extending from proximal stomach into small intestine

Cell

Mol

Gastroenterol

Hepatol

. 2017; 3:192-200.Slide21

Hereditary Diffuse Gastric Cancer

CDH1

gene

Encodes E-cadherin

Also associated with lobular breast cancers

Cell

Mol

Gastroenterol

Hepatol

. 2017; 3:192-200.Slide22

Hereditary Diffuse Gastric Cancer

Diagnosis should be considered

Families with 2 or more individuals with gastric cancer at any age

Individuals with diffuse gastric cancer before the age of 40

Families with both diffuse gastric cancer and lobular breast cancer

Individuals with bilateral lobular breast cancer before age 50Individuals with gastric cancer and cleft lip or cleft palate

Cell

Mol

Gastroenterol

Hepatol

. 2017; 3:192-200.Slide23

Lynch syndrome

Most common cause of inherited colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC)

Autosomal dominant

Am J

Gastroenterol

. 2015; 110:223-262.Slide24

Lynch syndrome

Site of disease

Lifetime risk (%)

Colon

50-80

Endometrium

40-60

Stomach

11-19

Ovary

9-12

Hepatobiliary tract

2-7

Upper urinary tract

4-5

Pancreas

3-4

Small bowel

1-4

CNS

1-3

Oncology Letters

. 13: 1499-1408, 2017.Slide25

Lynch syndrome

Lancet

Oncol

2009; 10:

400–08.Slide26

Lynch syndrome

Physical or non-malignant features, with the exception of

keratoacanthomas

and sebaceous adenomas/carcinomas, are rare

Oncology Letters

. 13: 1499-1408, 2017.Slide27

Lynch syndromeLynch syndrome tumors associated with changes in the length of nucleotide repeat sequences of tumor DNA

Termed “microsatellite instability” or MSI

MSI results from defective mismatch repair at the time of DNA replication

MSI and MMR used interchangeably

Am J

Gastroenterol

. 2015; 110:223-262.Slide28

Lynch syndrome

http://slideplayer.com/slide/7420300/24/images/8/Mismatch+Repair+Protein+Function.jpgSlide29

Lynch syndrome

Presence

in germline mutation in a DNA mismatch repair gene

MLH1, MSH2, MSH6, PMS2

EPCAM

Am J

Gastroenterol

. 2015; 110:223-262.Slide30

Lynch syndrome

https://www.researchgate.net/figure/The-frequency-of-mismatch-repair-gene-mutations-in-Lynch-syndrome_fig1_255788658Slide31

Lynch syndrome

Am J

Gastroenterol

. 2015; 110:223-262.Slide32

Lynch syndromeRecommendation:

Genetic testing in those with suspected Lynch should include germline testing for

MLH1, MSH2, MSH6

and

PMS2

Screening of cancers in patients with suspected Lynch starts with immunohistochemical (IHC) testing for MLH1, MSH2, MSH6 and PMS2 proteins

Am J

Gastroenterol

. 2015; 110:223-262.Slide33

Lynch syndromeRecommendation:

In individuals at risk for or affected with Lynch, screening for CRC by colonoscopy should be performed at least every 2 years, beginning between 20 and 25 years.

Annual colonoscopy should be considered in confirmed mutation carriers.

Am J

Gastroenterol

. 2015; 110:223-262.Slide34

Lynch syndromeRecommendation:

Colectomy with

ileorectal

anastomosis is the preferred treatment of patients affected with Lynch with colon cancer or colonic neoplasia not controllable by endoscopy.

Segmental colectomy is an option in patients unsuitable for total colectomy if regular postoperative surveillance is conducted.

Am J

Gastroenterol

. 2015; 110:223-262.Slide35

Lynch syndrome

Recommendation:

Hysterectomy with bilateral

salpingo-oophrectomy

should be offered to women who are known Lynch carriers and who have finished child bearing, optimally at age 40-45 years.

Am J

Gastroenterol

. 2015; 110:223-262.Slide36

Lynch syndromeRecommendation:

Screening for endometrial cancer and ovarian cancer should be offered to women at risk for or affected by Lynch by endometrial biopsy and transvaginal ultrasound annually, starting at age 30-35 years before undergoing surgery, or if surgery is deferred.

Am J

Gastroenterol

. 2015; 110:223-262.Slide37

Lynch syndromeRecommendation:

Screening for gastric and duodenal cancer can be considered in individuals at risk for or affected with Lynch by baseline EGD with gastric biopsy at age 30-35 years. Data for ongoing surveillance is limited, but may be appropriate every 3-5 years.

Am J

Gastroenterol

. 2015; 110:223-262.Slide38

Lynch syndromeRecommendation:

Screening beyond population-based recommendations for cancers of the urinary tract, pancreas, prostate, and breast (in the absence of additional risk factors or family history) has limited quality data.

Am J

Gastroenterol

. 2015; 110:223-262.Slide39

Hereditary Cancer SyndromesUntil 2017, identification of a cancer syndrome impacted:

Screening tests in affected individuals

Screening tests in relatives of affected individuals

Prophylactic organ removal or risk reduction

Definitive surgical management

Lacking treatment implicationsSlide40

Hereditary Cancer SyndromesUntil 2017: Lynch colorectal cancer treated identically to every other colorectal cancer

Cancer landscape is changing:

Translating

clinical genetics

into

bedside clinical careSlide41

https://

directorsblog.nih.gov

/2015/06/09/a-surprising-match-cancer-immunotherapy-and-mismatch-repair/Slide42

Clin

Cancer Res

. 2016 Feb 15;22(4):

813-20.Slide43

N

Engl

J Med

. 2015; 272:2509-2520.Slide44

PD-1 Blockade in MMR Deficiency

Phase 2 trial of

pembrolizumab

(anti-PD1 checkpoint inhibitor) in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency

Mismatch-repair deficient

mCRCMismatch-repair proficient mCRC

Mismatch-repair deficient non-CRC

N

Engl

J Med

. 2015; 272:2509-2520.Slide45

PD-1 Blockade in MMR DeficiencyEnd points:

Immune-related objective response rate

Immune-related progression-free survival at 20 weeks

ORR

PFS (20 week)

MMR-deficient CRC

40%

78%

MMR-proficient CRC

0%

11%

MMR-deficient non-CRC

71%

67%

N

Engl

J Med

. 2015; 272:2509-2520.Slide46

N

Engl

J Med

. 2015; 272:2509-2520.Slide47

N

Engl

J Med

. 2015; 272:2509-2520.Slide48

PD-1 Blockade in MMR Deficiency

N

Engl

J Med

. 2015; 272:2509-2520.Slide49
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