Hereditary Colorectal Cancer Syndromes

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Transcript Hereditary Colorectal Cancer Syndromes

Hereditary Colorectal Cancer Syndromes
Philip Kam
Queen Elizabeth Hospital
Overview
-Features and genetics basis
-Screening
-Surveillance protocol
-Surgical management
Colorectal cancers
-Colorectal cancer (CRC) is commonest cancer in HK (~4450 new
cases in 2011)
-Worldwide incidence estimated ~1 million annually
-about 20% has strong familial basis
HK Cancer registry, 2013
Lynch et al 2009
Colorectal cancers
-~5% hereditary
-Hereditary forms of colorectal cancers: strong penetrance among
families with known genetic basis, i.e. germline mutations
-Amongst them:
-Familial Adenomatous Polyposis (FAP)
-Lynch Syndrome (also known as Hereditary Non-Polyposis
Colorectal Cancer, HNPCC)
-Rustgi 2007
Familial Adenomatous Polyposis (FAP)
-Classical FAP:
-Presence of 100 or more polyps, with extra-colonic manifestations
-Attenuated FAP
-Less than100 adenomas (~average 30); frequent right sided distribution
-Presents with multiple colonic polyps since average of 16 year old
-By age 35, ~95% FAP have polyps
-Mean age of Colon cancer is 39 (~34-43)
-Extra-colonic involvement include:
-stomach, duodenum, osteoma, thyroid, congenital hypertrophy of the retinal
pigment epithelium (CHRPE), soft tissue tumor, desmoid tumor
FAP - Genetics
- Autosomal dominant
- Defect in gene APC (Adenomatous polyposis coli), on Chrm
5p22.2
- Pathogenic variants, with more than 1,500 germline mutations
found
- Detection by:
Sequence analysis: ~90%
FAP - Surveillance
-Sigmoidoscopy / Colonoscopy every 1-2 years from age 10-12
-Annual colonoscopy once polyp found
-OGD before colectomy or age 25, then every 1-3 years
-Annual cervical USG to screen for thyroid cancer from at 25-30
-CT or MRI abdomen as baseline to look for desmoid tumor if
strongly family history
-Small bowel enema / CT with oral contrast
NCCN 2014, Stoffel 2014
FAP - Treatment
● For classic FAP, colectomy is recommended once adenoma
emerge
● In presence of symptoms, or lesions with high grade dysplasia,
colectomy should be as soon as possible
Options:
● Total Colectomy with ileorectal anastomosis
-if Attenuated FAP / rectum is spared of polyp
●Restorative proctocolectomy with ileal pouch-anal anastomosis
(IPAA)
● Total procotcolectomy with permanent ileostomy
FAP - Treatment options
Total Colectomy + IRA
Proctocolectomy + IPAA
Total proctocolectomy +
stoma
Risk of Ca rectum
(5% in 10years)
No risk of future Ca rectum
Most “definitive”; but not the
first line
Lower complications risks
Less re-operative rate
Function might be poor: more
frequent bowel movement,
incontinence and soiling
Difficult for young patients
Quality of life better
Still has risks of polyp
formation in IPAA; but risk of
Ca rectum ?
~48% pouch adenoma
For few polyps and rectum
spared (<20)
Severe rectal adenoma (>20)
and severe colon load (>1000)
For tumor involving sphincter /
presence of desmoid tumor
Church 2013; Guillem et al 2006
Lynch Syndrome
Lynch Syndrome - Presentation
-Fulfills clinical criteria with germline mutation found
-Major outcome is colorectal cancer, with mean age of diagnosis
at 44-60 years old (vs. 69 in sporadic)
-Risk of CRC up to 75%-80% in life
-Majority are right side tumor (60-80%)
-High rate of metachronous tumor (16% in 10 years, 41% in 20
years)
-Also a wide variety of extracolonic tumors
-Risks of CRC and other tumors depend on which mutation
-In HK, about 170 families of Lynch Syndrome identified thus far
LS - Extracolonic involvements
Giardiello et al. 2014
Lynch Syndrome - Genetics
-Autosomal dominant
-At least 4 genes found implicated
-MLH1, MSH2, MSH6, PMS2
-All are Mismatch Repair (MMR) gene mutations
-Leading to a loss of “proofreading” in DNA replication
-Results in point-mutations, known as Microsatellite Instability (MSI)
-Accumulation of mutations cause more rapid adenoma-carcinoma
sequence → earlier onset
-Kohlmann 2014
What is MMR?
In areas of long,
tandem repeats of
nucleotides, MMR can
correct mismatch of
single nucleotide!
Vilar & Gruber 2010
Lynch Syndrome - who to suspect?
Two major clinical guidelines have been developed to screen for Lynch
Syndrome
-Amsterdam
-Revised
Criteria
Bethesda Guideline
- Guidelines help to initiate genetic testing in tumor specimen to confirm
diagnosis of LS in a proband
- Microsatellite Instablity (MSI)
-Immunohistochemical stain (IHC)
-Germline sequence analysis
Screening Algorithms
Amsterdam /
Bethesda criteria met
Endometrial Ca < age 50
Positive
Lynch Syndrome surveillance
Negative
Average risk surveillance
Mutation
known
Known LS in Family
Tumor a/v
Mutation
NOT
known
Tumor
NOT a/v
NCCN guideline 2014
Stoffel et al 2014
Test for MSI and IHC for
mutations, diagnosis and
screening strategy accordingly
Genetic for
4 MMR
genes
Positive = Lynch
syndrome surveillance
and screening for family
members
LS - Amsterdam Criteria
“3-2-1 rule”
Sensitivity 22%;
Specificity 98%
Giardiello et al. 2014
LS - Revised Bethesda
Developed to identify
patients who need MSItesting
Sensitivity 82%;
Specificity 77%
Giardiello et al. 2014
Lynch Syndrome - Genetics Testing
The tumor specimen can be tested for:
MSI stability
-A panel of 5 markers used; MSI-high, MSI-low, or MSI-stable
Immunohistochemistry (IHC) staining:
-To see which MMR gene protein is dysfunctional
-90% of LS tumors are MSI-high. But 10-15% of sporadic cases are also MSI-H
and abnormal IHC
Germline molecular testing by sequence analysis
-When tumor specimen is not available
Lynch 2009; Giardello 2014; NCCN guideline 2014
Lynch Syndrome - Surveillance
Surveillance strategy for extracolonic tumor once genetic test positive:
- Colorectal Ca: Colonoscopy every 1-2 years starting age 20-25; or 2-5
years before youngest age of CRC in family if diagnosed before 25yo
- Endometrial Ca: Annual pelvic exam and endometrial sampling at age 3035
- Ovarian Ca: annual TV USG from age 30-35
-Consider
prophylactic TAHBSO in women with LS at age 40 or finish child-bearing
Giardello et al 2014; Stoffel et
al 2014; NCCN 2014
Lynch Syndrome - Surveillance
Surveillance strategy:
- Gastric Ca: OGD from age 30-35 with antral biopsy and H.pylori
eradication; FU OGD every 2-3 years
- Small bowel Ca: lacks evidence for use of small bowel enema / capsule
endoscopy
-NCCN:
OGD with extended duodenoscopy
- Urinary Ca: annual urinalysis from age 30-35
- CNS cancer: annual neurological exam
Giardello et al 2014; Stoffel et al 2014; NCCN 2014
LS - Treatment of Ca Colon
If LS patient has CA colon or pre-malignant adenoma, colectomy
is the choice:
- If only partial colectomy, risks of 10-year CRC risks increases
from 16-19% despite vigilant colonoscopy
- Prophylactic subtotal colectomy or total colectomy with ileorectal anastomosis significantly reduced the risks to <3.4%
Win et al 2013, Edelstein et al 2011
- Retrospective review showed metachronous CRC reduced by
31% of every 10cm of large bowel resected
Parry 2011
LS - Treatment of Ca rectum
LS with Ca rectum (up to ~20% in LS):
- Total proctocolectomy with ileal pouch-anal anastomosis (IPAA)
theoretically attains smaller risks of metachronous tumor
- Anterior resection with intensive surveillance is an option?
-risk of metachronous cancer / advanced neoplasia up to 51%
Kalady et al 2012
Conclusion
-Lynch syndrome and FAP should be suspected in young patients
with cancer / multiple colonic adenoma
-Clear family history important
-Clinically should screen for other organ involvement
-Genetically should arrange appropriate genetic testing
-Surgically should tailor-made appropriate operation for curative and
prophylactic purpose
-Hopefully involving surgeons, oncologist, and geneticist
Thank you
References
•HK Cancer Registry 2013; available at http://www3.ha.org.hk/cancereg/Summary%20of%20CanStat%202011.pdf
•Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening,
differential diagnosis and medicolegal ramifications. Clin Genet. 2009; 76(1): 1–18
•Rustgi AK, The genetics of hereditary colon cancer. Genes & Dev. 2007; 21:2525–2538
•Giardello FM, Allen JI, Axibund JE, Boland CR. et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus
statement by the US Multi-Society Task Force on Colorectal Cancer. Dis Colon Rectum 2014; 57: 1025-1048
•Kohlmann W. Lynch Syndrome. GeneReviews, NCBI Bookshelf, last updated May 22, 2014. Available at
http://www.ncbi.nlm.nih.gov/books/NBK1211
•Vilar E, Gruber SB, Microsatellite instability in colorectal cancer—the stable evidence. Nature Review Cliincal Oncology, 2010 7(3):153-62
•Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, et al. Hereditary Colorectal Cancer Syndromes: American Society of Clinical Oncology
clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines.
J Clin Oncol 2014 (ahead of print; available at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.58.1322)
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•S. Parry, A.K. Win, B. Parry, et al., Metachronous colorectal cancer risk for mismatch repair gene mutation
carriers: the advantage of more extensive colon surgery. Gut 2011; 60:950–957.
•K. Win, S. Parry, B. Parry, et al., Risk of metachronous colon cancer following surgery for rectal cancer in
mismatch repair gene mutation carriers, Ann Surg Oncol 2013; 20:1829–1836.
•D.L. Edelstein, J.E. Axilbund, M. Baxter, et al., Rapid development of colorectal neoplasia in patients with lynch
syndrome, Clin Gastroenterol Hepatol 2011; 9:340–343.
•M.F. Kalady, J. Lipman, E. McGannon, et al., Risk of colonic neoplasia after proctectomy for rectal cancer in
hereditary non- polyposis colorectal cancer, Ann Surg 2012; 225:1121–1125
•Hedge M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited
colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis) Genetics in
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•Jasperson KW and Burt RW APC-associated polyposis condition.. GeneReviews, NCBI Bookshelf, last updated
March 27, 2014. Avaialble at http://www.ncbi.nlm.nih.gov/books/NBK1345
•Campos FG Surgical treatment of familial adenomatous polyposis: dilemmas and current recommendations.