Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Lynch syndrome (formerly referred to as hereditary nonpolyposis colorectal cancer or HNPCC)

Universal screening of all colorectal cancer (CRC) specimens (NCCN, ASCO, AGA, 2015) and endometrial cancer specimens (ASCO, NCCN, 2015; ESMO, 2013) is recommended
LS is an autosomal dominant inherited cancer syndrome that predisposes to colorectal, endometrial, gastric, ovarian, upper urinary tract, and other cancers
The presence of mismatch repair (MMR) deficiency helps identify patients at risk for Lynch syndrome (LS); however, it also occurs in ~15% of sporadic colorectal cancers
- Differentiating colorectal tumors with MMR deficiency due to a sporadic somatic event from colorectal tumors with MMR deficiency due to a LS germline mutation is important

Microsatellite instability (MSI)
Functions as a surrogate marker for MMR deficiency
Manifests as expansion or contraction of microsatellite repeats because of defects in MMR genes
Microsatellites are simple repeat sequences of 1-6 base pairs that are repeated up to 100 times and are prone to DNA replication errors; MMR genes function to identify and correct the replication errors

Adenomas are the precursor lesion for LS; however, not all adenomas are MMR deficient
Only 40-50% of adenomatous polyps in LS will be MMR deficient
Greater size of polyp tends to be associated with higher risk of MMR deficiency

Rare in non-LS polyps

Occurs in ~15% of sporadic colorectal cancers

5-10% of LS-associated colorectal carcinomas will have normal MMR protein expression as evaluated by immunohistochemistry (IHC) staining (NCCN, 2015)

Mutation(s)
LS
Epimutation – monoallelic

Sporadic colorectal cancer
Epimutation – biallelic

Acquired promoter methylation of MLH1

Absence of MLH1 and PMS2 proteins on IHC

Frequent mutations in BRAF

MMR gene mutations

MMR Gene Mutations
Mutations include point mutations and large genomic deletions or rearrangements
Common mutations ~90% of mutations in LS	MLH1 (mutL homolog1) – 50% MSH2 (mutS homolog 2) – 40%
Less common mutations	PMS2 (postmeiotic segregation increased 2) MSH6 (mutS homolog 6)
Heterodimeric complexes	Obligatory partners MLH1 and PMS2 MLH1 loss leads to concomitant PMS2 loss due to PMS2 degradation MSH2 and MSH6 MSH2 loss leads to concomitant MSH6 loss due to MSH6 degradation MSH6 or PMS2 losses are not associated with any other loss

BRAF V600E (c1779T>A) gene mutations
Not identified in patients with MLH1 germline mutations

Identified in ~15% of sporadic colorectal cancers

Highly associated with promoter methylation of MLH1

Diagnostic testing for Lynch syndrome (LS)

Diagnostic Testing for Lynch Syndrome
Initial testing* Use immunohistochemistry staining (IHC) or PCR initially to eliminate expense of full gene sequencing. Both tests are sensitive and usually produce concordant results.
Test	Test Interpretation
IHC Uses antibodies to MMR proteins MLH1, MSH2, MSH6, and PMS2 Protein loss identified on IHC directs mutation testing 5-10% false-negative rate (NCCN, 2015) Isolated PMS2 loss has been associated with germline MLH1	IHC Result	Likely Gene Mutation
	MLH1, PMS2 loss	MLH1
	MSH2, MSH6 loss	MSH2
	PMS2	PMS2
	MSH6	MSH6
BRAF V600E or MLH1 methylation When MLH1 loss is identified using IHC, perform prior to LS mutation analysis Loss of MLH1 is due to acquired hypermethylation in sporadic tumors, versus a germline mutation as in LS	If BRAF or MLH1 hypermethylation is positive LS unlikely; probably sporadic colorectal cancer LS gene mutation analysis not necessary unless high suspicion for LS still exists
PCR (panel of five mononucleotide microsatellites) Expansion or contraction of microsatellite repeats in the tumor Does not detect specific protein Patient tumor tissue is compared to patient normal tissue Highest sensitivity achieved when PCR is combined with IHC	Determination of MSI
	High – 2 or more markers with instability Consider gene mutation testing IHC can be used to target specific mutation testing
	Indeterminate – 1 marker with instability Instability in even 1 mononucleotide repeat can be associated with LS – suggest IHC
	Stable – no markers detected with instability Very low risk of LS Add IHC and possibly gene mutation testing if high suspicion of LS exists
MOLECULAR ANALYSIS IHC result guides choice of gene to target	Mutation testing is gold standard for diagnosing LS
*Refer to Lynch Syndrome Testing (HNPCC) algorithm Based on NCCN and AGA, 2015; US Multi-Society Task Force on Colorectal Cancer, 2014

Indications for Testing

All colorectal cancer (CRC) and/or endometrial tumors

Laboratory Testing

For additional information regarding testing strategies, refer to the following
- Key Points section for this topic
- Lynch Syndrome Testing (HNPCC) algorithm
- NCCN guidelines, Genetic/Familial High Risk Assessment (2015), page LS-2, for algorithm

Interpretation of tumor testing results

Tumor Testing Results and Additional Testing Strategies
Tumor Testing^A							Possible Diagnoses	Followup Testing^D,E
IHC				BRAF v600E^B	MLH1 Promoter Methylation	MSI
MLH1	MSH2	MSH6	PMS2	BRAF v600E^B	MLH1 Promoter Methylation	MSI
+	+	+	+	NA	NA	MSS/MSI-low	Sporadic cancer Other (not Lynch syndrome) hereditary CRC syndrome	None^C
+	+	+	+	NA	NA	MSI-high	Germline mutation in any LS gene Sporadic cancer	Germline LS genetic testing^F If germline testing negative, consider somatic MMR genetic testing^H
NA	NA	NA	NA	NA	NA	MSI-high	Sporadic cancer Germline mutation in any of the LS genes	Consider IHC analysis and additional testing depending on IHC results If IHC not performed, consider germline LS genetic testing^F
–	+	+	–	NA	NA	NA	Sporadic cancer Germline mutation MLH1 or rarely PMS2	Consider BRAF^B/methylation studies Germline LS genetic testing^F
–	+	+	–	Positive	NA	NA	Sporadic cancer Rarely germline MLH1 mutation or constitutional MLH1 epimutation	None, unless young age of onset or significant family history; then consider constitutional MLH1 epimutation testing^G and/or germline LS genetic testing^F
–	+	+	–	Negative	Positive	NA	Sporadic cancer Rarely germline MLH1 mutation or constitutional MLH1 epimutation
–	+	+	–	Negative	Negative	NA	Germline mutation MLH1 or rarely PMS2 Sporadic cancer	Germline LS genetic testing^F If germline testing negative, consider somatic MMR genetic testing^H
+	–	–	+	NA	NA	NA	Germline mutation MSH2/EPCAM; rarely germline mutation in MSH6 Sporadic cancer
+	+	+	–	NA	NA	NA	Germline mutation PMS2 Germline mutation MLH1
+	–	+	+	NA	NA	NA	Germline mutation MSH2/EPCAM Sporadic cancer
+	+	–	+	NA	NA	NA	Germline mutation MSH6 Germline mutation MSH2 Sporadic cancer/treatment effect^I	Germline LS genetic testing^F If applicable, consider MSI analysis or repeat IHC testing on nontreated tumor^I If germline testing negative, consider somatic MMR genetic testing^H
–	+	+	+	NA	NA	NA	Germline mutation MLH1; possible sporadic cancer or PMS2 mutation	Germline LS genetic testing^F If germline testing of MLH1 negative, consider BRAF^B/methylation studies Germline testing negative, consider somatic MMR genetic testing^H
–	–	–	–	NA	NA	NA	Germline mutation in any LS gene Sporadic cancer
NA = either testing was not done or results may not influence testing strategy; + = normal staining of protein; – = absent staining of protein
^ATumor testing strategies apply to colorectal and endometrial cancers; limited data exist regarding tumor testing in other LS tumors ^BTesting is not appropriate for tumors other than colorectal cancer ^CIf strong family history (ie, Amsterdam criteria) or additional features of hereditary cancer syndromes (multiple colon polyps) are present, additional testing may be warranted in the proband, or consider tumor testing in another affected family member due to the possibility of a phenocopy ^DIndividual with abnormal MSI and/or IHC tumor results and no germline mutation detected in the corresponding gene(s) may still have undetected Lynch syndrome; no consensus has been reached as to whether these patients should be managed as LS or managed based on personal/family history ^EPrior to germline genetic testing, proper pre-test counseling should be done by an individual with expertise in genetics ^FGermline LS genetic testing may include testing of the gene(s) that are indicated by the normal tumor test results, or instead, multi-gene testing the includes MLH1, MSH2, MSH6, PNS2, and EPCAM concurrently may be performed ^GEvaluation for constitutional MLH1 epimutation involves MLH1 promoter hypermethylation studies on blood or other sources of normal tissue ^HSomatic MMR genetic testing of the corresponding gene(s) could be performed on tumor DNA to asses for somatic mutations that might explain the abnormal IHC and/or MSI results ^IAbsent MSH6 in rectal tumor tissue may be due to treatment effect (neoadjuvant chemoradiotherapy)
Revised NCCN, 2015

Prognosis

Patients with MMR-deficient colorectal cancer have improved prognosis compared to patients without MMR deficiency

Lynch Syndrome (HNPCC) Testing Algorithm

Read more about Lynch Syndrome (HNPCC) Testing Algorithm

Refer to NCCN guidelines, Genetic/Familial High Risk Assessment (2015), ASCO (2015), ESMO (2013)

Refer to NCCN guidelines, Genetic/Familial High Risk Assessment (2015)

Colon cancer exhibits the characteristics of familial clustering in ~10-15% of cases. The most common cause of hereditary colon cancer is Lynch syndrome (LS – hereditary nonpolyposis colorectal cancer [HNPCC]). LS is caused by a germline mutation in one of the genes within the DNA mismatch repair system.

Epidemiology

Prevalence – 2-4% of colorectal cancer (CRC) (NCCN, 2015)
Age – mutation dependent (44-66 years mean)
- >75% risk of developing CRC by 70 years
Sex – M:F, equal

Inheritance

Autosomal dominant with incomplete penetrance
Germline mutations in 1 of 4 DNA MMR genes
- MLH1 – 50%
- MSH2 – 40%
  - Small percentage of MSH2 inactivation is due to EPCAM deletions
    - Included with MSH2 testing
- MSH6 – 7-10%
- PMS2 – <5%

Clinical Presentation

Early onset of proximal (right side) colorectal cancer – often <50 years
- Multiple metachronous and synchronous tumors are common
Early-onset extra colonic tumors, including endometrial, ovarian, small bowel, brain, pancreatic, gastric, renal pelvis, ureter, hepatobiliary tract
- Risk depends on mutation present
Penetrance – variable; patients may present with tumors at older age
- Especially true for MSH6 and PMS2
- Universal screening will identify these tumors and patients will not be mistakenly classified as sporadic CRC

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Mismatch Repair by Immunohistochemistry with Reflex to BRAF Codon 600 Mutation and MLH1 Promoter Methylation 2002327
Method: Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction

Recommended Use

Preferred screening test for Lynch Syndrome (LS) in individuals with colorectal cancer (CRC)

Reflex pattern – if MLH1 IHC is abnormal, evaluations of BRAF codon 600 and, possibly, MLH1 methylation are performed

Clinical sensitivity – 90%

Limitations

~10% of individuals with LS will have IHC tests which show normal staining of the MMR proteins

Since the correlation of MSI with IHC is not 100%, direct testing of MSI by PCR may be helpful

Follow-up

Definitive diagnosis of LS requires additional targeted MMR germline mutation studies

Mismatch Repair by Immunohistochemistry with Reflex to MLH1 Promoter Methylation 2005270
Method: Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction

Recommended Use

Preferred reflex screening test for LS in non-CRC tumors (eg, endometrial carcinoma)

Reflex pattern – if MLH1 IHC is abnormal, MLH1 methylation is performed

Clinical sensitivity – 90%

Limitations

~10% of individuals with LS will have IHC tests which show normal staining of the MMR proteins

Since the correlation of MSI with IHC is not 100%, direct testing of MSI by PCR may be helpful

Mismatch Repair by Immunohistochemistry 0049302
Method: Qualitative Immunohistochemistry

Recommended Use

First-line screening test for LS; directs additional molecular diagnostic testing for LS

Highly recommended prior to ordering MMR germline mutation analysis

Results guide subsequent genetic testing

Clinical sensitivity – 90%

Limitations

~10% of individuals with LS will have IHC tests which show normal staining of the MMR proteins

Since the correlation of MSI with IHC is not 100%, direct testing of MSI by PCR may be helpful

Microsatellite Instability (MSI), HNPCC/Lynch Syndrome, by PCR 0051740
Method: Polymerase Chain Reaction/Fragment Analysis

Recommended Use

First-line screening test for LS; directs additional molecular diagnostic testing for LS

Clinical sensitivity – 90%

Analytic sensitivity/specificity – 99%

Limitations

15% of sporadic CRCs are also MSI-H

Preoperative chemoradiation of rectal cancer

May complicate IHC interpretation and/or decrease tumor mass
May make MSI testing difficult

Evaluation of pretreatment biopsies will avoid this limitation

HNPCC/Lynch Syndrome (MLH1) Sequencing and Deletion/Duplication 0051650
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Recommended Use

Detect germline MLH1 mutations, diagnostic for LS

Use in MMR-deficient carcinoma with suggestive IHC (loss of MLH1 and PMS2 protein), absence of BRAF codon 600 mutation, and normal MLH1 methylation studies

Clinical sensitivity – >95% (combined sensitivity across all 4 genes [MLH1, MSH2, MSH6, and PMS2])

Analytic sensitivity/specificity – 99%

Limitations

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the MLH1 gene will not be detected

HNPCC/Lynch Syndrome (MSH2) Sequencing and Deletion/Duplication 0051654
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Recommended Use

Detect germline MSH2 mutations

Use in MMR-deficient carcinoma with suggestive IHC (loss of MSH2 and MSH6 protein)

Detects large MSH2 deletions and EPCAM 3 prime deletions

Clinical sensitivity – >95% (combined sensitivity across all 4 genes [MLH1, MSH2, MSH6, and PMS2])

Analytic sensitivity/specificity – 99%

Limitations

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the MSH2 gene will not be detected

HNPCC/Lynch Syndrome (MSH6) Sequencing and Deletion/Duplication 0051656
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Recommended Use

Detect germline MSH6 mutations

Use in MMR-deficient carcinoma with suggestive IHC (isolated loss of MSH6 protein)

Clinical sensitivity – >95% (combined sensitivity across all 4 genes [MLH1, MSH2, MSH6, and PMS2])

Analytic sensitivity/specificity – 99%

Limitations

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the MSH6 gene will not be detected

HNPCC/Lynch Syndrome (PMS2) Sequencing and Deletion/Duplication 0051737
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Recommended Use

Detect germline PMS2 mutations

Use in MMR-deficient carcinoma with suggestive IHC (isolated loss of PMS2 protein)

Clinical sensitivity – >95% (combined sensitivity across all 4 genes [MLH1, MSH2, MSH6, and PMS2])

Analytic sensitivity/specificity – 99%

Limitations

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the PMS2 gene will not be detected

BRAF Codon 600 Mutation Detection with Reflex to MLH1 Promoter Methylation 0051750
Method: Polymerase Chain Reaction/Pyrosequencing

Recommended Use

Recommended reflex test for differentiating between LS and sporadic CRC in tumors showing loss of MLH1

Reflex pattern – if no BRAF mutation is detected, MLH1 promoter methylation is evaluated

Analytic sensitivity – methylation levels >10% are reported as positive

Limitations

Mutations other than BRAF V600E will not be detected

Rare false negatives may occur due to primer- and probe-site mutations

BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498
Method: Polymerase Chain Reaction/Pyrosequencing

Recommended Use

Use to detect activating BRAF mutations at codon 600, which can indicate resistance to anti-EGFR therapy in colorectal cancer.

This test is also used within the Lynch syndrome reflex testing pathway (for colorectal cancer specimens only)

Use prior to BRAF V600E inhibitor initiation

Clinical sensitivity – activating BRAF mutation found in ~10% of CRCs

Analytic sensitivity/ specificity – 100%

Limitations

Limit of detection

MassARRAY and pyrosequencing − 10% mutant alleles
NGS – 5% mutant alleles

MassARRAY and pyrosequencing – oncogenic mutations outside of codon 600 will not be detected

HNPCC/Lynch Syndrome Deletion/Duplication 2001728
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Recommended Use

Order only if sequencing studies have been performed at another laboratory

Both sequencing and deletion/duplication testing are necessary to detect all pathogenic mutations in MMR genes

Requires permission from ARUP's Genetic Counselors (800-242-2787, x2141) before ordering

Guidelines

Balmana J, Balaguer F, Cervantes A, Arnold D, ESMO Guidelines Working Group. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2013; 24 Suppl 6: vi73-80. PubMed

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1): 35-41. PubMed

Giardiello FM, Allen JI, Axilbund JE, Boland R, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK, US Multi-Society Task Force on Colorectal Cancer. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology. 2014; 147(2): 502-26. PubMed

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1): 70-87. PubMed

Ladabaum U, Ford JM, Martel M, Barkun AN. American Gastroenterological Association Technical Review on the Diagnosis and Management of Lynch Syndrome Gastroenterology. 2015; 149(3): 783-813.e20. PubMed

NCCN Clinical Practice Guidelines in Oncology, Colorectal Cancer Screening. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jan 2016]

NCCN Clinical Practice Guidelines in Oncology, Uterine Neoplasms. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jul 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

Rubenstein JH, Enns R, Heidelbaugh J, Barkun A, Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome Gastroenterology. 2015; 149(3): 777-82; quiz e16-7. PubMed

Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, Lu KH, Roach N, Limburg PJ, American Society of Clinical Oncology, European Society of Clinical Oncology. 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. 2015; 33(2): 209-17. PubMed

Vasen HF, Möslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin J, Møller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007; 44(6): 353-62. PubMed

General References

Bedeir A, Krasinskas AM. Molecular diagnostics of colorectal cancer. Arch Pathol Lab Med. 2011; 135(5): 578-87. PubMed

Bodo S, Colas C, Buhard O, Collura A, Tinat J, Lavoine N, Guilloux A, Chalastanis A, Lafitte P, Coulet F, Buisine M, Ilencikova D, Ruiz-Ponte C, Kinzel M, Grandjouan S, Brems H, Lejeune S, Blanché H, Wang Q, Caron O, Cabaret O, Svrcek M, Vidaud D, Parfait B, Verloes A, Knappe UJ, Soubrier F, Mortemousque I, Leis A, Auclair-Perrossier J, Frébourg T, Fléjou J, Entz-Werle N, Leclerc J, Malka D, Cohen-Haguenauer O, Goldberg Y, Gerdes A, Fedhila F, Mathieu-Dramard M, Hamelin R, Wafaa B, Gauthier-Villars M, Bourdeaut F, Sheridan E, Vasen H, Brugières L, Wimmer K, Muleris M, Duval A, European Consortium “Care for CMMRD”. Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents Gastroenterology. 2015; 149(4): 1017-29.e3. PubMed

Boland R, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010; 138(6): 2073-2087.e3. PubMed

Djordjevic B, Broaddus RR. Role of the clinical pathology laboratory in the evaluation of endometrial carcinomas for Lynch syndrome. Semin Diagn Pathol. 2014; 31(3): 195-204. PubMed

Durno CA, Sherman PM, Aronson M, Malkin D, Hawkins C, Bakry D, Bouffet E, Gallinger S, Pollett A, Campbell B, Tabori U, International BMMRD Consortium. Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome Eur J Cancer. 2015; 51(8): 977-83. PubMed

Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011; 135(10): 1269-77. PubMed

Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010; 138(6): 2044-58. PubMed

Legolvan MP, Taliano RJ, Resnick MB. Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol. 2012; 43(8): 1157-68. PubMed

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. PubMed

Rybak C, Hall MJ. Interpretation of genetic testing for lynch syndrome in patients with putative familial colorectal cancer. J Natl Compr Canc Netw. 2011; 9(11): 1311-20. PubMed

Senter L. Genetic testing by cancer site: colon (nonpolyposis syndromes). Cancer J. 2012; 18(4): 334-7. PubMed

Sharma SG, Gulley ML. BRAF mutation testing in colorectal cancer. Arch Pathol Lab Med. 2010; 134(8): 1225-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Chadwick BE. Beyond cytomorphology: expanding the diagnostic potential for biliary cytology. Diagn Cytopathol. 2012; 40(6): 536-41. PubMed

Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, Working Group of the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1): 101-16. PubMed

Panarelli NC, Vaughn CP, Samowitz WS, Yantiss RK. Sporadic microsatellite instability-high colon cancers rarely display immunohistochemical evidence of Wnt signaling activation Am J Surg Pathol. 2015; 39(3): 313-7. PubMed

Patil DT, Bronner MP, Portier BP, Fraser CR, Plesec TP, Liu X. A five-marker panel in a multiplex PCR accurately detects microsatellite instability-high colorectal tumors without control DNA. Diagn Mol Pathol. 2012; 21(3): 127-33. PubMed

Samowitz WS. Evaluation of colorectal cancers for Lynch syndrome: practical molecular diagnostics for surgical pathologists Mod Pathol. 2015; 28 Suppl 1: S109-13. PubMed

Slattery ML, Wolff RK, Curtin K, Fitzpatrick F, Herrick J, Potter JD, Caan BJ, Samowitz WS. Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res. 2009; 660(1-2): 12-21. PubMed

Szankasi P, Reading S, Vaughn CP, Prchal JT, Bahler DW, Kelley TW. A quantitative allele-specific PCR test for the BRAF V600E mutation using a single heterozygous control plasmid for quantitation: a model for qPCR testing without standard curves. J Mol Diagn. 2013; 15(2): 248-54. PubMed

Tomsic J, Senter L, Liyanarachchi S, Clendenning M, Vaughn CP, Jenkins MA, Hopper JL, Young J, Samowitz W, de la Chapelle A. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013; 83(3): 238-43. PubMed

Vaughn CP, Baker CL, Samowitz WS, Swensen JJ. The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. Genes Chromosomes Cancer. 2013; 52(1): 107-12. PubMed

Walter AW, Ennis S, Best H, Vaughn CP, Swensen JJ, Openshaw A, Gripp KW. Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies. Pediatr Blood Cancer. 2013; 60(11): E135-6. PubMed