Lynch Syndrome

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2021-01-18

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PMS2, MSH2, MSH6, EPCAM, MLH1, APC, MLH3, TGFBR2, CD44, MRC1, BRCA1, BRAF, BRCA2, MUTYH, TP53, PTEN, CDKN2A, MSH3, KRAS, CTNNB1, RINT1, PALB2, NHS, CD274, PMS1, H3P10, CHEK2, RAD51C, CDH1, POLD1

PMS2, MSH2, MSH6, EPCAM, MLH1, APC, MLH3, TGFBR2, CD44, MRC1, BRCA1, BRAF, BRCA2, MUTYH, TP53, PTEN, CDKN2A, MSH3, KRAS, CTNNB1, RINT1, PALB2, NHS, CD274, PMS1, H3P10, CHEK2, RAD51C, CDH1, POLD1, MTHFR, POLE, EGFR, ATM, PMS2CL, XRCC6P5, FAP, ARID1A, LRRFIP2, CTCF, ANXA10, RNF43, AIP, SEC63, GREM1, NPTN, SOCS1, SGSM3, KAT2A, ALK, NLRP2, GSTK1, MIR18B, MIR31, MIR23B, MIR223, MIR152, MIR148A, HEPACAM, APEX1, SLCO6A1, EMB, MUC16, ATAD1, BRIP1, VHL, XPA, TGFB1, CEACAM5, MDM2, CYP17A1, ELK3, MMP7, EPHB1, MGMT, MEN1, MAX, MYC, MAT2A, SMAD7, ERBB2, ERCC2, ITGA9, GSTP1, CYP1B1, NBN, TIMP2, RNASEL, COL11A2, GJA8, ZEB1, STK11, ST8, SLC6A2, PTPRG, CYP1A1, COMT, MAP2K7, CTLA4, PARP1, PDCD1, PCNA, NAT1

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Summary

Clinical characteristics.

Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen:

CRC: 52%-82% (mean age at diagnosis 44-61 years)
Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years)
Gastric cancer: 6%-13% (mean age at diagnosis 56 years)
Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years).

The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.

Diagnosis/testing.

The diagnosis of Lynch syndrome is established in a proband by identification of a germline heterozygous pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or an EPCAM deletion on molecular genetic testing.

Management.

Treatment of manifestations: For colon cancer, full colectomy with ileorectal anastomosis is recommended. Other tumors are managed as in the general population.

Prevention of primary manifestations: Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed. Prophylactic colectomy prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because screening colonoscopy with polypectomy is an effective preventive measure.

Surveillance: Colonoscopy with removal of precancerous polyps every one to two years beginning between age 20 and 25 years or two to five years before the earliest age of diagnosis in the family, whichever is earlier. The efficacy of surveillance for cancer of the endometrium, ovary, stomach, duodenum, distal small bowel, urinary tract, and central nervous system is unknown.

Agents/circumstances to avoid: Cigarette smoking.

Evaluation of relatives at risk: When a diagnosis of Lynch syndrome has been confirmed in a proband, molecular genetic testing for the Lynch syndrome-related pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for Lynch syndrome is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18.

Genetic counseling.

Lynch syndrome is inherited in an autosomal dominant manner. The majority of individuals diagnosed with Lynch syndrome have inherited the condition from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction as a result of screening or prophylactic surgery, or early death, not all individuals with a pathogenic variant in one of the genes associated with Lynch syndrome have a parent who had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family is known.

Diagnosis

Suggestive Findings

A diagnosis of Lynch syndrome should be suspected in a proband with:

A diagnosis of colorectal cancer (CRC) or endometrial cancer and one or more of the following*:
- Colorectal or endometrial cancer diagnosed before age 50 years
- Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, stomach, small intestinal, hepatobiliary, renal pelvic, ureteral)
- Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern)
- Microsatellite instability (MSI) testing showing that tumor tissue (e.g., colon, endometrial) is MSI-high (For information on MSI testing including advantages and disadvantages, click here.)
- Tumor tissue (e.g., colon, endometrial) immunohistochemistry (IHC) demonstrates loss of expression of one or more of the mismatch repair (MMR) gene products: MSH2, MLH1, MSH6, and PMS2. (For information on advantages and disadvantages of IHC testing, click here.)
- At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years
- At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis
A family member with colorectal or endometrial cancer who meets one of the above criteria
Note: Molecular genetic testing ideally begins with a person who has had a Lynch syndrome-related cancer. However, in some families there may be no affected individual who is alive or willing to be tested.
A family member with a confirmed diagnosis of Lynch syndrome
A greater-than-5% probability of having a pathogenic variant in one of the genes listed in Table 1 based on risk assessment models
Note: Several risk assessment models including PREMM_1,2,6 [Kastrinos et al 2011] and MMRPro [Chen et al 2006] predict the likelihood of identifying a germline pathogenic variant in one of the genes listed in Table 1. Both models have good predictive value in a clinical and population-based setting when using a 5% threshold for testing [Win et al 2013a, Kastrinos et al 2015].

*Adapted from revised Bethesda Guidelines and National Comprehensive Cancer Network (NCCN) Guidelines; click here (no-fee registration and log-in required).

Population screening strategies for Lynch syndrome. Lynch syndrome screening guidelines for individuals with CRC have been developed by the NCCN; click here (no-fee registration and log-in required). The Lynch Syndrome Screening Network was established to help develop best-practice approaches for screening individuals with Lynch syndrome-related cancers and to collect long-term data on the outcomes of these programs [Mange et al 2015].

Screening approaches include:

Screen all CRC with MSI or IHC testing. This was shown to be a cost-effective approach for identifying individuals who should be offered germline molecular genetic testing for Lynch syndrome [EGAPP 2009, Ladabaum et al 2011]. (For information on advantages and disadvantages of IHC testing, click here. For information on MSI testing including advantages and disadvantages, click here.)
Screen all CRC and endometrial cancers with MSI or IHC testing [EGAPP 2009, Mange et al 2015].
Use age of onset and pathologic features to predict which individuals are more likely to have a germline MMR pathogenic variant [Rabban et al 2014].

Targeted molecular genetic testing on tumor tissue should be considered in individuals with MLH1/PMS2 loss of expression on IHC. Targeted testing includes the following:

Targeted analysis of BRAF pathogenic variant p.Val600Glu
Note: (1) BRAF p.Val600Glu is not present in Lynch syndrome-associated colorectal tumors (see Differential Diagnosis, Sporadic colorectal cancer). (2) BRAF pathogenic variants are not common in sporadic endometrial cancers; thus, BRAF testing is not helpful in distinguishing endometrial cancers that are sporadic from those that are Lynch syndrome related.
MLH1 promoter methylation analysis on tumor tissue
Note: Lynch syndrome-related cancers do not have hypermethylation of the MLH1 promoter (see Differential Diagnosis, Sporadic colorectal cancer).

Establishing the Diagnosis

The diagnosis of Lynch syndrome is established in a proband by identification of a heterozygous germline pathogenic variant in one of the genes listed in Table 1.

Molecular genetic testing approaches can include a multigene panel, serial single-gene testing, and more comprehensive genomic testing.

Option 1 (recommended)

A multigene panel that includes MLH1, MSH2, MSH6, and PMS2 as well as EPCAM deletion analysis (see Table 1) and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2 (not often recommended)

Serial single-gene testing. IHC results on tumor tissue testing may show loss of expression of one or more of the MMR genes indicating that loss of function of a particular MMR gene is most likely (see Table 2). However, this correlation is not 100% and testing of more than one gene may be necessary. Therefore, molecular genetic testing using a multigene panel is often more cost effective than serial single-gene testing.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., a pathogenic variant in a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Lynch Syndrome

Gene ¹	Proportion of Lynch Syndrome Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ² Detectable by Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion/duplication analysis ⁴
MLH1	50% ^5, 6	90%-95%	5%-10%
MSH2	40% ⁵	<80%	>20%
MSH6	7%-10% ⁷	>95%	<5%
PMS2	<5% ^8, 9	See footnote 10	See footnote 10
EPCAM	~1%-3% ¹¹	See footnote 12	100% ¹²
Unknown ¹³		NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: Smith et al [2016]
6.: Constitutional inactivation of MLH1 by methylation, along with somatic loss of heterozygosity of the functional allele, has been reported to be a rare cause of Lynch syndrome. Such cases are not detectable by either sequence analysis or duplication/deletion analysis of MLH1 (see Molecular Genetics).
7.: Miyaki et al [1997], Berends et al [2002], Peltomäki [2003]
8.: Senter et al [2008]
9.: Due to the high level of homology between PMS2 and pseudogenes, testing and interpretation of findings in this gene is difficult. A laboratory that adheres to ACMG guidelines for analysis of PMS2 and that has expertise in testing this gene should be selected when a PMS2 pathogenic variant is suspected in a family [Hegde et al 2014].
10.: Methods to sequence and identify large rearrangements in PMS2 have been developed and improved over time, making it difficult to determine the proportion of pathogenic variant detected by each method in an affected population. Nearly 200 sequence variants and more than 100 large rearrangements in PMS2 have been reported [Human Gene Mutation Database]. Variants detectable by sequence analysis appear to be more common; however, large rearrangements may comprise more than 40%-50% of pathogenic variants in this gene [van der Klift et al 2010, Vaughn et al 2010, Smith et al 2016].
11.: Although EPCAM is not a mismatch repair gene, recurrent germline deletions of the 3' region result in silencing of the adjacent downstream MSH2 by hypermethylation [Niessen et al 2009, Goel et al 2011, Kuiper et al 2011].
12.: Germline deletions of EPCAM result in silencing of the adjacent MSH2 allele by hypermethylation. The adjacent MSH2 allele itself is not mutated (see Molecular Pathogenesis). Sequence analysis of EPCAM is not appropriate for diagnosis of Lynch syndrome.
13.: There are a few case reports of germline EXO1, MLH3, MSH3, PMS1, or TGFBR2 variants in some families with Lynch syndrome; the clinical significance (if any) of allelic variants in these genes in Lynch syndrome has not yet been determined [Lu et al 1998, Peltomäki 2003].

Table 2.

Summary of Tumor Tissue Test Results, Interpretation, and Additional Tiered Testing Options

Tumor Testing ¹							Plausible Etiologies	Additional Tiered Testing Options ²
Immunohistochemistry (IHC)				MSI	BRAF V600E ³	MLH1 Promoter Methylation
MLH1	MSH2	MSH6	PMS2	MSI	BRAF V600E ³	MLH1 Promoter Methylation
+	+	+	+	MSS/ MSI-Low			Sporadic cancer	None ⁴
+	+	+	+	MSI-High			Germline MMR gene path var	1. MLH1 & MSH2 germline testing 2. MSH6 & possibly PMS2 germline testing
				MSI-High			Sporadic cancer Germline MMR gene path var	IHC to guide germline testing; OR 1. MLH1 & MSH2 germline testing 2. MSH6 & possibly PMS2 germline testing
–	+	+	–				Sporadic cancer Germline MLH1 path var	1. BRAF V600E ³ & MLH1 promoter methylation 2. MLH1 germline testing
–	+	+	–		Pos		Sporadic cancer	None ⁴
–	+	+	–		Neg	Pos	Sporadic cancer Rarely, germline MLH1 path var Constitutional MLH1 epimutation	If no significant family history: none Significant family history &/or early onset: MLH1 germline testing Early onset only: constitutional MLH1 epimutation testing
–	+	+	–		Neg	Neg	Germline MLH1 pathogenic variant	MLH1 germline testing
+	–	–	+				Germline MSH2 path var Germline EPCAM deletion Rarely, germline MSH6 path var	1. MSH2 germline testing 2. EPCAM deletion testing 3. MSH6 germline testing
–	+	+	+				Germline MLH1 pathogenic variant	MLH1 germline testing
+	+	+	–				Germline PMS2 path var Germline MLH1 path var	1. PMS2 germline testing 2. MLH1 germline testing
+	–	+	+				Germline MSH2 path var Germline EPCAM deletion	1. MSH2 germline testing 2. EPCAM deletion testing
+	+	–	+				Germline MSH6 path var Germline MSH2 path var Germline EPCAM deletion	FindZebra contact@findzebra.com