Lynch Syndrome: Symptoms, Types, Causes and Treatment

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is one of the most common inherited cancer syndromes. It not only raises the risk of colorectal cancer but also increases susceptibility to several other cancer types. Thanks to advances in genetic testing, surveillance, and precision medicine, individuals and families affected by Lynch syndrome have more options than ever for prevention, early detection, and treatment. This comprehensive article explores the key aspects of Lynch syndrome: its symptoms, the different types, underlying causes, and current treatment strategies.

Symptoms of Lynch Syndrome

Lynch syndrome can be silent for years, often only revealing its presence when cancer develops. Understanding the signs and patterns associated with this syndrome helps individuals and clinicians recognize it earlier, leading to life-saving interventions.

Symptom	Cancer Risk	Typical Age	Source(s)
Colorectal	50-70%	Young (<50)	1, 2, 9
Endometrial	40-60%	Young (<50)	1, 2, 9
Ovarian	Increased	Young/Adult	1, 2, 9
Other Cancers	Elevated	Variable	1, 2, 3, 9

Table 1: Key Symptoms and Cancer Risks in Lynch Syndrome

Common Symptoms and Cancer Patterns

Colorectal Cancer

• Most frequent manifestation
• Early onset, often before age 50
• Tumors more likely to be in the proximal (right-sided) colon
• Can occur as synchronous (multiple at once) or metachronous (sequential) tumors 1, 2, 9

Endometrial and Ovarian Cancer

• Endometrial cancer is the most common extracolonic cancer in Lynch syndrome, especially in women under 50 1, 2
• Ovarian cancer risk is also increased, though to a lesser extent 2, 9

Other Associated Cancers

• Stomach, small intestine, hepatobiliary tract, pancreas, urinary tract, brain (glioblastoma), and certain skin cancers (Muir-Torre variant) are also linked to Lynch syndrome 2, 3, 9
• Family history may reveal patterns of these cancers across generations

Absence of Precancerous Polyps

• Unlike other inherited colon cancer syndromes, Lynch syndrome does not cause multiple precancerous polyps 1

Non-Cancer Symptoms

• Lynch syndrome typically lacks visible, premonitory physical signs 1
• Some rare variants, like Muir-Torre syndrome, may present with skin tumors 2

Types of Lynch Syndrome

There is more than one way Lynch syndrome can manifest, both in genetic and clinical terms. Understanding the subtypes helps tailor screening and treatment.

Type	Main Feature	Genetic Basis	Source(s)
Lynch I	Colon cancer only	MMR gene mutation	1
Lynch II	Colon + other cancers	MMR gene mutation	1, 2
Muir-Torre	Skin & visceral tumors	MMR gene mutation	2
EPCAM-Associated	MSH2 silencing	EPCAM deletion	2, 10
Lynch-like	No germline mutation	Unclear/complex	5, 7

Table 2: Major Types and Variants of Lynch Syndrome

Lynch Syndrome I vs. II

Lynch Syndrome I

• Site-specific: Predominantly early-onset colon cancer 1
• Less frequent association with extracolonic tumors

Lynch Syndrome II

• Broader spectrum: Includes colon cancer plus elevated risk of endometrial, ovarian, stomach, pancreatic, and other cancers 1, 2
• Family history often reveals multiple cancer types

Muir-Torre Variant

• Combines Lynch syndrome-associated internal cancers with specific skin tumors (sebaceous adenomas, carcinomas) 2

EPCAM-Associated Lynch Syndrome

• Caused by deletions at the 3’ end of the EPCAM gene, which epigenetically silences the adjacent MSH2 gene 2, 10
• Cancer risk pattern similar to MSH2 mutation carriers, but with slightly lower endometrial cancer risk 10

Lynch-like Syndrome

• Tumors show microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression, but no germline MMR mutation is found
• Likely a mixed group: some cases due to unidentified hereditary changes, others sporadic or caused by double somatic mutations 5, 7
• Cancer risk for relatives is intermediate between classic Lynch and sporadic cases 5

Causes of Lynch Syndrome

At the heart of Lynch syndrome is a genetic defect that disrupts the body's ability to repair DNA errors, allowing mutations to accumulate and cancer to develop.

Cause	Mechanism	Main Genes Involved	Source(s)
Germline Mutation	Inherited MMR gene defect	MLH1, MSH2, MSH6, PMS2	2, 3, 9, 15
EPCAM Deletion	Silences MSH2 via methylation	EPCAM, MSH2	2, 10
Double Somatic Mut.	Acquired, not inherited	MLH1, MSH2 (tumor only)	7
Unknown Mechanism	Possible new genes/factors	?	5, 7

Table 3: Causes and Mechanisms of Lynch Syndrome

Germline Mutations in MMR Genes

Key Genes

• MLH1, MSH2, MSH6, PMS2: These DNA mismatch repair (MMR) genes detect and fix replication errors 2, 3, 4, 9, 15
• In Lynch syndrome, one defective allele is inherited; cancer develops when the second allele is lost or inactivated in a cell 2

EPCAM and MSH2 Interaction

• Some individuals have deletions in the 3’ end of EPCAM, which leads to methylation and silencing of the adjacent MSH2 gene 2, 10
• This is considered a distinct genetic mechanism for Lynch syndrome

Lynch-like Syndrome and Somatic Mutations

• In Lynch-like syndrome, tumors display mismatch repair deficiency, but no inherited (germline) mutation is found
• Over half of these cases can be explained by two acquired (somatic) mutations in a mismatch repair gene in the tumor itself 7
• Other cases remain unexplained, highlighting the need for further research 5

Pathogenesis: How DNA Repair Failure Leads to Cancer

• Loss of MMR function allows mutations to accumulate, especially in regions called microsatellites (leading to microsatellite instability, or MSI) 2, 8, 9
• This genetic instability drives the development of cancer, particularly in tissues with rapid cell turnover like the colon and endometrium 2, 8
• Different MMR gene mutations may lead to differing cancer risk profiles and ages of onset 4, 14

Treatment of Lynch Syndrome

Managing Lynch syndrome is multidimensional, involving cancer surveillance, preventive actions, and evolving treatments tailored to the genetic basis of the syndrome.

Approach	Purpose	Key Features/Examples	Source(s)
Surveillance	Early detection/prevention	Colonoscopy, endometrial biopsy	1, 3, 11, 13
Surgery	Remove/prevent cancer	Subtotal colectomy, prophylactic hysterectomy	1, 11
Chemoprevention	Lower cancer risk	Aspirin	12, 13
Immunotherapy	Treat advanced cancers	Immune checkpoint inhibitors	3, 13, 14, 15

Table 4: Main Treatment and Prevention Strategies in Lynch Syndrome

Surveillance and Early Detection

Colonoscopy

• Gold standard: Regular colonoscopy starting at age 25 (or earlier if family history indicates) 1, 3, 11
• Annual or biennial intervals recommended due to rapid progression from adenoma to carcinoma 1, 11

Additional Screenings

• Endometrial cancer: Women should undergo regular gynecological exams and may have endometrial sampling or ultrasound 1, 3, 11
• Other cancers: Depending on family tumor spectrum, screening may target the stomach, urinary tract, or other sites 1, 3, 11

Surgical Interventions

For Colorectal Cancer

• Subtotal colectomy with ileorectal anastomosis is often recommended due to risk of multiple primaries 1
• Less extensive surgery may be considered in select cases

Risk-Reducing Surgery

• Women who have completed childbearing may consider prophylactic hysterectomy and bilateral salpingo-oophorectomy to prevent endometrial and ovarian cancer 1, 11

Chemoprevention

• Long-term daily aspirin has been shown to significantly reduce the risk of colorectal cancer in Lynch syndrome carriers, with benefits appearing after at least two years of use 12, 13
• Ongoing research is exploring optimal dosing and other agents

Immunotherapy

• Immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab) are highly effective in treating mismatch repair-deficient (dMMR) tumors, including those in Lynch syndrome 3, 13, 14, 15
• These drugs harness the body's immune system to target cancer cells and have revolutionized care for advanced disease

Genetic Counseling and Family Testing

• Once a germline MMR mutation is identified, predictive testing and counseling should be offered to at-risk relatives 6, 11
• This allows for timely surveillance and early intervention

Experimental and Future Directions

• Research is ongoing into vaccines that target neoantigens formed by MMR deficiency 8, 13
• Further studies aim to optimize surveillance intervals and develop new preventive agents

Conclusion

Lynch syndrome is a complex, inherited cancer syndrome that demands a multidisciplinary approach. Advances in molecular genetics, diagnostics, prevention, and treatment have transformed the outlook for affected individuals and families.

Key takeaways:

• Symptoms: Lynch syndrome is most recognized by early-onset colorectal and endometrial cancers, but can affect many organs.
• Types: There are distinct subtypes, including classic Lynch I and II, Muir-Torre, and EPCAM-associated forms, with varying cancer risks.
• Causes: The syndrome is caused by inherited mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or EPCAM deletions; some related syndromes arise from double somatic mutations.
• Treatment: Management combines frequent surveillance, preventive surgery, chemoprevention (notably aspirin), and innovative therapies such as immunotherapy.
• Family Impact: Genetic counseling and cascade testing are crucial for identifying and protecting at-risk relatives.

By staying informed and proactive, individuals with Lynch syndrome can take meaningful steps to reduce their cancer risk and improve outcomes for themselves and their families.