OncChats: Understanding Lynch Syndrome and Cancer Risk

, of Columbia University Herbert Irving Comprehensive Cancer Center, Fay Kastrinos, MD, MPH, shares future considerations for optimizing the identification of Lynch syndrome and other efforts underway to prevent colorectal cancer in those who have this condition.

It’s fair to say that many advances have been made related to Lynch syndrome. Future considerations also involve immunoprevention in Lynch syndrome, as well as the consideration of germline genetic testing in all colon cancers—even in the general population—specifically to optimize the identification of Lynch syndrome.

Immunoprevention may be an option for the prevention of microsatellite instability–related colon cancer. Lynch syndrome represents an ideal condition for the development of a preventive cancer vaccine. The mutations induced by mismatch repair deficiency are predictable, and therefore, can result in a defined set of neoantigens. As such, Lynch syndrome carriers may be able to potentially benefit from a cancer prevention vaccine.

Current studies are underway [to further explore] the prevention of CRC in patients with Lynch syndrome, in addition to those who have survived colon cancer or those who have metastatic disease.

Germline genetic testing should be considered in all colon cancer cases; this would not miss any Lynch syndrome carrier. Since institutions vary currently in what type of tumor testing is performed, germline testing for all colon cancers would seem foolproof. Germline testing can always be paired with any tumor testing that is conducted and this approach can also provide equitable care which would extend to historically marginalized populations, many of whom do not have regular access to genetic evaluation.

Identifying all Lynch syndrome carriers with colon cancer allows us to also target the at-risk family members, which is done through cascade testing. When the identified familial gene variant is detected in the patients [with colon cancer], we have the opportunity to test the at-risk relatives, many of whom do not have cancer. If they’re identified [to have] Lynch syndrome, we can then pursue screening and prevention strategies; these are our “pre-vivors” that we aim to keep cancer free.

Lastly, I want you to consider population-based testing for Lynch syndrome. The Office of Public Health Genomics of the Centers of Disease Control and Prevention have currently identified Lynch syndrome, as well as hereditary breast and ovarian cancer syndrome, as tier 1 conditions that are eligible for population-based genetic testing in the future. This is because testing for these conditions has significant potential for positive impact on public health based on all the [accumulated] evidence and the guideline recommendations to reduce cancer risk and mortality. In the future, we may very well be testing for Lynch syndrome in healthy young adults, even in the absence of family cancer history.

In summary, many advances have been made for the identification, management, and the treatment of Lynch syndrome. Additional work will continue to optimize cancer prevention and potential cure for Lynch syndrome. Thank you.

Videos

In this sixth episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, shares future considerations for optimizing the identification of Lynch syndrome and other efforts underway to prevent colorectal cancer in those who have this condition.

Understanding Lynch Syndrome and Associated Cancer Risk: Future Preventive Considerations 

, Fay Kastrinos, MD, MPH, Columbia University Herbert Irving Comprehensive Cancer Center, highlights progress made with regard to colon cancer treatment and Lynch syndrome, including leveraging immunotherapy.

With respect to colon cancer treatment and Lynch syndrome, improved outcomes have been appreciated for many years. In recent years, [the progress made] has been more notable with the use of immunotherapy. Tumors that develop by the MSI pathway have more somatic mutations than tumors that develop through other pathways; this could imply that mismatch repair [MMR]–deficient tumors may have more potential neoantigens and be more responsive to immune system manipulation than mismatch repair–proficient tumors.

In a recent study [published in 2022 in] the 

, a complete clinical response was noted in 12 patients with locally advanced, MMR-deficient rectal cancer after 6 months of neoadjuvant therapy with PD-1 blockade. Mutational analysis of the tumor specimens by sequencing confirmed MSI. [In] patients for whom testing was performed, tumors also revealed a high mutational burden.

Germline analysis, interestingly enough, identified pathogenic alterations in 57% of all patients and these individuals had Lynch syndrome; MSH2 was most common. Notably, however, none of these patients with Lynch syndrome had a known family history of the condition and may have been missed without germline testing.

Check back next Wednesday for the final episode in this series.

In this fifth episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, highlights progress made with regard to colon cancer treatment and Lynch syndrome, including leveraging immunotherapy.

Understanding Lynch Syndrome and Associated Cancer Risk: Treatment Advances

, Fay Kastrinos, MD, MPH, of Columbia University Herbert Irving Comprehensive Cancer Center, explains the implications of Lynch syndrome genotype on risk of colorectal cancer.

It’s important to consider the implications of the Lynch syndrome genotype because gene-specific considerations for screening are related to the associated CRC risks by genotype. Among the Lynch syndrome genes, MLH1 and MSH2 genes, which were originally thought to be most common, have now been deemed to be less common than MSH6 and PMS2 pathogenic variants. The prevalence of MSH6 and PMS2 has increased now, with the improved DNA mutational analysis and universal tumor screening of all colon cancers. In fact, PMS2 variants are quite commonly detected in extracolonic cancers.

The colon cancer incidence varies by genotype and has been consistently shown in multiple cohort studies. At present, it’s estimated that MLH1 and MSH2 lifetime CRC risk is between 35% and 60%, while MSH6 is 10% to 20% and PMS2 is on the order of 3% to 10%. These cancer risks dictate colon cancer screening recommendations. It has been well established from controlled screening trials that intensive colonoscopy reduces the incidence of colon cancer as well as colon cancer–specific mortality in individuals from Lynch syndrome families.

Because of the variability, however, in gene-specific colon cancer risks, experts in the field have proposed gene-specific screening and surveillance recommendations and this has also been supported by cost effectiveness studies. [As such], most organizations now tailor surveillance recommendations based on the specific gene and a more aggressive screening schedule may be considered on an individual basis; sometimes, [though, it is] being guided by family history.

Our present guidelines for MLH1 and MSH2 support colonoscopy initiation in [those] aged 20 to 25 years and to be repeated every 1 to 2 years. For MSH6 and PMS2, colonoscopy…is recommended at age 30 to 35 years [and to be repeated] every 1 to 3 years. There are additional cancers associated with Lynch syndrome, including cancers of the stomach, small intestine, transitional cell carcinoma of the uterus, ureters and renal pelvis, the pancreas and brain, as well as sebaceous adenomas of the skin. Screening is often individualized and directed [based on] family cancer history.

Check back next Wednesday for the next episode in this series.

In this fourth episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, explains the implications of Lynch syndrome genotype on risk of colorectal cancer.

Understanding Lynch Syndrome and Associated Cancer Risk: Implications of Genotype on Cancer Risk 

, Fay Kastrinos, MD, MPH, of Columbia University Herbert Irving Comprehensive Cancer Center, discusses testing guidance for identifying Lynch syndrome.

Universal testing with MSI or immunohistochemistry [IHC] in all newly diagnosed colorectal cancer [CRC] is a firm guideline, and that’s regardless of the age of cancer diagnosis or family history of CRC. Multiple studies have consistently proven it to be clinically feasible to take this approach on. This approach is more sensitive than existing clinical criteria, as many individuals with Lynch syndrome are diagnosed at older ages and may have less striking family histories than what was previously appreciated. [As such,] universal testing of CRC, as well as endometrial tumors with MSI and IHC have been recommended by many professional organizations and they’re still widely being adopted.

However, these days, tumor testing is far more often used to advance treatment decision-making in a more personalized approach, particularly in individuals with metastatic disease. Tumor testing for decision making, as it relates to treatment, most often includes MSI testing, as well as tumor DNA testing and sequencing. MSI testing across all tumor types has really been an important screening tool to select patients who may have a favorable response to immune checkpoint inhibitor therapy. These results may potentially be also used to screen for Lynch syndrome in tumors beyond CRC, and this is relevant because there are a number of additional cancers beyond colon cancer that are associated with Lynch syndrome.

A recent study evaluated MSI across a wide variety of malignancies and [examined] its use as a potential means to identify Lynch syndrome regardless of tumor type. In this study, data from over 15,000 individuals with more than 50 types of cancer were evaluated and were used to determine MSI and germline status from the tumor, as well as DNA sequencing. CRC and endometrial cancer comprised the majority of cancers [that were] MSI high in this study, but 38% of MSI-high tumors were of other types. Germline testing across the board confirmed a diagnosis of Lynch syndrome in 16.3% [of patients.] Among those who had Lynch syndrome[–associated] cancers other than colon and endometrial cancer, nearly half failed to meet clinical criteria for testing on the basis of the cancer type or family cancer history. These individuals would not have been identified with Lynch syndrome.

Another means in directing treatment options relies on next-generation tumor sequencing, particularly for CRC. [The] detection of Lynch syndrome amongst those who undergo next-generation sequencing of CRC has also been compared with protocols that include MSI testing, IHC staining, as well as germline testing. [As such,] when correlating the results from next-generation tumor sequencing to that of germline DNA testing, 100% of individuals identified with Lynch syndrome [from] tumor sequencing were also identified by germline DNA testing. This suggests that we might be able to use tumor sequencing as an effective method [to also identify] Lynch syndrome in addition to guiding treatment options. However, whether this is cost effective as a strategy remains to be determined.

Germline testing is the gold standard for identifying Lynch syndrome but extends beyond just looking at Lynch syndrome–associated genes through multigene panel testing. In evaluating multigene panel testing results in all colon cancers unselected for age at diagnosis, personal or family cancer history, or tumor testing results, pathogenic variants in cancer susceptibility genes are identified in up to 10% of patients. [Although] 3% of individuals with unselected colon cancer cases have Lynch syndrome, 7% of pathogenic variants [are] in non-Lynch syndrome–associated genes, all of which have specialized screening protocols that these patients would benefit from.

In this third episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, discusses testing guidance for identifying Lynch syndrome.

Understanding Lynch Syndrome and Associated Cancer Risk: Identification 

, Fay Kastrinos, MD, MPH, of Columbia University Herbert Irving Comprehensive Cancer Center, delves into the epidemiology of Lynch syndrome, the pathogenic variants in the mismatch-repair genes that cause the condition, and criteria utilized to identify it.

Lynch syndrome is the most commonly inherited colon cancer syndrome, and it accounts for approximately 3% of all newly diagnosed cases of colorectal cancer. However, the percent likelihood of identifying Lynch syndrome increases as the age of colon cancer diagnosis decreases. This is particularly relevant now, since the prevalence of early-onset colon cancer—specifically in individuals identified and diagnosed at less than 50 years is increasing in the United States. Lynch syndrome is identified in about 10% [of the] patients [with colon cancer] diagnosed at less than 50 years. In those who are identified at less than 35 years, [the percent likelihood of] Lynch syndrome identification increases to 23%. This has been the rationale for the recommendation to offer germline genetic testing to all patients [with colon cancer] who are diagnosed before the age of 50 years.

Lynch syndrome is an autosomal-dominant condition, and it is caused by pathogenic variants in the mismatch-repair genes MLH1, MSH2, MSH6, PMS2, as well as the gene EPCAM, in which deletions [can] cause epigenetic silencing of MSH2. Because of its autosomal-dominant inheritance, many families have come to the attention of oncologists and gastroenterologists in cancer registries because of their increased burden of colorectal cancer.

Family history of colon cancer, as well as an early diagnosis of colon cancer, served [as] the backbone for the clinical criteria that were originally developed [by Dr Henry Lynch] and were used to identify Lynch syndrome, dating back to the 1960s. However, with the advent of molecular tumor testing, and the detection and discovery of germline alterations associated with Lynch syndrome in the 1990s and early 2000s, improvements have been made beyond the use of the clinical criteria to optimally identify Lynch syndrome.

The genetics of both the tumor and the germline have an important role in the development and diagnosis of Lynch syndrome. Tumor DNA in Lynch syndrome–associated cancers exhibit its hallmark feature, notably microsatellite instability [MSI]. In these cases, there’s typically loss of immunohistochemical expression of 1 or more of the proteins associated with the mismatch-repair genes. As such, tumor testing is a key component in the diagnosis of Lynch syndrome in addition to family history.

In this second episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, delves into the epidemiology of Lynch syndrome, the pathogenic variants in the mismatch-repair genes that cause the condition, and criteria utilized to identify it.

Understanding Lynch Syndrome and Associated Cancer Risk: Epidemiology 

, Fay Kastrinos, MD, MPH, of Columbia University Herbert Irving Comprehensive Cancer Center, provides a brief overview of Lynch syndrome and its prevalence in the United States and beyond.

Hi, my name is Fay Kastrinos. I’m an associate professor at Columbia University in the Division of Digestive and Liver Diseases, [and at] the Herbert Irving Comprehensive Cancer Center, I am [also] the director of the Inherited GI Cancer Risk and Prevention Clinic. I am with you today [to speak] about Lynch syndrome.

Lynch syndrome is a common inherited cancer syndrome; it’s mostly associated with colorectal cancer, as well as endometrial cancer. What many people don’t appreciate is that its prevalence is comparable to the well described and tested for hereditary breast and ovarian cancer syndromes associated with the BRCA genes. In the general population, about 1 in 300 individuals have Lynch syndrome, and most of them don’t even know it. In the United States, it’s estimated that nearly 1 million individuals with Lynch syndrome are unaware of their condition—that is, until cancer develops.

Our research has really focused on standardizing the identification of inherited cancer susceptibility through genetic testing in health; that is [done] before the diagnosis of cancer. [We want to] apply screening tests and risk-reducing strategies to prevent cancer in these patients; that is so that we can optimally identify “pre-vivors” with Lynch syndrome. 

In the next few minutes, I will review the epidemiology related to Lynch syndrome, advances made for the optimal identification of Lynch syndrome, its associated colon cancer risks, and prevention strategies, as well as treatment advances. To end, I will present some future considerations associated with Lynch syndrome, as it relates specifically to prevention.

Check back next Wednesday for the next episode in the series.

In this first episode of OncChats: Understanding Lynch Syndrome and Cancer Risk, Fay Kastrinos, MD, MPH, provides a brief overview of Lynch syndrome and its prevalence in the United States and beyond.

Fay Kastrinos, MD, MPH

Articles

Understanding Lynch Syndrome and Associated Cancer Risk: Future Preventive Considerations

Understanding Lynch Syndrome and Associated Cancer Risk: Treatment Advances

Understanding Lynch Syndrome and Associated Cancer Risk: Implications of Genotype on Cancer Risk

Understanding Lynch Syndrome and Associated Cancer Risk: Identification

Understanding Lynch Syndrome and Associated Cancer Risk: Epidemiology

Understanding Lynch Syndrome and Associated Cancer Risk: Prevalence