Evaluation of yield and experiences of age‐related molecular investigation for heritable and nonheritable causes of mismatch repair deficient colorectal cancer to identify Lynch syndrome

Abstract

Universal mismatch repair deficiency (dMMR) testing of colorectal cancer (CRC) is promoted as routine diagnostics to prescreen for Lynch syndrome. We evaluated the yield and experience of age‐related molecular investigation for heritable and nonheritable causes of dMMR in CRC below age 70 to identify Lynch Syndrome. In a prospective cohort of 3602 newly diagnosed CRCs below age 70 from 19 hospitals, dMMR, MLH1 promoter hypermethylation, germline MMR gene and somatic MMR gene testing was assessed in daily practice. Yield was evaluated using data from the Dutch Pathology Registry (PALGA) and two regional genetic centers. Experiences of clinicians were evaluated through questionnaires. Participating clinicians were overwhelmingly positive about the clinical workflow. Pathologists routinely applied dMMR‐testing in 84% CRCs and determined 10% was dMMR, largely due to somatic MLH1 hypermethylation (66%). Of those, 69% with dMMR CRC below age 70 without hypermethylation were referred for genetic testing, of which 55% was due to Lynch syndrome (hereditary) and 43% to somatic biallelic pathogenic MMR (nonhereditary). The prevalence of Lynch syndrome was 18% in CRC < 40, 1.7% in CRC age 40‐64 and 0.7% in CRC age 65‐69. Age 65‐69 represents most cases with dMMR, in which dMMR due to somatic causes (13%) is 20 times more prevalent than Lynch syndrome. In conclusion, up to age 65 routine diagnostics of (non‐)heritable causes of dMMR CRCs effectively identifies Lynch syndrome and reduces Lynch‐like diagnoses. Above age 64, the effort to detect one Lynch syndrome patient in dMMR CRC is high and germline testing rarely needed.

Identifying mismatch repair‐deficient colon cancer: near‐perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population‐based series

“…Restriction to stage 2 and stage 3 cancers will also have enhanced this proportion, as MMR deficiency is less common at stage 1 and stage 4 57–59 . A further limitation of this study is the unavailability of either constitutive or somatic (tumour) MMR gene mutation status, making an accurate evaluation of the contributions of Lynch syndrome and somatic biallelic MMR gene mutations to colon cancer in this population not possible 10–12 …”

“…Sporadic MSI‐H CRCs are much more common than those related to Lynch syndrome, accounting for ~15% of all new CRC diagnoses. Biallelic somatic mutations in MMR genes account for a significant proportion of MSI‐H CRCs lacking constitutive mutation in MMR genes, somatic BRAF mutation, or MLH1 promoter hypermethylation, especially among patients in older age groups 10–12 …”

“…Biallelic somatic mutations in MMR genes account for a significant proportion of MSI-H CRCs lacking constitutive mutation in MMR genes, somatic BRAF mutation, or MLH1 promoter hypermethylation, especially among patients in older age groups. [10][11][12] For these reasons, and driven primarily by health economics indicating the cost-effectiveness of global screening for Lynch syndrome, an increasing number of surgical or molecular pathology laboratories now offer reflex testing of all new diagnoses of CRC for MSI status, with some form of concurrent or subsequent algorithmic testing, notably tumour BRAF mutation status, to determine likely constitutive or somatic pathogenesis. 13,14 Such reflex testing is now advocated by many major national and international groups.…”

Age‐dependent performance of BRAF mutation testing in Lynch syndrome diagnostics

“…Even if patients <50 years with a BRAF-mutant MSI CRC may not have LS, they may still suffer from other inherited tumor syndromes. BRAF testing is particularly cost-efficient in this group of patients, thereby showing accordance with the strategy of currently applied universal MMR testing of CRC patients under 70 years in order to identify LS 29,37. In general, the upper age limit for BRAF testing should be guided by the upper age limit applied for the molecular analysis performed afore, such as MSI/MMR testing.In addition to tumor MMR/MSI testing followed by BRAF muta-…”

“…For patients >60 years, we could confirm previous reports suggesting BRAF mutation testing as a useful tool in LS diagnostics: Here, BRAF mutation testing has only a very minor risk of excluding LS patients from germline MMR gene mutation analysis, but offers a significant cost reduction across all cost ratio scenarios (Figures 3 and 4). As the sporadic‐to‐hereditary ratio in MSI CRCs among patients younger than 70 has been reported to be highest in patients diagnosed between 65 and 70 years, 37 BRAF testing is particularly cost‐efficient in this group of patients, thereby showing accordance with the strategy of currently applied universal MMR testing of CRC patients under 70 years in order to identify LS 29,37 . In general, the upper age limit for BRAF testing should be guided by the upper age limit applied for the molecular analysis performed afore, such as MSI/MMR testing.…”