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Single NGS test could replace multistep approach for Lynch syndrome testing

Roshini Claire Anthony
10 Apr 2018

Upfront tumour sequencing with a single next-generation sequencing (NGS) test demonstrated improved sensitivity and comparable specificity with the currently used universal screening multitest approach for Lynch syndrome in patients with colorectal cancer, which highlights its role as a potential replacement for universal screening, a recent study found.

Researchers used tumour DNA from 465 patients with colorectal cancer (mean age at diagnosis 59.9 years, 51.8 percent female, 89.0 percent Caucasian) enrolled in the Ohio Colorectal Cancer Prevention Initiative (OCCPI). Of these, 419 had been scheduled to undergo universal tumour screening and germline genetic testing while the other 46 had already been determined as having Lynch syndrome due to presence of germline MMR mutations (validation group).

Tumour sequencing (which included BRAF testing) identified all 46 cases of Lynch syndrome in the validation group as well as the 12 cases of Lynch syndrome from the main cohort. In contrast, five and six cases of Lynch syndrome were missed using microsatellite instability (MSI) testing followed by BRAF and immunohistochemical (IHC) staining followed by BRAF, respectively. 

Tumour sequencing demonstrated better sensitivity in identifying Lynch syndrome compared with IHC staining plus BRAF V600E testing (100 percent vs 89.7 percent; p=0.04). The sensitivity of tumour sequencing was also superior to that of MSI plus BRAF V600E testing, though the findings were not significant (100 percent vs 91.4 percent; p=0.07). [JAMA Oncol 2018;doi:10.1001/jamaoncol.2018.0104]

Tumour sequencing showed comparable specificity with IHC plus BRAF V600E testing (95.3 percent vs 94.6 percent; p>0.99) and MSI plus BRAF V600E testing (94.8 percent; p=0.88).

Tumour sequencing also demonstrated potential in directing treatment selection with the identification of eight patients with germline DPYD mutations, a group for whom fluorouracil chemotherapy would be contraindicated due to toxicity.

According to the researchers, one of the disadvantages of the current universal tumour screening method is false negative results with IHC having a sensitivity of 83 percent for MLH1, MSH2, or MSH6 mutations, and MSI sensitivity ranging between 77 percent for MSH6 mutations and 87 percent for MLH1 or MSH2 mutations. [Genet Med 2009;11:42-65]

The extended period of testing with universal screening also presents a potential for loss to follow-up, they said.

“The sensitivity of tumour sequencing for Lynch syndrome screening is superior to the current standard-of-care approach. Tumour sequencing can also simplify the complex and time-consuming multistep algorithm to screen for Lynch syndrome,” said the researchers.

The researchers acknowledged that tumour sequencing is, as of yet, unable to detect all germline mutations. Individuals who have germline mutations detected through tumour sequencing will also need to undergo germline sequencing to confirm the findings, though a complete NGS panel may not be necessary in these cases, they said.

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