Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative

Abstract

PURPOSE Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.

Review article: Lynch Syndrome—a mechanistic and clinical management update

“…Among the 1462 individuals who had testing based on these criteria, 16% had a PV in a cancer risk gene; 142 had a PV in an LS‐associated gene, and 101 in a non‐LS associated gene. Other studies have been consistent in demonstrating among individuals with CRC that MGPT has comparable or even higher yield for detection of LS compared to tumour‐based testing, and that an additional 3%‐13% of individuals with a personal history of CRC tested with this approach will have a PV in a non‐LS associated cancer risk gene 71‐74 . Of note, all studies to date are subject to potential selection bias that could have resulted in higher yield for cancer risk gene detection, as these studies either enrolled patients with CRC at tertiary referral centres or included some preselection criteria based on age, number of LS‐associated tumours or family history.…”

“…For example, in a populationbased study in Ohio of 3310 individuals with CRC, MGPT with a panel including at least 25 cancer susceptibility genes was offered to those with MMR deficiency in their tumours, age <50 at diagnosis, multiple primary tumours or a first-degree relative with CRC or EC. 71 Among the 1462 individuals who had testing based on these criteria, 16% had a PV in a cancer risk gene; 142 had a PV in an LS-associated gene, and 101 in a non-LS associated gene. Other studies have been consistent in demonstrating among individuals with CRC that MGPT has comparable or even higher yield for detection of LS compared to tumour-based testing, and that an additional 3%-13% of individuals with a personal history of CRC tested with this approach will have a PV in a non-LS associated cancer risk gene.…”

“…A simplified strategy of offering germline MGPT to evaluate for LS‐associated and other cancer risk genes, without preselection based on family history or tumour characteristics has been best studied for individuals with a personal history of CRC. Available evidence suggests that MGPT testing has comparable, or even higher yield for identifying individuals with a personal history of CRC and LS compared to tumour and family history‐based selection for screening 70‐72 . Further, MGPT identifies PVs in cancer susceptibility genes beyond those associated with LS.…”

“…Further, MGPT identifies PVs in cancer susceptibility genes beyond those associated with LS. For example, in a population‐based study in Ohio of 3310 individuals with CRC, MGPT with a panel including at least 25 cancer susceptibility genes was offered to those with MMR deficiency in their tumours, age <50 at diagnosis, multiple primary tumours or a first‐degree relative with CRC or EC 71 . Among the 1462 individuals who had testing based on these criteria, 16% had a PV in a cancer risk gene; 142 had a PV in an LS‐associated gene, and 101 in a non‐LS associated gene.…”

Worldwide prevalence of Lynch syndrome in patients with colorectal cancer: Systematic review and meta-analysis

“…Recent alternative approaches described for LS screening include germline testing not only for patients with MMR deficiency but also for patients diagnosed before the age of 50 years, patients with multiple primary tumors, or patients with a first-degree relative with CRC or endometrial cancer. 69 This could identify cases of LS beyond those ascertained on MMR deficiency on IHC. Multipaneled germline testing also provides the opportunity of identifying genetic predispositions, other than LS, in patients presenting with CRC.…”