Lynch syndrome: five unanswered questions

Castellsagué, Ester; Foulkes, William D.

doi:10.1111/cge.12580

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…While the LS tumor spectrum has been well established as including colon, endometrial, ovarian, stomach, small bowel, hepatobiliary tract, ureter/renal pelvis, pancreas, brain, and sebaceous neoplasms, the risks of other cancers, including breast, prostate, and adrenocortical tumors, are less clearly delineated. 1 , 2 …”

Section: Introductionmentioning

confidence: 99%

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

Roberts¹,

Jackson²,

Susswein³

et al. 2018

Genetics in Medicine

127

100

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PurposeAn association of Lynch syndrome (LS) with breast cancer has been long suspected; however, there have been insufficient data to address this question for each of the LS genes individually.MethodsWe conducted a retrospective review of personal and family history in 423 women with pathogenic or likely pathogenic germ-line variants in MLH1 (N = 65), MSH2 (N = 94), MSH6 (N = 140), or PMS2 (N = 124) identified via clinical multigene hereditary cancer testing. Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in our study population with those in the general population (Surveillance, Epidemiology, and End Results 18 data).ResultsWhen evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% confidence interval (CI), 1.56–2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17–3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% CI, 0.42–1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72–2.06).ConclusionOur data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.

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Section: Introductionmentioning

confidence: 99%

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

Roberts¹,

Jackson²,

Susswein³

et al. 2018

Genetics in Medicine

127

100

View full text Add to dashboard Cite

show abstract

“…However, neither the revised Amsterdam criteria for LS diagnosis nor the revised Bethesda criteria for MSI tests include BC (13), despite the data suggesting the link between BC and LS. In the recent publication "Lynch syndrome: five unanswered questions" the authors suggest that whether BC should be included or excluded from LS-related tumors is a perhaps the most important question in a field of "LS tumor spectrum" (14).…”

Section: Introductionmentioning

confidence: 99%

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants

et al. 2020

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Genome instability-the increased tendency of acquiring mutations in the genome and ability of a cell to tolerate high mutation burden-is one of the drivers of cancer. Genome instability results from many causes including defects in DNA repair systems. Previously, it has been shown that germline pathogenic mutations in DNA Mismatch Repair (MMR) pathway cause cancer-predisposing Lynch Syndrome. We proposed that Lynch Syndrome-related germline mutations (LS-mutations) are associated with breast cancer (BC). In this study, we performed Targeted Next-Generation Sequencing of MMR pathway genes MLH1, MSH2, MSH6, EPCAM, and PMS2 in a cohort of 711 patients with hereditary BC, 60 patients with sporadic BC, and 492 healthy donors. Sixty-nine patients (9.7%) with hereditary BC harbored at least one germline mutation in the MMR pathway genes, of them 32 patients (4.5%) harbored mutations in MMR pathway genes which we define as pathogenic or likely pathogenic, and of them 26 patients (3.6%) did not have any pathogenic mutations in DDR pathway genes, compared to two mutations in MMR pathway genes (0.4%) detected in a group of 492 healthy donors [p = 0.00013, OR = 8.9 (CI 95% 2.2-78.4)]. Our study demonstrates that LS-mutations are present in patients with hereditary BC more frequently than in healthy donors, and that there is an association of hereditary BC and mutations c.1321G>A in MLH1, c.260C>G and c.2178G>C in MSH2, c.3217C>T in MSH6, c.1268C>G and c.86G>C in PMS2 genes. This finding provides a rationale for including pathogenic LS-mutations into genetic counseling tests for patients with hereditary BC.

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“…As a secondary analysis, we also explored the data to assess evidence of enrichment of MMR gene pathogenic variants in individuals with BC, given the debate about the potential role of MMR genes in BC risk (Castellsague & Foulkes, 2015; Møller et al, 2018; Nikitin et al, 2020). Our analysis found no consistent evidence that MMR gene pathogenic variants were enriched in EC patients that also had a BC diagnosis unless they also had a family history of EC, a core LS cancer , interpreted as evidence against the hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Case–case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer

et al. 2021

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Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair genes. Evidence supports the existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n = 5292) referred for diagnostic multigene cancer panel testing were annotated for presence of a pathogenic gene variant; personal history of prior, concurrent, or subsequent cancer of another type; reported family history of Lynch syndrome or EC. The Pearson χ2 test was used to assess differences in gene variant prevalence between case sub‐groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with a prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p = 3.5 × 10−7), MSH2 (p = 3.1 × 10−7), and PMS2 (p = .02). Consistent with expectations for a breast cancer gene also predisposing to EC, the variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p = 1.7 × 10−5) and PALB2 (p = .0002). Strategic case–case analyses to address cohort ascertainment bias have provided a rationale to direct future studies of candidate hereditary EC genes.

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Lynch syndrome: five unanswered questions

Cited by 5 publications

References 35 publications

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants

Case–case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer

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