arise sporadically in older patients, associated with acquired (somatic in origin) aberrant methylation of the MLH1 promoter in the tumor. 4 – 6 Approximately 20% of MMRd CRC cases are associated with Lynch syndrome (LS), caused by a germline
Search Results
Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair–Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger
Megan P. Hitchins, Estela Dámaso, Rocio Alvarez, Lisa Zhou, Yajing Hu, Marcio A. Diniz, Marta Pineda, Gabriel Capella, Rachel Pearlman, and Heather Hampel
Hormone Receptor–Positive Breast Cancer Sensitive to Pembrolizumab: Evidence of the Pathogenicity of the MLH1 Variant 1835del3
Henry G. Kaplan, Jeffrey R. Whiteaker, Brianna Nelson, Richard G. Ivey, Travis D. Lorentzen, Uliana Voytovich, Lei Zhao, David J. Corwin, Robert Resta, and Amanda G. Paulovich
dysfunction of the c.1835 1837del variant of MLH1 , whose pathogenicity has been uncertain, was the driver of the disease, rendering it susceptible to PD-1 blockade. This study received Providence St. Joseph Institutional Review Board approval (study
Adolescent and Young Adult Colorectal Cancer
Joleen M. Hubbard and Axel Grothey
summarized in Table 1 . HNPCC is caused by germline mutations in 1 of 4 mismatch repair (MMR) genes: MLH1, MSH2, MSH6 , and PMS2 . Ninety percent of mutations affect MLH1 or MSH2 , whereas mutations in PMS2 are the most infrequent. The biologic
Gastroesophageal Adenocarcinomas With Defective Mismatch Repair: Current Knowledge and Clinical Management
Matthew R. Strickland, Eric M. Lander, Michael K. Gibson, David H. Ilson, Jaffer A. Ajani, and Samuel J. Klempner
mismatch recognition and initiation of repair ( Figure 1 ). MutSalpha binds double-stranded DNA at the site of mismatch and recruits additional protein-binding partners. MLH1 forms a heterodimer with PMS2, and this complex, named MutLalpha, binds MutSalpha
Tumor Mutational Burden and Mismatch Repair Deficiency Discordance as a Mechanism of Immunotherapy Resistance
Agata A. Bielska, Walid K. Chatila, Henry Walch, Nikolaus Schultz, Zsofia K. Stadler, Jinru Shia, Diane Reidy-Lagunes, and Rona Yaeger
colon masses. At total colectomy, the most advanced lesion was stage IIB. Pathology was notable for tumor-infiltrating lymphocytes (TILs) and the absence of MLH1 and PMS2 staining on immunohistochemistry ( Figure 1A ). Germline genetic testing revealed a
Risk Assessment, Genetic Testing, and Management of Lynch Syndrome
Shilpa Grover and Sapna Syngal
. Background Lynch syndrome, the most common familial CRC syndrome, results from a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 , or PMS2 . After Aldred Warthin 6 initially described it in a family with endometrial cancer and CRC, Henry
Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology
Dawn Provenzale, Samir Gupta, Dennis J. Ahnen, Travis Bray, Jamie A. Cannon, Gregory Cooper, Donald S. David, Dayna S. Early, Deborah Erwin, James M. Ford, Francis M. Giardiello, William Grady, Amy L. Halverson, Stanley R. Hamilton, Heather Hampel, Mohammad K. Ismail, Jason B. Klapman, David W. Larson, Audrey J. Lazenby, Patrick M. Lynch, Robert J. Mayer, Reid M. Ness, Scott E. Regenbogen, Niloy Jewel Samadder, Moshe Shike, Gideon Steinbach, David Weinberg, Mary Dwyer, and Susan Darlow
immunohistochemistry (IHC)-based staining of one or more DNA mismatch repair proteins ( MLH1, MSH2, MSH6, PMS2 ) within the tumor; Synchronous or metachronous Lynch syndrome-associated cancers; High PREMM[1,2,6] Lynch syndrome prediction model score 5% or higher
Point: Justification for Lynch Syndrome Screening Among All Patients With Newly Diagnosed Colorectal Cancer
Heather Hampel
cancer surveillance, 4 – 6 hysterectomy and bilateral salpingo-oophorectomy seem to be effective at preventing endometrial and ovarian cancers in women with Lynch syndrome. 7 Lynch syndrome is caused by germline mutations in an MMR gene, such as MLH1
Counterpoint: Implementing Population Genetic Screening for Lynch Syndrome Among Newly Diagnosed Colorectal Cancer Patients—Will the Ends Justify the Means?
Michael J. Hall
gene ( MLH1, MSH2, MSH6 , or PMS2 ) have an elevated lifetime risk for cancer, including CRC (∼60%–80%), endometrial (∼40%–60%), gastric (∼15%–20%), and a smaller increased risk for several other cancers. Mutation carriers are advised to pursue
Germline and Somatic Mutations in Prostate Cancer for the Clinician
Heather H. Cheng, Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small, and Celestia S. Higano
, ATM , PALB2 , CHEK2 , MLH1 , MSH2 , MSH6 , and PMS2 should be included due to potential treatment implications, although this list is expected to be refined over time. In specific research or clinical contexts, a larger gene panel may be
