ICARE Social Media Post March 2020

MLH1: Cancer Risks and Risk Management

Gene: MLH1

Cancer Risks and Management (per NCCN version 3.2019):


Endometrial cancer risk: Elevated at 43%-57% – Consider risk-reducing hysterectomy.

Ovarian cancer risk: Elevated at 5%-20% – Recommend risk-reducing bilateral salpingo-oophorectomy (removal of ovaries and fallopian tubes).

Breast cancer risk: Elevated at 12%-17% – Manage same as general population.

Men and Women:

Colorectal cancer risk: Elevated at 46%-49% – Recommend colonoscopy every 1-2 years starting at age 20-25.

Gastric cancer risk: Elevated at 5%-7% – Consider upper endoscopy every 3-5 years beginning at age 40 for select MLH1 carriers (see NCCN for details).

Pancreatic cancer risk: Elevated at 6% – Consider MRI/MRCP or endoscopic ultrasound for MLH1 carriers with a family history of pancreatic cancer in first-degree relative.

Urothelial cancer risk: Elevated at 0.2%-5% – Consider urinalysis annually starting at age 30-35 for MLH1 carriers with a family history of urothelial cancer.


Prostate cancer risk: Elevated at 0%-17% – Manage same as general population.

Inheritance: Autosomal dominant, thus parents, full siblings, and children have a 50% risk for the gene mutation. If both parents have an MLH1 mutation, the child is at risk for autosomal recessive Constitutional mismatch repair deficiency (CMMRD) syndrome.

Family Testing: At-risk family members should consider genetic counseling and genetic testing. For adult-onset conditions, recommend delaying genetic testing on minors until they are at least 18 years old.

Reproductive Considerations: Option for preimplantation genetic diagnosis (PGD) may be available to ensure future generations do not inherit the known gene mutation. PGD is a procedure available for certain gene mutations to screen the embryo prior to achievement of pregnancy.

Check out the full management guidelines by creating a FREE account at https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf and https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

ICARE Newsletter Winter 2017

The Potential Promise of Immunotherapy Targeted to Those with Bi-Allelic Mutations in Lynch Syndrome Genes

People with Lynch Syndrome have a non-working Lynch gene (“mutation”), while the other copy of that gene is normal (recognizing that all of these genes come in pairs, with one member of the pair coming from each parent). Over the last few years, there has been an increased realization that some individuals have a mutation in both copies of their Lynch gene, which leads to a condition called Constitutional Mismatch Repair Deficiency (CMMRD). Those affected with CMMRD often develop cancer in childhood, with the most frequent types of cancer being brain tumors, gastrointestinal (colon or small bowel) cancers, and leukemias.1 Screening guidelines for children with CMMRD, developed through consortium-based efforts, include upper and lower GI scopes and brain imaging in childhood, followed by additional screening in adulthood.2 These efforts form the basis of collecting data to someday develop evidence-based screening guidelines.

Recently, a study of tumors from children with CMMRD showed some unique findings. Specifically, these tumors accumulate mutations at a very high rate (~600 mutations/cell cycle) but do not exceed ~20,000 mutations in <6 months.3 This finding suggests a new mechanism of cancer progression. The exciting component of this is now that the high mutation load and threshold effect are known, this information can be used to target more effective treatments for these cancers. To this end, high mutation load (which also leads to high neoantigen loads) may respond to immune checkpoint inhibition, which is a new class of immunotherapy drugs. In fact, a recent study demonstrated that neoantigen loads of individuals with CMMRD was substantially higher than those without the condition.4 Furthermore, based on this preclinical data, study investigators treated two siblings with CMMRD with recurrent glioblastoma multiforme (a rare and aggressive form of brain cancer) with an immune checkpoint inhibitor (PD-1 inhibitor) called nivolumab, which led to a clinically significant response and substantial shrinkage of the tumor on MRI scans. These findings suggest that cancers with exceptionally high mutation loads may more likely respond to immunotherapy because there is a higher chance they have specific neoantigens which activate T cells. Taken together, it is possible that all CMMRD-related cancers may benefit from this type of treatment approach. To investigate this further, a group of international researchers has developed a pilot study of nivolumab in pediatric patients with hypermutated cancers (clinicaltrials.gov identifier NCT02992964) and anticipates beginning enrolling patients in early 2017.

1Bakry D, et al. Eur J Cancer. 2014 Mar. PMID: 24440087.
2Durno CA, et al. Eur J Cancer. 2015 May. PMID: 25883011.
3Shlien A, et al. Nat Genet. 2015 Mar. PMID:25642631.
4Bouffet E, et al. J Clin Oncol. 2016 Jul 1. PMID: 27001570.