Table 1 Recommendations. a: Diagnosis recommendations. b: Genetic counselling recommendations. c: Surveillance recommendations. d: Quality of life recommendations. e: Clinical management recommendations.

Indications for testing

Rec. 1

CMMRD testing should be offered to all cancer patients who reach a minimum of three scoring points according to the revised C4CMMRD indication criteria (Table 2).

Strong

Rec. 2

CMMRD testing should be offered to all cancer patients aged <18 years with a tumour that has a paediatric-high* tumour mutational burden (TMB), regardless of presence or absence of a somatic POLE or POLD1 pathogenic variant.

*(Gröbner et al. [61])

Strong

Rec. 3

CMMRD testing should be offered to all cancer patients with a tumour that has expression loss of one or more of the four MMR proteins by immunohistochemical staining in neoplastic and in non-neoplastic cells including tumour infiltrating leukocytes and/or endothelial cells.

Strong

Rec. 4

CMMRD testing should be offered to all cancer patients aged <18 years in whom a heterozygous (likely) pathogenic variant in one of the MMR genes was found by germline sequencing.

Strong

Rec. 5

A family history assessment and physical examination should be performed for any patient who fulfils inclusion criteria of CMMRD testing as described in Rec. 2–4.

Strong

Rec. 6

CMMRD testing should probably be offered following an interdisciplinary discussion to all children suspected to have sporadic NF1/Legius syndrome without cancer and without an NF1/SPRED1 germline (L)PV after comprehensive genetic analysis and who have at least one additional feature defined by the C4CMMRD guidelines (Suerink et al. [20], Table 3).

Strong

Testing strategy

Rec. 7

Any testing strategy should aim to come to a definite diagnosis that either confirms or refutes CMMRD in the patient, and to identify the causative variants in the relevant MMR gene.

Strong

Rec. 8

Wherever possible, CMMRD testing of a patient with a (pre-)malignancy should include immunohistochemical staining of all four MMR proteins in tumour tissue to determine MMR protein expression in neoplastic and in non-neoplastic cells, including tumour infiltrating leukocytes and/or endothelial cells.

Strong

Rec. 9

The laboratory performing genetic CMMRD testing should be able to offer transcript analysis of all four MMR genes and should be able to apply assays that circumvent potential diagnostic pitfalls that result from the high homology of PMS2 and its pseudogene PMS2CL (either by partnership with a different laboratory or in their own laboratory).

Strong

Rec. 10

The laboratory performing genetic CMMRD testing of an index patient with a (pre-)malignancy should probably have one or more validated ancillary assay(s) available (either by partnership with a different laboratory or in their own laboratory) that can definitively confirm or refute the diagnosis of CMMRD if genetic testing renders an inconclusive result (the currently available ancillary assays testing for constitutional MMR deficiency are listed in Table 4).

Strong

Rec. 11

The laboratory performing genetic CMMRD testing of an index patient without a (pre-)malignancy should have one or more validated ancillary assay(s) available (either by partnership with a different laboratory or in their own laboratory) that can definitively confirm or refute the diagnosis of CMMRD if genetic testing renders an inconclusive result (the currently available ancillary assays testing for constitutional MMR deficiency are listed in Table 4).

Strong

Diagnostic criteria

Rec. 12

The diagnosis of CMMRD should be considered confirmed in an individual fulfilling one or more of the suggested criteria for CMMRD testing (Rec.1, Rec.2, Rec.3, Rec.4, Rec.6) if, according to the Table “Criteria for the confirmation of CMMRD” (Table 5):

(i) in one of the four MMR genes, two variants classified according to internationally accepted classification criteria* as (likely) pathogenic (PV or LPV) are identified and are confirmed to be located in trans (note that in some cases additional criteria need to be fulfilled);

OR

(ii) in one of the four MMR genes, one of two variants identified and confirmed to be located in trans is classified as a PV or LPV or variant of unknown significance (VUS) and the other one is classified as a VUS and one or more clinically validated ancillary test results is consistent with a CMMRD diagnosis;

OR

(iii) in one of the four MMR genes, one variant is identified and classified as a PV or LPV or VUS and there is evidence for (a) faulty splicing not explained by the identified variant or (b) reduced expression of the wild-type allele by transcript analysis and one or more clinically validated ancillary test results is consistent with a CMMRD diagnosis;

OR

(iv) no MMR gene variant classified as a PV or LPV or VUS is identified, but one or more clinically validated ancillary test results is consistent with a CMMRD diagnosis and there is evidence by transcript analysis for (a) faulty splicing or (b) reduced expression of the wild-type allele(s) of one of the MMR genes. *ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MMR genes.

Moderate

Rec. 13

Cancer patients fulfilling the suggested criteria for CMMRD testing, Rec.1, Rec.2 or Rec.4, in whom the diagnosis CMMRD cannot be confirmed, should probably be tested for a germline (likely) pathogenic variant in the exonuclease domains of POLE and POLD1.

Strong

Rec. 14

In a deceased cancer patient fulfilling one or more of the suggested criteria for CMMRD testing (Rec.1, Rec.2, Rec.4) for whom no germline DNA/RNA is available and the diagnosis of CMMRD cannot be confirmed by one or more of the criteria outlined in Rec.12 and Table 5, the diagnosis of CMMRD should be considered confirmed if immunohistochemical staining shows expression loss of one or more MMR proteins in neoplastic and in non-neoplastic cells, including tumour infiltrating leukocytes and/or endothelial cells, of the patient and expression in an appropriate positive control.

Moderate

Rec. 1

Genetic counselling should be offered to parents and siblings of a confirmed CMMRD patient, preferentially by a multidisciplinary team with knowledge of CMMRD, consisting of a medical geneticist, a paediatric oncologist and a psychologist.

Strong

Rec. 2

To confirm their carrier status, parents of a CMMRD patient should be offered genetic testing for the (likely) pathogenic MMR gene variants found in their child.

Strong

Rec. 3

Cascade genetic testing for (likely) pathogenic variants should be offered to all adult relatives of a CMMRD patient, in both parental branches.

Strong

Rec. 4

Siblings of a genetically confirmed CMMRD patient should be offered genetic CMMRD testing regardless of age and phenotype.

Strong

Rec. 5

When performing CMMRD predictive testing in a minor or prenatal testing, pros and cons of revealing results of genetic testing regarding Lynch syndrome should be discussed on a case-by-case basis with the parents and the patient depending on their age.

Moderate

Rec. 6

If the diagnosis of CMMRD is not confirmed by the identification of two (likely) pathogenic variants in one MMR gene but by ancillary tests in the patient, siblings should probably be offered ancillary tests to exclude a CMMRD diagnosis for them.

Moderate

Rec. 7

Prenatal or preimplantation genetic testing should be discussed with parents of reproductive age of a CMMRD patient.

Strong

Rec. 8

Prenatal or preimplantation genetic testing should be discussed with couples of reproductive age if both carry a pathogenic variant in the same MMR gene.

Strong

Rec. 9

Testing the partner of a CMMRD patient for the MMR gene involved should probably be discussed during genetic counselling, considering possible consanguinity, common founder effect, and family history suggestive of Lynch syndrome.

Strong

Rec. 10

The partner of a Lynch syndrome carrier should be offered genetic testing of MMR genes if consanguinity is reported by the couple or the partner is coming from a population with a known founder variant or the family history of the partner is suggestive of Lynch syndrome and genetic testing has not been performed yet.

Strong

Rec. 11

The partner of a Lynch syndrome carrier should not be actively offered genetic testing of MMR genes in the absence of consanguinity, a known founder mutation or a family history suggestive of Lynch syndrome.

Moderate

Rec. 12

The child of a Lynch syndrome carrier should probably be offered CMMRD testing, if the child has clinical features that add up to ≥ 2 C4CMMRD scoring points according to the revised criteria (Table 2: scoring points assigned to additional features in the patient).

Strong

Rec. 1

CMMRD patients and/or their parents should be educated about tumour risks associated with CMMRD.

Strong

Rec. 2

CMMRD patients and/or their parents should be educated about symptoms related to the main tumours, especially dyspnoea and superior vena cava syndrome for mediastinal lymphomas, symptoms associated with pancytopenia for leukaemia, neurological symptoms for brain tumours, and bleeding for colorectal tumours.

Strong

Rec. 3

Pros and cons should be discussed among the CMMRD patient and/or their parents and clinician to make a joint decision to participate in a surveillance program.

Strong

Rec.4

CMMRD patients and/or their parents should probably be encouraged to communicate their screening results in research projects or databases to improve knowledge on CMMRD.

Strong

Rec. 5

In children and adults with CMMRD, clinical examination should be performed every 6 months.

Strong

Rec. 6

Brain MRI should probably start at the initial CMMRD diagnosis or at least at the age of 2 years.

Strong

Rec. 7

In CMMRD patients up to age 20 years, brain MRI should be performed every 6 months.

Strong

Rec. 8

In CMMRD patients older than 20 years, a brain MRI should be performed at least annually.

Moderate

Rec. 9

The first brain MRI should probably be performed with contrast enhancement for all CMMRD patients.

Moderate

Rec. 10

In patients with CMMRD without a previous brain tumour, MRI should probably include anatomical sequence T2 FLAIR (if possible in 3D) combined with MRI diffusion sequence.

Moderate

Rec.11

In patients with CMMRD with a previous brain tumour, MRI should include anatomical sequences T2-FLAIR, diffusion sequence, and T1+ contrast enhancement if possible in 3D.

Moderate

Rec. 12

Abdominal ultrasound should probably not be performed to screen for abdominal lymphomas in CMMRD patients.

Weak

Rec. 13

Blood counts should probably not be performed to screen for haematological (pre-)malignancies in CMMRD patients.

Weak

Rec. 14

Colonoscopy should be performed at least annually in CMMRD patients and should probably start from the age of 6 years in children with CMMRD.

Strong

Rec. 15

Upper gastrointestinal endoscopy should be performed annually in CMMRD patients and should probably start at the same age as colonoscopy or at least at the age of 10 years.

Weak

Rec. 16

Upper endoscopy should probably visualize the whole duodenum and include careful inspection of the ampullary region in CMMRD patients.

Weak

Rec. 17

Upper endoscopy and colonoscopy should probably be done with coloration in the context of CMMRD.

Weak

Rec. 18

The frequency of upper or lower endoscopy should probably increase up to 6 months-interval once polyps are detected in the context of CMMRD.

Strong

Rec. 19

Digestive tract surveillance for CMMRD patients, including children, should probably be done in a centre with gastroenterologists experienced in Lynch syndrome screening.

Moderate

Rec. 20

The interval between two digestive tract examinations should not exceed 12 months for CMMRD patients.

Strong

Rec. 21

Video capsule endoscopy should be performed annually in CMMRD patients and should probably be performed from the age of 10 years.

Moderate

Rec. 22

Gynaecologic surveillance should probably be performed annually from age 20 years in CMMRD patients and should include clinical examination and transvaginal ultrasound.

Strong

Rec. 23

Prophylactic hysterectomy should probably be discussed once family planning of the CMMRD patient is completed.

Moderate

Rec. 24

Annual urine cytology and urine dipstick should probably not be offered to CMMRD patients.

Moderate

Rec. 25

Abdominopelvic ultrasound for gynaecological and urinary tract cancer screening should probably be offered annually to CMMRD patients, starting at 20 years of age.

Strong

Rec. 26

Breast cancer screening should probably follow general population guidelines for CMMRD patients.

Moderate

Rec. 27

Whole body MRI should probably be offered to CMMRD patients at least once, at diagnosis or when anaesthesia is no longer required, for a general screening of low-grade tumours and malformations to guide targeted screening.

Strong

Rec. 28

Resection or specific surveillance of low-grade lesions should be offered to CMMRD patients.

Strong

Rec. 29

Even though evidence of its efficacy in screening is still weak in CMMRD, whole-body MRI should probably be discussed with CMMRD patients as an option for annual surveillance.

Moderate

Rec. 1

Psychological support should be offered to the patient and the family during the entire process of evaluation before the diagnosis of CMMRD.

Strong

Rec. 2

Psychological support should be offered to patients with CMMRD and their families at any time during treatment and cancer surveillance.

Strong

Rec. 3

Age adapted education about CMMRD should probably be offered to CMMRD patients and their families.

Strong

Rec. 4

Healthcare professionals involved in diagnosis and surveillance should address the psychosocial implications of a diagnosis of CMMRD.

Strong

Rec. 1

Multiple patients with CMMRD have been cured from a cancer diagnosis. Thus, in a CMMRD patient diagnosed with cancer, a curative approach should be considered and evaluated.

Strong

Rec. 2

For several cancer types, no CMMRD specific treatment recommendations exist. Treatment of patients with CMMRD related neoplasms should, therefore, probably be discussed in a multidisciplinary board with a treating physician, an expert for the patient’s cancer type as well as a CMMRD expert.

Strong

Rec. 3

Patients with CMMRD associated neoplasms should probably be included in clinical trials whenever possible.

Strong

Rec. 4

CMMRD is probably not a contraindication for radiotherapy, if indicated.

Moderate

Rec. 5

CMMRD is probably not a contraindication for haematopoietic stem cell transplantation, if indicated.

Moderate

Rec. 6

Temozolomide should probably be avoided in patients with CMMRD-associated high-grade glioma.

Strong

Rec. 7

The use of immunotherapy with a PD1 inhibitor should be considered for CMMRD patients with high-grade glioma, preferentially within a clinical trial.

Strong

Rec. 8

CMMRD-associated low grade glioma should probably be resected whenever possible without excessive neurological risks.

Strong

Rec. 9

Front-line treatment of CMMRD-associated medulloblastoma should probably not differ from treatment of sporadic medulloblastoma/primitive neuro-ectodermal tumours.

Moderate

Rec. 10

In case of CMMRD-associated non-Hodgkin lymphoma, chemotherapy should probably be similar to the treatment of the same tumour without CMMRD.

Moderate

Rec. 11

In case of a second primary non-Hodgkin lymphoma in a CMMRD patient, standard first-line treatment adapted to the non-Hodgkin lymphoma subtype taking into account cumulative doses of chemotherapy previously received should probably be given rather than a relapse treatment.

Moderate

Rec. 12

In case of CMMRD-associated leukaemia, chemotherapy should probably be similar to the treatment of the same cancer without CMMRD.

Moderate

Rec. 13

In case of diagnosis of a cancer of the Lynch spectrum in a CMMRD patient, treatment guidelines designed for patients with Lynch syndrome associated tumours should be followed.

Strong

Rec. 14

Immunotherapy should be recommended as front-line treatment of large, unresectable or metastatic colorectal tumours in a CMMRD patient

Strong

Rec. 15

Immunotherapy should be performed front-line for all extra-colorectal Lynch-related tumours in CMMRD patients ideally in therapeutic trials.

Strong

Rec. 16

Immunotherapy should be encouraged in interdisciplinary discussions for any non-Lynch related tumour at any time during treatment (diagnosis or relapse) of a CMMRD patient, especially if standard therapeutic guidelines offer only low chance of cure.

Moderate

Rec. 17

CMMRD patients with multiple colonic adenomas should probably be surgically managed in line with general practice for other polyposis syndromes.

Strong

Rec. 18

CMMRD patients may present with multiple tumours at the same time or may develop additional tumours during treatment. Thus, cancer surveillance around the time of diagnosis and during the period of cancer treatment should be offered.

Strong

Rec. 19

In CMMRD patients with a suspected relapse, a second primary disease should be considered. This may influence the treatment choice.

Strong

Rec. 20

In case of relapse of a CMMRD-associated tumour, molecular analysis of samples at initial diagnosis and relapse should be performed to differentiate a relapse from a second primary tumour.

Strong

Rec. 21

Fresh tumour specimens should be collected and stored (or directly molecularly analysed) whenever possible and if the CMMRD patient and/or their family approves. This may be relevant for research as well as for clinical purposes (e.g. see Rec 19).

Strong

Rec. 22

Advantages and potential side effects of preventive treatment with acetylsalicylic acid should probably be discussed with CMMRD patients.

Moderate

Rec. 23

CMMRD patients with IgG/A reduced levels/deficiency should not be treated to compensate for the inherent deficit in the absence of clinical manifestations.

Strong