Germline variants in CDKN2A wild-type melanoma prone families

Abstract

Germline pathogenic variants in CDKN2A are well established as an underlying cause of familial malignant melanoma. While pathogenic variants in other genes have also been linked to melanoma, most familial cases remain unexplained. We assessed pathogenic germline variants in 360 cancer-related genes in 56 Norwegian melanoma-prone families. The index cases were selected based on familial history of melanoma and/or multiple primary melanomas, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants in BRCA2, MRE11, ATM, MSH2, CHEK2, and AR. One family member with melanoma (not index case) carried a pathogenic variant in MAP3K6. In addition, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance in xeroderma pigmentosum-related genes. In particular, XPC^L48F was found in 8 indexes; thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (0.02-0.03; P-values from 0.007 to 0.014). In conclusion, we found that several melanoma-prone families have pathogenic variants in genes not usually linked to melanoma.

Keywords: cancer risk; germline variants; inheritance; melanoma.

Fig. 1

Germline variants in melanoma‐prone families. Oncoplot presenting the germline variants detected in selected genes (rows) in index patients (columns) of melanoma‐prone families. Red squares indicate pathogenic or likely pathogenic variants, blue squares indicate variants of uncertain significance (VUS) while dark gray squares indicate variants previously defined as benign but with a possible enrichment in the present cohort. Numbers on top indicate the number of primary malignant melanomas in each index individual (out of 56 enrolled indexes, 53 had one or more melanoma diagnoses, while 3 were included on the basis of family history alone). Out of the 6 indexes with pathogenic variants, two had more than one melanoma, three had a single melanoma, and one had an unknown number of melanomas.

Fig. 2

Family pedigree and germline variant overview for family C10. Blue arrow indicates the index individual. Asterisk (*) indicates individual status for the BRCA2:NM_000059:exon11:c.G5857T:p.E1953X variant; red asterisk indicates variant carriers while green asterisk indicates wild‐type allele only. A plus symbol (+) indicates individual status for the AR:NM_000044:exon6:c.C2395G:p.Q799E variant; red + indicates variant carriers while green + indicates wild‐type allele only. Black color indicates a diagnosis of malignant melanoma while white color indicates no melanoma diagnosis. Diagonal line indicates deceased individuals. Black and blue fill indicates malignant melanoma and additional cancer diagnosis (pancreatic cancer). Dashed outer line indicates that malignant melanoma is suspected based on self‐reporting from family members but has not been confirmed by medical records.

Fig. 3

Family pedigree with an overview of gene variants in family A05. The blue arrow indicates the index individual. An asterisk (*) indicates individual status for the MRE11:NM_005591:exon4:c.201delC:p.S68Qfs*12 variant; a red asterisk indicates variant carriers, while a green asterisk indicates wild‐type allele only. A plus symbol (+) indicates individual status for the MAP3K6:NM_004672:exon19:c.2544delC:p.F849Sfs*143 variant; a red + indicates variant carriers, while a green + indicates wild‐type allele only. Black color indicates a diagnosis of malignant melanoma, while white color indicates no melanoma diagnosis. A diagonal line indicates deceased individuals. Black and blue fill indicates malignant melanoma and additional cancer diagnosis (rectal cancer).

Fig. 4

Family pedigree for family E01 and C07. Blue arrow indicates the index individual. (A) Family E01: Asterisk (*) indicates individual status for the ATM:NM_000051:exon22:c.3244_3247insTGdelC:p.H1082Lfs*13 variant; red asterisk indicates variant carriers while green asterisk indicates wild‐type allele only. A plus symbol (+) indicates individual status for the ERCC4:NM_005236:exon11:c.A2546T:p.Q849L variant; red + indicates variant carriers while green + indicates wild‐type allele only. Black fill indicates a diagnosis of malignant melanoma while white color indicates no melanoma diagnosis. Diagonal line indicates deceased individuals. Blue fill indicates cancer diagnosis other than melanoma (prostate cancer). (B) Family C07: Asterisk (*) indicates individual status for the MSH2:NM_000251:exon12:c.1786_1788del:p.596_596del variant; red asterisk indicates variant carriers while green asterisk indicates wild‐type allele only. A plus symbol (+) indicates individual status for the TERT:NM_198253:exon2:c.1323_1325del:p.441_442del variant; red + indicates variant carriers while green + indicates wild‐type allele only. Note that due to low‐quality samples, the sequencing of this deletion was not conclusive in C07‐02 and 03. A hash symbol (#) indicates individual status for the ATM truncating variant, ATM:NM_000051:exon13:c.C1931A:p.S644X variant; red # indicates variant carriers while green # indicates wild‐type allele only. The pathogenic variant in MSH2 and ATM was not detected in any parent of the index, indicating these to be de novo variants. Black color indicates a diagnosis of malignant melanoma while white color indicates no melanoma diagnosis. Diagonal line indicates deceased individuals. Black and blue fill indicates malignant melanoma and additional cancer diagnoses (uterine cancer and basal cell carcinoma). Blue fill only indicates cancer diagnoses other than melanoma (breast, colon, and lung cancer).

Fig. 5

Family pedigree for family C08. Blue arrow indicates the index individual. Asterisk (*) indicates individual status for the CHEK2:NM_007194:exon4:c.T470C:p.I157T variant; red asterisk indicates variant carriers while green asterisk indicates wild‐type allele only. Black color indicates a diagnosis of malignant melanoma, while white color indicates no melanoma diagnosis. Diagonal line indicates deceased individuals.