Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing

Abstract

A family with an aggregation of rare early onset multiple primary tumors has been managed in our oncogenetics department: the proband developed four early onset carcinomas between ages 31 and 33 years, including acral melanoma, bilateral clear cell renal carcinoma (RC), and follicular variant of papillary thyroid carcinoma. The proband’s parent developed orbital lymphoma and small intestine mucosa-associated lymphoid tissue (MALT) lymphoma between 40 and 50 years old. Whole-exome-sequencing (WES) of the nuclear family (proband, parents, and sibling) identified in the proband a de novo deleterious heterozygous mutation c.1003C > T (p.Arg335∗) in the phosphatase and tensin homolog (PTEN) gene. Furthermore, WES allowed analysis of the nuclear family’s genetic background, and identified deleterious variants in two candidate modifier genes: CEACAM1 and MIB2. CEACAM1, a tumor suppressor gene, presents loss of expression in clear cell RC and is involved in proliferation of B cells. It could explain in part the phenotype of proband’s parent and the occurrence of clear cell RC in the proband. Deleterious mutations in the MIB2 gene are associated with melanoma invasion, and could explain the occurrence of melanoma in the proband. Cowden syndrome is a hereditary autosomal dominant disorder associated with increased risk of muco-cutaneous features, hamartomatous tumors, and cancer. This atypical presentation, including absence of muco-cutaneous lesions, four primary early onset tumors and bilateral clear cell RC, has not been described before. This encourages including the PTEN gene in panel testing in the context of early onset RC, whatever the histological subtype. Further studies are required to determine the implication of CEACAM1 and MIB2 in the severity of Cowden syndrome in our proband and occurrence of early onset MALT lymphoma in a parent.

Early-onset renal cell carcinoma in PTEN harmatoma tumour syndrome

“…Based on these results, screening for kidney cancer was recommended to begin at 33 years of age to capture 95% of cases, or at 28 years of age (the youngest reported case) to capture 100% of cases 22 . Lowering the age of surveillance to 30 years of age for CS-RCC has been suggested in more recent reports as well 8,13 . A study at the Institut Bergonié Genetic Laboratory (Bordeaux, France) identified 146 individuals with deleterious germline PTEN pathogenic variants and detailed phenotypic information 8 .…”

“…It was hypothesized that rare tumours in these children resulted from combined pathogenic variants in tumour suppressor genes/oncogenes and PTEN, but no suggestions for updating surveillance criteria for CS-RCC were given 23 . Finally, an atypical presentation of CS, where the proband did not meet diagnostic or testing criteria, identified four tumours within two years from 31 to 33 years of age 13 . This included acral melanoma, a follicular variant of papillary thyroid carcinoma, and two clear cell RCCs 13 .…”

“…Finally, an atypical presentation of CS, where the proband did not meet diagnostic or testing criteria, identified four tumours within two years from 31 to 33 years of age 13 . This included acral melanoma, a follicular variant of papillary thyroid carcinoma, and two clear cell RCCs 13 . Exome sequencing on the proband and family identified many variants of interest, including a de novo heterozygous deleterious pathogenic variant in PTEN and variants in genes somatically associated with melanoma (MIB2) and with clear cell RCC (CEACAM1) 13 .…”

“…This included acral melanoma, a follicular variant of papillary thyroid carcinoma, and two clear cell RCCs 13 . Exome sequencing on the proband and family identified many variants of interest, including a de novo heterozygous deleterious pathogenic variant in PTEN and variants in genes somatically associated with melanoma (MIB2) and with clear cell RCC (CEACAM1) 13 . Although early diagnosis of clear cell RCC has a good prognosis, these tumours were identified incidentally, as screening for CS would not begin for another decade 13 .…”

Genetic Modifiers and Rare Mendelian Disease

“…These approaches often rely on manual variant prioritization from candidate variants by human. In such process, human experts infer functional similarity between the candidate variants and the target causal mutation by reviewing relevant knowledge-bases [41,[111][112][113]. Incorporation of a computational method that can comprehensively analyze and prioritize modifiers from candidate modifier variants is still an open area for research.…”