Two Sisters Under 25 With Colorectal Cancer: A Mitochondrial Gene Variant Raises New Questions

When a 22-year-old woman walked into a hospital in Kunming, China, in June 2022 with three years of intermittent rectal bleeding, colorectal cancer was not the first thing anyone expected. Yet a complete colonoscopy revealed an ulcerated tumor roughly 15 centimeters from the anal verge, and biopsies showed high-grade neoplasia with focal intramucosal carcinoma. Days later, surgeons removed the affected segment of her rectum along with regional lymph nodes. The pathology report confirmed a moderately differentiated adenocarcinoma that had invaded through the bowel wall — stage IIA — although all 14 examined lymph nodes were free of metastatic disease. What transformed this from an unusual single case into a genuinely puzzling scientific story was the family history: her elder sister had already been diagnosed with rectal adenocarcinoma at just 19 years of age.

That clustering of very-early-onset colorectal cancer within one family is what drew a team at the First Affiliated Hospital of Kunming Medical University to investigate. In a case report published in Frontiers in Oncology, the researchers describe how germline genetic testing of the younger sister — the proband in clinical genetics parlance — identified a variant in the SDHB gene, designated NM_003000.3:c.268C>T, which produces a protein change written as p.Arg90Ter. This is not an obscure or novel alteration. It is a known pathogenic loss-of-function variant, one that prematurely terminates the SDHB protein at position 90 and is firmly established as a cause of hereditary tumor predisposition syndromes. The twist is that the tumors those syndromes typically involve are not colorectal cancers.

SDHB encodes the iron-sulfur subunit of mitochondrial complex II, a molecular machine with a dual role: it participates in the tricarboxylic acid cycle, the metabolic engine that oxidizes nutrients, and it feeds electrons into the electron-transport chain that generates cellular energy. Pathogenic germline SDHB variants are established causes of hereditary predisposition to pheochromocytoma and paraganglioma, tumors of the adrenal medulla and sympathetic nervous tissue. They have also been linked to gastrointestinal stromal tumors and renal cell carcinoma. Colorectal carcinoma, however, is not currently part of the classical SDHB-associated tumor spectrum. That mismatch between the variant’s established disease context and the family’s actual phenotype is precisely why the report is framed as hypothesis-generating rather than as a definitive new hereditary colorectal cancer syndrome.

The molecular workup of the proband’s tumor adds technical nuance to the story. Next-generation sequencing of surgically resected tissue and peripheral blood, using an 87-gene hereditary cancer panel, confirmed the heterozygous germline SDHB variant. But in the tumor itself, the variant showed a variant allele frequency of only 20.75 percent, SDHB protein expression was retained on immunohistochemistry, and no biallelic inactivation of the gene could be demonstrated. In conventional SDH-deficient tumors, the second allele is typically lost or silenced, SDHB protein staining disappears, and succinate accumulates in the cell, driving tumorigenesis through metabolic signaling rather than through the classical driver pathways. None of that signature was present here. The staining showed strong granular cytoplasmic signal in tumor cells, with adjacent normal mucosa serving as an internal positive control — a pattern that provides no immunohistochemical evidence of an SDH-deficient phenotype.

The tumor did harbor other alterations that are far more familiar in colorectal cancer biology: a somatic TP53 frameshift mutation with a variant allele frequency of 57.66 percent and a copy-number loss of SMAD4, a gene central to the TGF-beta signaling pathway that suppresses epithelial proliferation. Common colorectal driver genes including KRAS, NRAS, and BRAF were wild type. The tumor was microsatellite stable, which argues against Lynch syndrome, and no pathogenic germline variants were found in the tested mismatch-repair and polyposis genes — MLH1, MSH2, MSH6, PMS2, APC, and MUTYH — reducing the likelihood of several established hereditary colorectal cancer syndromes. The laboratory-reported tumor mutational burden of 10.72 mutations per megabase was classified as high by the laboratory’s internal percentile system, though the authors caution that this designation is assay-specific and not a universally validated colorectal cancer threshold.

Family history deepened the mystery. The proband’s elder sister, diagnosed in 2016 at 19 years of age, had a moderately differentiated rectal adenocarcinoma measuring roughly 3.5 by 3.0 by 0.8 centimeters that extended through the bowel wall into perirectal fat, with metastatic carcinoma in one of 14 regional lymph nodes. Her mismatch-repair protein expression was retained. The sisters’ father underwent colonoscopy at 47 years of age and was found to have two small rectal polyps, about 0.6 and 0.8 centimeters, which histopathology identified as tubular adenomas — benign precursor lesions, not carcinomas. The paternal grandfather was reported to have died from a rectal malignant tumor of unspecified type, but no genetic testing or archival tissue from him was available. Sanger sequencing records confirmed that the heterozygous SDHB variant was present in the proband, her sister, and her father, while the proband’s brother-in-law and the sister’s two children carried the wild-type sequence.

Here lies the central scientific tension of the report. Although both sisters with colorectal carcinoma and their father carry the variant, the available data do not demonstrate formal disease-specific co-segregation. The father’s phenotype consisted of benign adenomas rather than carcinoma, and the affected grandfather was never genetically characterized. Tumor-level findings in the proband provide limited support for an SDHB-driven mechanism: the variant allele frequency alone cannot establish allele-specific copy-number status, no biallelic inactivation was shown, and SDHB protein expression was retained. The authors therefore consider several non-mutually-exclusive explanations. The germline SDHB variant may be an incidental hereditary finding unrelated to the colorectal phenotype. Alternatively, incomplete penetrance and variable expressivity of SDHB-associated predisposition may contribute to phenotypic heterogeneity, while unidentified hereditary factors or tissue-specific somatic events could also be involved. Functional cooperation between the somatic TP53 and SMAD4 alterations and germline SDHB has not been demonstrated.

One curious detail stands out: p53 immunostaining was reported as negative in the colorectal tumors of both sisters. In the proband, sequencing identified a somatic TP53 frameshift, but corresponding tumor-sequencing data from the elder sister were unavailable. These observations do not establish a germline TP53 syndrome, yet they reinforce the need to consider alternative hereditary mechanisms that may not have been fully assessed by the original targeted assay. Some patients with marked familial clustering or very-early-onset colorectal cancer remain genetically unexplained after standard hereditary cancer testing, and such families may reflect currently unrecognized genetic factors, variant classes outside the detection range of the original panel, polygenic susceptibility, shared environmental influences, or combinations of these.

From a clinical standpoint, the report carries practical implications. Individuals carrying pathogenic SDHB variants should continue to receive surveillance for established SDHB-associated tumor risks according to current recommendations for hereditary SDHx-related predisposition: annual clinical assessment, biochemical testing with plasma-free or urinary fractionated metanephrines every two years during childhood and annually in adults, and MRI-based imaging approximately every two to three years. In contrast, there is currently insufficient evidence to establish an SDHB-specific colorectal surveillance protocol. In this family, intensified colorectal surveillance should be justified primarily by the extraordinary family history of colorectal carcinoma at 19 and 22 years of age and by each individual’s colorectal findings, rather than by the SDHB genotype alone.

The authors acknowledge the limitations of a single-family report: only a subset of relatives has independently verifiable genetic data, extended family characterization remains incomplete, archival tumor material from the affected grandfather was unavailable, and no colorectal-cancer-specific functional experiments were performed. The prevalence and enrichment of pathogenic germline SDHB variants among patients with familial or very-early-onset colorectal cancer remain unknown, and comprehensive germline analyses capable of assessing all copy-number and structural variants were not performed. For the proband herself, the experience underscored the value of genetic counseling and continued follow-up. Her hope, and that of the research team, is that further investigation of her family may clarify the hereditary basis of the disease and inform the health management of her relatives. Until additional families, larger cohorts, comprehensive genomic analyses, and colorectal-cancer-specific functional studies determine whether germline SDHB variants contribute to colorectal tumorigenesis, this remarkable family stands as a compelling clinical observation — a hypothesis waiting to be tested.

Subject of Research: Genetics

Article Title: Case Report: A germline SDHB c.268C>T (p.Arg90Ter) variant in a family with very-early-onset colorectal neoplasia

Article References: Liu, C., Zhou, D., Xu, W., Pan, H., Ji, X., Huang, J., & Zhu, Z. (2026). Case Report: A germline SDHB c.268C>T (p.Arg90Ter) variant in a family with very-early-onset colorectal neoplasia. Frontiers in Oncology, 16, Article 1938314. https://doi.org/10.3389/fonc.2026.1938314

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1938314

Keywords: colorectal cancer, SDHB, germline variant, very-early-onset cancer, hereditary cancer, mitochondrial complex II, case report, Case, Report, germline, Arg90Ter, variant